{"id":"prostate-roadmap","name":"Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch","route":"/roadmaps/prostate-roadmap/","eras":[{"era":"1941 to 1966","title":"A cancer is shown to depend on a hormone, and systemic cancer therapy begins","description":"Huggins and Hodges measured serum phosphatases in men with metastatic prostate cancer, then castrated them or gave them oestrogen and watched the disease regress; androgen injection sent it the other way. No cancer in any organ had previously been made to shrink by anything other than surgery or radiation. Huggins shared the 1966 Nobel Prize for it. High-dose oestrogen was the first medical castration and was abandoned for cardiovascular harm rather than for lack of effect, which is why luteinising hormone-releasing hormone agonists replaced it and why transdermal oestradiol, which avoids first-pass hepatic effects, is still being tested as an alternative.","status":"historic","refs":[{"id":"paper-huggins-hodges-castration-serum-phosphatases-prostate-1941","kind":"paper","name":"Huggins and Hodges 1941: the effect of castration, of oestrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate","route":"/key-papers/paper-huggins-hodges-castration-serum-phosphatases-prostate-1941/","tldr":"In 1941 two Chicago surgeons showed that removing a man's testicles, or giving him oestrogen, made advanced prostate cancer shrink and his blood chemistry improve, and that giving testosterone made it worse. It was the first time any cancer in any organ had been made to regress by a drug or a hormone."},{"id":"paper-langley-lancet","kind":"paper","name":"Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme","route":"/key-papers/paper-langley-lancet/","tldr":"Paper cited by one trial page, indexed on Europe PMC as PubMed record 33581820 and published in The Lancet; the citing page links this DOI, which is how the record was matched."},{"id":"hormonal-therapy-roadmap","kind":"roadmap","name":"Hormonal therapy roadmap: removing the ovaries → tamoxifen → oral degraders switched by a blood test","route":"/roadmaps/hormonal-therapy-roadmap/","tldr":"Cutting off the hormones that breast and prostate cancers feed on has kept people alive for decades. The therapy is now moving from blocking the hormone to destroying its receptor, and from waiting for a scan to switching drugs when a blood test sees resistance coming."}],"trials":[],"papers":[{"id":"paper-huggins-hodges-castration-serum-phosphatases-prostate-1941","name":"Huggins and Hodges 1941: the effect of castration, of oestrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate","route":"/key-papers/paper-huggins-hodges-castration-serum-phosphatases-prostate-1941/","journal":"Cancer Research","year":1941,"whatItMeans":"The origin of hormone therapy for cancer, and the reason prostate cancer is treated by taking something away rather than adding a cytotoxic drug. More than eighty years later, every man who starts androgen deprivation is having this experiment repeated on him, and the disease is still defined by whether it has stopped responding to it."},{"id":"paper-langley-lancet","name":"Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme","route":"/key-papers/paper-langley-lancet/","journal":"The Lancet","year":2021,"whatItMeans":"One trial page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand."}]},{"era":"1987 to 2005","title":"A blood test arrives, and an epidemic of diagnoses follows it","description":"Stamey described prostate-specific antigen as a marker that tracked tumour volume, fell to nothing after prostatectomy and rose again on recurrence, and stated in the same paper that it is not specific. Catalona turned it into a screening test in 1991 with a threshold of 4.0 micrograms per litre and showed it found cancers a digital rectal examination missed. Testing spread through United States primary care over the following decade without a randomised trial of mortality. By 2005 the consequence was measurable: relative incidence against 1986 was 7.23 in men under 50 and 0.56 in men aged 80 and over, an extra 1,305,600 diagnoses and 1,004,800 definitive treatments.","status":"historic","refs":[{"id":"paper-stamey-psa-serum-marker-nejm-1987","kind":"paper","name":"Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate","route":"/key-papers/paper-stamey-psa-serum-marker-nejm-1987/","tldr":"The paper that turned a protein made by the prostate into the blood test now used on millions of men a year. It showed the level tracked how much cancer there was, fell to nothing after surgery, and rose again when the cancer came back."},{"id":"paper-catalona-psa-screening-test-nejm-1991","kind":"paper","name":"Measurement of prostate-specific antigen in serum as a screening test for prostate cancer","route":"/key-papers/paper-catalona-psa-screening-test-nejm-1991/","tldr":"This is where the number 4.0 came from. Screening 1,653 healthy men over 50 with a blood test and biopsying those above that level found cancers that a finger examination would have missed, and the threshold entered practice worldwide."},{"id":"paper-welch-albertsen-psa-era-diagnosis-treatment-jnci-2009","kind":"paper","name":"Prostate cancer diagnosis and treatment after the introduction of prostate-specific antigen screening, 1986 to 2005","route":"/key-papers/paper-welch-albertsen-psa-era-diagnosis-treatment-jnci-2009/","tldr":"Counting what the blood test did to a country. In the twenty years after PSA testing began in the United States, an extra 1.3 million men were diagnosed with prostate cancer and about a million were definitively treated, for a benefit that on the most generous assumption reached one man in twenty of them."},{"id":"paper-damico-risk-groups-jama-1998","kind":"paper","name":"D'Amico risk groups: biochemical outcome after radical prostatectomy, external beam radiotherapy or brachytherapy","route":"/key-papers/paper-damico-risk-groups-jama-1998/","tldr":"This analysis of nearly 1,900 men introduced the low, intermediate and high-risk groups for localised prostate cancer based on PSA, Gleason score and stage, a classification still used to choose between surveillance, surgery and radiotherapy."},{"id":"early-detection-roadmap","kind":"roadmap","name":"Early detection roadmap: organ screening → blood tests for many cancers","route":"/roadmaps/early-detection-roadmap/","tldr":"From mammograms and colonoscopies to a single blood draw that might screen for dozens of cancers, with the FDA's first decision imminent."}],"trials":[],"papers":[{"id":"paper-stamey-psa-serum-marker-nejm-1987","name":"Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate","route":"/key-papers/paper-stamey-psa-serum-marker-nejm-1987/","journal":"New England Journal of Medicine","year":1987,"whatItMeans":"The origin of the blood test that defines how prostate cancer is found, monitored and declared to have recurred. Its strength was always monitoring a known cancer; the problems began when the same test was used to look for cancer in men who had no symptoms."},{"id":"paper-catalona-psa-screening-test-nejm-1991","name":"Measurement of prostate-specific antigen in serum as a screening test for prostate cancer","route":"/key-papers/paper-catalona-psa-screening-test-nejm-1991/","journal":"New England Journal of Medicine","year":1991,"whatItMeans":"The paper that made opportunistic prostate-specific antigen testing routine, and the source of the threshold still printed on laboratory reports. Everything in the overdiagnosis literature is, in effect, an audit of what this recommendation did when it was applied to whole populations."},{"id":"paper-welch-albertsen-psa-era-diagnosis-treatment-jnci-2009","name":"Prostate cancer diagnosis and treatment after the introduction of prostate-specific antigen screening, 1986 to 2005","route":"/key-papers/paper-welch-albertsen-psa-era-diagnosis-treatment-jnci-2009/","journal":"JNCI: Journal of the National Cancer Institute","year":2009,"whatItMeans":"The number that anchors the overdiagnosis argument in prostate cancer: over a million American men treated for a cancer that, for most of them, was never going to surface. It is the reason active surveillance exists as a formal pathway and the reason magnetic resonance imaging was brought in front of the biopsy."},{"id":"paper-damico-risk-groups-jama-1998","name":"D'Amico risk groups: biochemical outcome after radical prostatectomy, external beam radiotherapy or brachytherapy","route":"/key-papers/paper-damico-risk-groups-jama-1998/","journal":"JAMA","year":1998,"whatItMeans":"The D'Amico system, refined by the NCCN, remains the framework for the very-low to very-high-risk categories used on this site's prostate pages."}]},{"era":"1989 to 2023","title":"Does treating localised disease help? Three trials, three answers, one rule","description":"SPCG-4 randomised 695 men with clinically detected cancer from 1989 and found, at 29 years, that surgery cut prostate cancer death by 45 percent and added a mean of 2.9 years of life. PIVOT randomised a largely prostate-specific antigen-detected population from 1994 and found no significant difference at 19.5 years, with more incontinence and sexual dysfunction and less treatment for biochemical progression. ProtecT randomised men found by screening and, at 15 years, found prostate cancer mortality of around 3 percent in all three arms. The rule those three produce is the one that matters at diagnosis: how much radical treatment helps depends on how the cancer was found and how aggressive it is, and a Gleason score above 7 carried ten times the risk of death of a score of 6 or lower in SPCG-4.","status":"historic","refs":[{"id":"paper-bill-axelson-spcg-4-29-year-nejm-2018","kind":"paper","name":"SPCG-4: radical prostatectomy or watchful waiting in prostate cancer, 29-year follow-up","route":"/key-papers/paper-bill-axelson-spcg-4-29-year-nejm-2018/","tldr":"Men with prostate cancer found because it caused a lump or symptoms, randomised in the years before PSA testing, were followed for nearly thirty years. Surgery roughly halved the chance of dying of prostate cancer and added an average of 2.9 years of life."},{"id":"paper-wilt-pivot-prostatectomy-observation-nejm-2017","kind":"paper","name":"PIVOT: follow-up of prostatectomy versus observation for early prostate cancer","route":"/key-papers/paper-wilt-pivot-prostatectomy-observation-nejm-2017/","tldr":"In men whose prostate cancer was mostly found by a blood test, surgery did not significantly reduce deaths after nearly twenty years. It did cause more incontinence and sexual problems, and it did reduce later treatment for the cancer growing."},{"id":"paper-protect-nejm-2016","kind":"paper","name":"ProtecT: 10-year outcomes after monitoring, surgery or radiotherapy for localised prostate cancer","route":"/key-papers/paper-protect-nejm-2016/","tldr":"In the only randomised trial to compare active monitoring, surgery and radiotherapy for PSA-detected localised prostate cancer, deaths from prostate cancer were rare and equal at ten years in all three groups, though monitoring led to more metastases and progression."},{"id":"paper-protect-15-year-nejm-2023","kind":"paper","name":"ProtecT: fifteen-year outcomes after monitoring, surgery or radiotherapy for prostate cancer","route":"/key-papers/paper-protect-15-year-nejm-2023/","tldr":"Fifteen years on, ProtecT still found no difference in prostate cancer deaths between monitoring, surgery and radiotherapy, with about 97 percent of men alive from their cancer in every group, confirming that many men can defer or avoid treatment."},{"id":"paper-klotz-active-surveillance-jco-2015","kind":"paper","name":"Long-term follow-up of a large active surveillance cohort of patients with prostate cancer (Sunnybrook)","route":"/key-papers/paper-klotz-active-surveillance-jco-2015/","tldr":"In nearly a thousand men with low-risk prostate cancer followed for up to 20 years on active surveillance, only 1.5 percent died of the disease and most never needed treatment, the strongest evidence that surveillance is safe."},{"id":"surgery-roadmap","kind":"roadmap","name":"Surgery roadmap: radical operations → less surgery → no surgery when a drug has done the work","route":"/roadmaps/surgery-roadmap/","tldr":"Surgery cures more cancers than any other treatment. Its story for a century has been learning how much can safely be left in, and now whether the operation is needed at all once drugs and radiation have cleared the tumour."}],"trials":[],"papers":[{"id":"paper-bill-axelson-spcg-4-29-year-nejm-2018","name":"SPCG-4: radical prostatectomy or watchful waiting in prostate cancer, 29-year follow-up","route":"/key-papers/paper-bill-axelson-spcg-4-29-year-nejm-2018/","journal":"New England Journal of Medicine","year":2018,"whatItMeans":"The clearest evidence that radical treatment of localised prostate cancer saves lives when the cancer was found clinically rather than by a blood test, and the clearest single statement of what grade does: a Gleason score above 7 carried ten times the risk of death of a score of 6 or lower in the same trial."},{"id":"paper-wilt-pivot-prostatectomy-observation-nejm-2017","name":"PIVOT: follow-up of prostatectomy versus observation for early prostate cancer","route":"/key-papers/paper-wilt-pivot-prostatectomy-observation-nejm-2017/","journal":"New England Journal of Medicine","year":2017,"whatItMeans":"The trial that made observation a defensible choice for low-risk prostate cancer found by a blood test, and that supplied the number a man needs when weighing surgery: the progression it prevents is mostly progression on a scan or a blood test, and the harms it causes are felt every day."},{"id":"paper-protect-nejm-2016","name":"ProtecT: 10-year outcomes after monitoring, surgery or radiotherapy for localised prostate cancer","route":"/key-papers/paper-protect-nejm-2016/","journal":"New England Journal of Medicine","year":2016,"whatItMeans":"Most men with low- and favourable intermediate-risk prostate cancer can safely choose monitoring, and treatment choice should weigh urinary, sexual and bowel side effects against a small difference in progression."},{"id":"paper-protect-15-year-nejm-2023","name":"ProtecT: fifteen-year outcomes after monitoring, surgery or radiotherapy for prostate cancer","route":"/key-papers/paper-protect-15-year-nejm-2023/","journal":"New England Journal of Medicine","year":2023,"whatItMeans":"Long-term data support active surveillance as a safe choice for low and much intermediate-risk disease, while the lower metastasis rate with treatment informs the discussion for men with longer life expectancy."},{"id":"paper-klotz-active-surveillance-jco-2015","name":"Long-term follow-up of a large active surveillance cohort of patients with prostate cancer (Sunnybrook)","route":"/key-papers/paper-klotz-active-surveillance-jco-2015/","journal":"Journal of Clinical Oncology","year":2015,"whatItMeans":"Active surveillance is the preferred management for low-risk prostate cancer, and this cohort's triggers for intervention shaped surveillance protocols worldwide."}]},{"era":"2009 to 2018","title":"The screening trials disagree, and the policy swings twice","description":"ERSPC randomised 162,243 men in its core age group and found a rate ratio for prostate cancer death of 0.80, an absolute difference of 0.71 death per 1,000 men, 1,410 to screen and 48 extra cancers to treat for each death prevented, and cumulative incidence of 8.2 percent against 4.8. PLCO, published the same day, found no difference, with control-group screening rising to 52 percent by year six. The United States task force issued a grade D recommendation against screening in 2012 and in 2018 moved men aged 55 to 69 to grade C, shared decision-making, quoting about 1.3 deaths and about 3 metastatic cases prevented per 1,000 men screened against 1 in 5 developing long-term incontinence and 2 in 3 long-term erectile dysfunction after prostatectomy. The modelling work that ran alongside showed why a single overdiagnosis figure is not meaningful: lead time of 5.4 to 6.9 years and overdiagnosis of 23 to 42 percent in the United States calibration, 7.9 years and 66 percent in the Rotterdam one.","status":"historic","refs":[{"id":"paper-schroder-erspc-screening-mortality-nejm-2009","kind":"paper","name":"ERSPC: screening and prostate cancer mortality in a randomised European study","route":"/key-papers/paper-schroder-erspc-screening-mortality-nejm-2009/","tldr":"The trial that showed PSA screening does save lives, and showed what it costs. Screening cut the death rate from prostate cancer by a fifth, but 1,410 men had to be screened and 48 extra cancers treated to prevent one death."},{"id":"paper-andriole-plco-prostate-screening-nejm-2009","kind":"paper","name":"PLCO: mortality results from a randomised prostate cancer screening trial","route":"/key-papers/paper-andriole-plco-prostate-screening-nejm-2009/","tldr":"The American screening trial, published in the same issue as the European one and reaching the opposite conclusion. It found more cancers in the screened group and no difference in deaths, which is partly because half the men in the comparison group were being screened anyway."},{"id":"paper-draisma-lead-time-overdiagnosis-psa-jnci-2009","kind":"paper","name":"Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context","route":"/key-papers/paper-draisma-lead-time-overdiagnosis-psa-jnci-2009/","tldr":"Estimates of how many screen-detected prostate cancers would never have caused trouble ranged from a quarter to more than four fifths. Three independent models were run side by side to find out why, and showed the answer depends almost entirely on how the question is asked."},{"id":"paper-moyer-uspstf-prostate-screening-ann-intern-med-2012","kind":"paper","name":"USPSTF 2012: screening for prostate cancer, recommendation statement (grade D)","route":"/key-papers/paper-moyer-uspstf-prostate-screening-ann-intern-med-2012/","tldr":"In 2012 the American preventive services body recommended against PSA screening for every man at every age. It is the most consequential negative screening recommendation ever made, and it was reversed six years later."},{"id":"paper-uspstf-prostate-screening-jama-2018","kind":"paper","name":"USPSTF 2018: screening for prostate cancer, recommendation statement (grade C at 55 to 69, grade D at 70 and over)","route":"/key-papers/paper-uspstf-prostate-screening-jama-2018/","tldr":"Six years after recommending against PSA testing for everyone, the same body changed its mind for men aged 55 to 69 and said the decision should be theirs. The statement puts the numbers on both sides: about 1.3 deaths prevented per 1,000 men screened, and one in five who have surgery left with long-term incontinence."},{"id":"paper-hugosson-eur-urol","kind":"paper","name":"A 16-yr Follow-up of the European Randomized study of Screening for Prostate Cancer","route":"/key-papers/paper-hugosson-eur-urol/","tldr":"Paper cited by one technology page, indexed on Europe PMC as PubMed record 30824296 and published in European Urology; the citing page links this DOI, which is how the record was matched."},{"id":"paper-martin-jama","kind":"paper","name":"Prostate-Specific Antigen Screening and 15-Year Prostate Cancer Mortality: A Secondary Analysis of the CAP Randomized Clinical Trial","route":"/key-papers/paper-martin-jama/","tldr":"Paper cited by one technology page, indexed on Europe PMC as PubMed record 38581198 and published in JAMA; the citing page links this DOI, which is how the record was matched."}],"trials":[],"papers":[{"id":"paper-schroder-erspc-screening-mortality-nejm-2009","name":"ERSPC: screening and prostate cancer mortality in a randomised European study","route":"/key-papers/paper-schroder-erspc-screening-mortality-nejm-2009/","journal":"New England Journal of Medicine","year":2009,"whatItMeans":"The evidence that prostate-specific antigen screening works, stated together with the price. It is the reason screening programmes are debated rather than simply adopted, and the reason every subsequent proposal, from magnetic resonance imaging first to risk-model invitation, is judged on whether it keeps the mortality benefit while reducing the 48."},{"id":"paper-andriole-plco-prostate-screening-nejm-2009","name":"PLCO: mortality results from a randomised prostate cancer screening trial","route":"/key-papers/paper-andriole-plco-prostate-screening-nejm-2009/","journal":"New England Journal of Medicine","year":2009,"whatItMeans":"The trial that made prostate screening contested in the United States, and the reason the 2012 task force recommended against it. Its main lesson is methodological: a screening trial whose control group screens itself cannot measure the effect of screening."},{"id":"paper-draisma-lead-time-overdiagnosis-psa-jnci-2009","name":"Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context","route":"/key-papers/paper-draisma-lead-time-overdiagnosis-psa-jnci-2009/","journal":"JNCI: Journal of the National Cancer Institute","year":2009,"whatItMeans":"The reference for anyone quoting an overdiagnosis figure in prostate cancer. The honest statement is a range with its definition and its population attached, and the paper is the reason this page does not print one number."},{"id":"paper-moyer-uspstf-prostate-screening-ann-intern-med-2012","name":"USPSTF 2012: screening for prostate cancer, recommendation statement (grade D)","route":"/key-papers/paper-moyer-uspstf-prostate-screening-ann-intern-med-2012/","journal":"Annals of Internal Medicine","year":2012,"whatItMeans":"The clearest case in cancer screening of a national body acting on the harms rather than the headline. Whether it was right is still argued: testing and localised-stage diagnosis fell, and the long-term effect on metastatic presentation and mortality is the subject of the studies that followed."},{"id":"paper-uspstf-prostate-screening-jama-2018","name":"USPSTF 2018: screening for prostate cancer, recommendation statement (grade C at 55 to 69, grade D at 70 and over)","route":"/key-papers/paper-uspstf-prostate-screening-jama-2018/","journal":"JAMA","year":2018,"whatItMeans":"The current shape of the screening question in the United States, and the best short statement of the trade-off in numbers a man can weigh. The three-to-one ratio between metastatic cases prevented and deaths prevented is also the argument for using metastatic presentation, not mortality, to judge a screening programme sooner."},{"id":"paper-hugosson-eur-urol","name":"A 16-yr Follow-up of the European Randomized study of Screening for Prostate Cancer","route":"/key-papers/paper-hugosson-eur-urol/","journal":"European Urology","year":2019,"whatItMeans":"One technology page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand."},{"id":"paper-martin-jama","name":"Prostate-Specific Antigen Screening and 15-Year Prostate Cancer Mortality: A Secondary Analysis of the CAP Randomized Clinical Trial","route":"/key-papers/paper-martin-jama/","journal":"JAMA","year":2024,"whatItMeans":"One technology page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand."}]},{"era":"2004 to 2014","title":"Chemotherapy works, a little, and then the receptor drugs arrive","description":"TAX 327 and SWOG 9916, published in the same issue in October 2004, both showed docetaxel extends survival in castration-resistant disease, by 2.4 and 1.9 months respectively over mitoxantrone, and TAX 327 also improved pain and quality of life. TROPIC opened the second line in 2010 with cabazitaxel, 15.1 against 12.7 months. Then the hormonal drugs designed on the Visakorpi and Chen biology arrived: abiraterone after chemotherapy in COU-AA-301 and before it in COU-AA-302, enzalutamide after chemotherapy in AFFIRM (18.4 against 13.6 months) and before it in PREVAIL (radiographic progression-free survival 65 percent against 14 percent at 12 months). Within four years castration-resistant prostate cancer went from one treatment to five.","status":"historic","refs":[{"id":"paper-tannock-tax-327-docetaxel-prednisone-nejm-2004","kind":"paper","name":"TAX 327: docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer","route":"/key-papers/paper-tannock-tax-327-docetaxel-prednisone-nejm-2004/","tldr":"The first treatment ever shown to help men live longer once prostate cancer stopped responding to hormones. Docetaxel every three weeks added about two and a half months to median survival compared with the older drug, and made pain and quality of life better as well."},{"id":"paper-petrylak-swog-9916-docetaxel-estramustine-nejm-2004","kind":"paper","name":"SWOG 9916: docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer","route":"/key-papers/paper-petrylak-swog-9916-docetaxel-estramustine-nejm-2004/","tldr":"Published in the same issue as TAX 327 and reaching the same conclusion by a different route: docetaxel extends life in advanced prostate cancer. The extra drug it was paired with, estramustine, brought enough side effects that it was dropped from practice."},{"id":"paper-de-bono-tropic-cabazitaxel-lancet-2010","kind":"paper","name":"TROPIC: prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel","route":"/key-papers/paper-de-bono-tropic-cabazitaxel-lancet-2010/","tldr":"The first drug shown to extend life after docetaxel has stopped working. Cabazitaxel, a taxane designed to get past the pumps that expel docetaxel from resistant cells, added about two and a half months, at the cost of a high rate of low white cell counts."},{"id":"paper-cou-aa-301-abiraterone-de-bono-nejm-2011","kind":"paper","name":"COU-AA-301: abiraterone and increased survival in metastatic castration-resistant prostate cancer after docetaxel","route":"/key-papers/paper-cou-aa-301-abiraterone-de-bono-nejm-2011/","tldr":"Abiraterone, a pill that blocks androgen synthesis throughout the body, lengthened survival in men with metastatic prostate cancer that had progressed after docetaxel, proving that the disease remains hormone-driven even when castration-resistant."},{"id":"paper-abiraterone-acetate-prostate-n-engl-j-med-2013","kind":"paper","name":"Abiraterone in metastatic prostate cancer without previous chemotherapy","route":"/key-papers/paper-abiraterone-acetate-prostate-n-engl-j-med-2013/","tldr":"Phase 2 or 3 results paper on Abiraterone acetate in Prostate cancer, in New England Journal of Medicine (2013), one of the most cited Europe PMC records with Abiraterone acetate in its title."},{"id":"paper-scher-affirm-enzalutamide-nejm-2012","kind":"paper","name":"AFFIRM: increased survival with enzalutamide in prostate cancer after chemotherapy","route":"/key-papers/paper-scher-affirm-enzalutamide-nejm-2012/","tldr":"Enzalutamide, an oral tablet that blocks the androgen receptor at several points at once, added nearly five months to median survival in men whose cancer had already been through chemotherapy. More than half had their PSA halve, against two percent on placebo."},{"id":"paper-beer-prevail-enzalutamide-nejm-2014","kind":"paper","name":"PREVAIL: enzalutamide in metastatic prostate cancer before chemotherapy","route":"/key-papers/paper-beer-prevail-enzalutamide-nejm-2014/","tldr":"The same drug given before chemotherapy rather than after it. At one year, 65 percent of men on enzalutamide had no sign of the cancer growing on scans, against 14 percent on placebo, and the need for chemotherapy was pushed a long way back."},{"id":"paper-alsympca-radium-223-nejm-2013","kind":"paper","name":"ALSYMPCA: alpha emitter radium-223 and survival in metastatic prostate cancer with bone metastases","route":"/key-papers/paper-alsympca-radium-223-nejm-2013/","tldr":"Radium-223, an injected alpha-emitting radioisotope that homes to bone, lengthened survival and delayed skeletal complications in men with castration-resistant prostate cancer that had spread to bone but not to organs."},{"id":"chemotherapy-roadmap","kind":"roadmap","name":"Chemotherapy roadmap: mustard gas → curative combinations → the warhead inside smarter drugs","route":"/roadmaps/chemotherapy-roadmap/","tldr":"Chemotherapy went from a poison that sometimes worked to the backbone of most cures, and is now being given more precisely: to fewer people, at better doses, and increasingly delivered inside an antibody so that it reaches the tumour and not the whole body."}],"trials":[],"papers":[{"id":"paper-tannock-tax-327-docetaxel-prednisone-nejm-2004","name":"TAX 327: docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer","route":"/key-papers/paper-tannock-tax-327-docetaxel-prednisone-nejm-2004/","journal":"New England Journal of Medicine","year":2004,"whatItMeans":"The end of therapeutic nihilism in castration-resistant prostate cancer. It is also the trial that set the field's expectation of what a positive result looks like in this disease: a hazard ratio near 0.75 and a median gain measured in months, not years."},{"id":"paper-petrylak-swog-9916-docetaxel-estramustine-nejm-2004","name":"SWOG 9916: docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer","route":"/key-papers/paper-petrylak-swog-9916-docetaxel-estramustine-nejm-2004/","journal":"New England Journal of Medicine","year":2004,"whatItMeans":"The confirmatory half of the 2004 result. Two independent trials, two different docetaxel regimens, the same direction of effect: this is why docetaxel was adopted quickly and why it survived the move into hormone-sensitive disease a decade later."},{"id":"paper-de-bono-tropic-cabazitaxel-lancet-2010","name":"TROPIC: prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel","route":"/key-papers/paper-de-bono-tropic-cabazitaxel-lancet-2010/","journal":"The Lancet","year":2010,"whatItMeans":"Proof that a cancer resistant to one taxane is not resistant to all of them, and the beginning of treatment sequencing in castration-resistant disease. The CARD trial later showed that after an androgen receptor drug has failed, cabazitaxel beats switching to the other androgen receptor drug."},{"id":"paper-cou-aa-301-abiraterone-de-bono-nejm-2011","name":"COU-AA-301: abiraterone and increased survival in metastatic castration-resistant prostate cancer after docetaxel","route":"/key-papers/paper-cou-aa-301-abiraterone-de-bono-nejm-2011/","journal":"New England Journal of Medicine","year":2011,"whatItMeans":"Abiraterone became a standard treatment for metastatic castration-resistant prostate cancer and, after later trials, for hormone-sensitive and high-risk localised disease."},{"id":"paper-abiraterone-acetate-prostate-n-engl-j-med-2013","name":"Abiraterone in metastatic prostate cancer without previous chemotherapy","route":"/key-papers/paper-abiraterone-acetate-prostate-n-engl-j-med-2013/","journal":"New England Journal of Medicine","year":2013,"whatItMeans":"One of the most cited trial reports Europe PMC returns for Abiraterone acetate in Prostate cancer, so it is a natural first reading for anyone weighing the idea it is linked from. The record was linked automatically by title and abstract; read the abstract above and the paper itself before relying on any figure."},{"id":"paper-scher-affirm-enzalutamide-nejm-2012","name":"AFFIRM: increased survival with enzalutamide in prostate cancer after chemotherapy","route":"/key-papers/paper-scher-affirm-enzalutamide-nejm-2012/","journal":"New England Journal of Medicine","year":2012,"whatItMeans":"An oral drug that works after chemotherapy has failed, in a disease where the previous option was more chemotherapy. Together with abiraterone it moved castration-resistant prostate cancer from a chemotherapy disease to a hormonal one, and set up the sequencing questions the field is still arguing about."},{"id":"paper-beer-prevail-enzalutamide-nejm-2014","name":"PREVAIL: enzalutamide in metastatic prostate cancer before chemotherapy","route":"/key-papers/paper-beer-prevail-enzalutamide-nejm-2014/","journal":"New England Journal of Medicine","year":2014,"whatItMeans":"The trial that made an androgen receptor inhibitor the usual first treatment for castration-resistant prostate cancer, and that delayed chemotherapy by a long margin for most men. Its effect sizes are why later trials in this setting are judged against a hazard ratio near 0.7 for survival."},{"id":"paper-alsympca-radium-223-nejm-2013","name":"ALSYMPCA: alpha emitter radium-223 and survival in metastatic prostate cancer with bone metastases","route":"/key-papers/paper-alsympca-radium-223-nejm-2013/","journal":"New England Journal of Medicine","year":2013,"whatItMeans":"Radium-223 is an option for symptomatic bone-predominant castration-resistant prostate cancer, now less used since lutetium-PSMA, and should not be combined with abiraterone after the ERA 223 fracture signal."}]},{"era":"2005 to 2016","title":"The genome: a quiet sequence, a rearranged structure, and one actionable fifth","description":"Tomlins found the TMPRSS2-ERG fusion in 2005, the first recurrent rearrangement in a common carcinoma, putting a growth gene under androgen control. Taylor showed copy-number pattern separates risk better than Gleason score. Grasso sequenced 50 lethal cancers at rapid autopsy and found only 2.00 mutations per megabase even after years of treatment, with the recurrent damage in chromatin-modifying genes. Baca named chromoplexy, chains of rearrangement arriving in a burst. In 2015 TCGA classified 333 primary tumours into seven subtypes covering 74 percent of them, and the Stand Up To Cancer cohort sequenced 150 metastatic biopsies prospectively and found DNA repair alterations in 19.3 percent. Gundem reconstructed how the cancer travels and found that metastases seed other metastases, often several clones at a time. Pritchard then showed 11.8 percent of men with metastatic disease carry an inherited DNA repair mutation, with no relation to family history or age.","status":"historic","refs":[{"id":"paper-tomlins-tmprss2-ets-fusion-science-2005","kind":"paper","name":"Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer","route":"/key-papers/paper-tomlins-tmprss2-ets-fusion-science-2005/","tldr":"Gene fusions were thought to be a feature of leukaemias, not common solid cancers. This study found one in prostate cancer that joins a switch controlled by testosterone to a growth gene, and found it in most of the tumours it looked at."},{"id":"paper-taylor-integrative-genomic-profiling-cancer-cell-2010","kind":"paper","name":"Integrative genomic profiling of human prostate cancer","route":"/key-papers/paper-taylor-integrative-genomic-profiling-cancer-cell-2010/","tldr":"The first large look at prostate cancer across copy number, gene expression and sequence at once. Its most useful finding for patients was that the pattern of gained and lost chromosome segments separates low-risk from high-risk disease better than the Gleason score does."},{"id":"paper-grasso-mutational-landscape-lethal-crpc-nature-2012","kind":"paper","name":"The mutational landscape of lethal castration-resistant prostate cancer","route":"/key-papers/paper-grasso-mutational-landscape-lethal-crpc-nature-2012/","tldr":"Fifty men who died of prostate cancer had their tumours sequenced within hours of death. Even after years of treatment the cancers carried few mutations, and the recurring ones were in genes that control how DNA is packaged and read rather than in classic cancer genes."},{"id":"paper-baca-punctuated-evolution-chromoplexy-cell-2013","kind":"paper","name":"Punctuated evolution of prostate cancer genomes","route":"/key-papers/paper-baca-punctuated-evolution-chromoplexy-cell-2013/","tldr":"Cancer is usually described as accumulating damage one change at a time. Sequencing 57 whole prostate cancer genomes showed something else: chains of translocations and deletions that happen together in one burst, disrupting several cancer genes at once."},{"id":"paper-tcga-molecular-taxonomy-primary-prostate-cell-2015","kind":"paper","name":"TCGA: the molecular taxonomy of primary prostate cancer","route":"/key-papers/paper-tcga-molecular-taxonomy-primary-prostate-cell-2015/","tldr":"The Cancer Genome Atlas classified 333 prostate cancers taken out at surgery and found that three quarters fall into one of seven groups defined by a fusion or a mutation. A quarter had a change that a drug could in principle be aimed at, and one in five had a broken DNA repair gene."},{"id":"paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015","kind":"paper","name":"SU2C-PCF: integrative clinical genomics of advanced prostate cancer","route":"/key-papers/paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015/","tldr":"One hundred and fifty men with prostate cancer that had spread and stopped responding to hormones had their tumours biopsied and sequenced prospectively. Nine in ten had a genetic change that a drug could in principle be aimed at, and one in five had a broken DNA repair gene."},{"id":"paper-gundem-evolutionary-history-lethal-metastatic-prostate-nature-2015","kind":"paper","name":"The evolutionary history of lethal metastatic prostate cancer","route":"/key-papers/paper-gundem-evolutionary-history-lethal-metastatic-prostate-nature-2015/","tldr":"By sequencing many separate deposits from ten men who died of prostate cancer, this study reconstructed how the cancer travelled. Metastases seeded other metastases, and often did it in groups of cells rather than one at a time."},{"id":"paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016","kind":"paper","name":"Inherited DNA-repair gene mutations in men with metastatic prostate cancer","route":"/key-papers/paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016/","tldr":"Nearly one man in eight with prostate cancer that has spread carries an inherited fault in a DNA repair gene, most often BRCA2. Family history and age at diagnosis did not predict who: the only way to find them is to test everybody."}],"trials":[],"papers":[{"id":"paper-tomlins-tmprss2-ets-fusion-science-2005","name":"Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer","route":"/key-papers/paper-tomlins-tmprss2-ets-fusion-science-2005/","journal":"Science","year":2005,"whatItMeans":"The most common single molecular event in prostate cancer, present in roughly half of tumours in most series, and the reason prostate cancer is classified by fusion status. It is also a standing reminder that finding the driver and drugging it are different problems: no ETS-directed therapy has reached the clinic."},{"id":"paper-taylor-integrative-genomic-profiling-cancer-cell-2010","name":"Integrative genomic profiling of human prostate cancer","route":"/key-papers/paper-taylor-integrative-genomic-profiling-cancer-cell-2010/","journal":"Cancer Cell","year":2010,"whatItMeans":"The origin of the idea that a prostate tumour's copy-number pattern carries prognostic information the pathologist's grade does not. That idea became Decipher and the other genomic classifiers, which are now used in some systems to decide whether a man needs radiotherapy after surgery."},{"id":"paper-grasso-mutational-landscape-lethal-crpc-nature-2012","name":"The mutational landscape of lethal castration-resistant prostate cancer","route":"/key-papers/paper-grasso-mutational-landscape-lethal-crpc-nature-2012/","journal":"Nature","year":2012,"whatItMeans":"The explanation for why prostate cancer has so few targeted drugs outside the hormone axis and the DNA-repair genes: it is a quiet genome with structural rather than point-mutational damage, and the recurrent changes sit in the machinery that reads DNA rather than in kinases."},{"id":"paper-baca-punctuated-evolution-chromoplexy-cell-2013","name":"Punctuated evolution of prostate cancer genomes","route":"/key-papers/paper-baca-punctuated-evolution-chromoplexy-cell-2013/","journal":"Cell","year":2013,"whatItMeans":"A different picture of how a cancer genome is built, and one that explains why prostate cancer has few point mutations and a great deal of structural damage. It is also why whole-genome rather than exome sequencing is the right assay for this disease."},{"id":"paper-tcga-molecular-taxonomy-primary-prostate-cell-2015","name":"TCGA: the molecular taxonomy of primary prostate cancer","route":"/key-papers/paper-tcga-molecular-taxonomy-primary-prostate-cell-2015/","journal":"Cell","year":2015,"whatItMeans":"The reference classification of prostate cancer as it presents, and the source of the two numbers that drive most molecular treatment decisions in the disease: a quarter with a PI3K or MAPK lesion, which is the rationale for capivasertib in PTEN-deficient disease, and a fifth with DNA repair inactivation, which is the rationale for PARP inhibitors."},{"id":"paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015","name":"SU2C-PCF: integrative clinical genomics of advanced prostate cancer","route":"/key-papers/paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015/","journal":"Cell","year":2015,"whatItMeans":"The genomic definition of advanced prostate cancer, and the evidence that made molecular testing standard in it. The 19.3 percent DNA repair figure is the direct ancestor of PROfound, TRITON3, PROpel and TALAPRO-2, and the 8 percent germline figure is why a tumour result in this disease has implications for a man's relatives."},{"id":"paper-gundem-evolutionary-history-lethal-metastatic-prostate-nature-2015","name":"The evolutionary history of lethal metastatic prostate cancer","route":"/key-papers/paper-gundem-evolutionary-history-lethal-metastatic-prostate-nature-2015/","journal":"Nature","year":2015,"whatItMeans":"Metastatic prostate cancer is a communicating population, not a set of independent colonies, which is an argument for treating the whole body rather than chasing individual deposits, and an argument that resistance to androgen receptor drugs will emerge in several places at once because it emerges convergently."},{"id":"paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016","name":"Inherited DNA-repair gene mutations in men with metastatic prostate cancer","route":"/key-papers/paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016/","journal":"New England Journal of Medicine","year":2016,"whatItMeans":"The evidence that made germline testing standard for every man with metastatic prostate cancer, whatever his family history. It changes his treatment, because PARP inhibitors and platinum work better in these tumours, and it changes his relatives' screening, because BRCA2 carries breast, ovarian and pancreatic risk as well."}]},{"era":"2013 to 2022","title":"Everything moves to the first day of metastatic diagnosis","description":"GETUG-AFU 15 gave docetaxel with androgen deprivation from the start and found nothing, and told the field not to do it. CHAARTED and STAMPEDE then found the opposite, and the STOpCaP adaptive meta-analysis resolved the three: in metastatic disease, a hazard ratio of 0.77 and an absolute 9 percent gain in four-year survival, with no evidence of benefit from zoledronic acid at all. LATITUDE and STAMPEDE did the same for abiraterone, TITAN for apalutamide, ENZAMET for enzalutamide, and ARASENS and PEACE-1 established the triplet of androgen deprivation, docetaxel and an androgen receptor pathway inhibitor. STAMPEDE also showed that irradiating the prostate itself improves survival in men with a low burden of metastases. In non-metastatic castration-resistant disease, SPARTAN, PROSPER and ARAMIS moved the same class earlier again.","status":"current","refs":[{"id":"paper-gravis-getug-afu-15-docetaxel-lancet-oncol-2013","kind":"paper","name":"GETUG-AFU 15: androgen deprivation alone or with docetaxel in non-castrate metastatic prostate cancer","route":"/key-papers/paper-gravis-getug-afu-15-docetaxel-lancet-oncol-2013/","tldr":"The first trial to give chemotherapy at the same time as hormone therapy in newly diagnosed metastatic prostate cancer. It found no survival benefit and concluded against the approach, two years before two larger trials found the opposite."},{"id":"paper-chaarted-nejm-2015","kind":"paper","name":"CHAARTED: chemohormonal therapy in metastatic hormone-sensitive prostate cancer","route":"/key-papers/paper-chaarted-nejm-2015/","tldr":"Giving six cycles of docetaxel at the start of hormone therapy for metastatic prostate cancer lengthened survival by over a year in men with high-volume disease, the first trial to show that early chemotherapy helps."},{"id":"paper-stampede-lancet-2016","kind":"paper","name":"Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial","route":"/key-papers/paper-stampede-lancet-2016/","tldr":"Published report from the STAMPEDE trial registered as NCT00268476, in The Lancet (2016), chosen as the most cited paper whose own text cites the registry id."},{"id":"paper-vale-stopcap-docetaxel-bisphosphonates-lancet-oncol-2016","kind":"paper","name":"STOpCaP: docetaxel or bisphosphonates added to standard of care in hormone-sensitive prostate cancer, a systematic review and meta-analysis","route":"/key-papers/paper-vale-stopcap-docetaxel-bisphosphonates-lancet-oncol-2016/","tldr":"Three trials of chemotherapy at the start of hormone therapy had reported, two positive and one negative. Pooling them showed the treatment does work in metastatic disease, improving four-year survival by about nine percent, and that zoledronic acid does not."},{"id":"paper-latitude-nejm-2017","kind":"paper","name":"LATITUDE: abiraterone plus prednisone in newly diagnosed high-risk metastatic castration-sensitive prostate cancer","route":"/key-papers/paper-latitude-nejm-2017/","tldr":"Adding abiraterone to hormone therapy at the time of diagnosis of high-risk metastatic prostate cancer cut deaths by more than a third, establishing early intensification instead of waiting for castration resistance."},{"id":"paper-stampede-abiraterone-nejm-2017","kind":"paper","name":"STAMPEDE: adding abiraterone to hormone therapy at diagnosis of advanced prostate cancer","route":"/key-papers/paper-stampede-abiraterone-nejm-2017/","tldr":"Giving the hormone-pathway drug abiraterone from the start, alongside standard testosterone suppression, cut deaths by more than a third in men newly diagnosed with high-risk or metastatic prostate cancer."},{"id":"paper-nct02489318-n-engl-j-med-2019","kind":"paper","name":"Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer","route":"/key-papers/paper-nct02489318-n-engl-j-med-2019/","tldr":"Published report from the TITAN trial registered as NCT02489318, in New England Journal of Medicine (2019), chosen as the most cited paper whose own text cites the registry id."},{"id":"paper-enzamet-n-engl-j-med-2019","kind":"paper","name":"Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer","route":"/key-papers/paper-enzamet-n-engl-j-med-2019/","tldr":"Published report from the ENZAMET trial registered as NCT02446405, in New England Journal of Medicine (2019), chosen as the most cited paper whose own text cites the registry id."},{"id":"paper-arasens-nejm-2022","kind":"paper","name":"ARASENS: darolutamide added to androgen deprivation and docetaxel in metastatic hormone-sensitive prostate cancer","route":"/key-papers/paper-arasens-nejm-2022/","tldr":"Adding the androgen receptor inhibitor darolutamide to hormone therapy and docetaxel chemotherapy cut deaths by a third in metastatic hormone-sensitive prostate cancer, establishing triplet therapy for men fit for chemotherapy."},{"id":"paper-peace-1-lancet-2022","kind":"paper","name":"Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design","route":"/key-papers/paper-peace-1-lancet-2022/","tldr":"Published report from the PEACE-1 trial registered as NCT01957436, in The Lancet (2022), chosen as the most cited paper whose own text cites the registry id."},{"id":"paper-parker-lancet","kind":"paper","name":"Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial","route":"/key-papers/paper-parker-lancet/","tldr":"Paper cited by one trial page, indexed on Europe PMC as PubMed record 30355464 and published in The Lancet; the citing page links this DOI, which is how the record was matched."},{"id":"paper-spartan-nejm-2018","kind":"paper","name":"SPARTAN: apalutamide for non-metastatic castration-resistant prostate cancer","route":"/key-papers/paper-spartan-nejm-2018/","tldr":"In men whose PSA was rising rapidly on hormone therapy but who had no visible metastases, apalutamide delayed the appearance of metastases by two years and later showed a survival benefit."},{"id":"paper-prosper-nejm-2018","kind":"paper","name":"PROSPER: enzalutamide in men with non-metastatic castration-resistant prostate cancer","route":"/key-papers/paper-prosper-nejm-2018/","tldr":"Enzalutamide delayed metastases by almost two years in men with rapidly rising PSA on hormone therapy and no visible spread, and longer follow-up showed it also lengthened survival."},{"id":"paper-aramis-nejm-2019","kind":"paper","name":"ARAMIS: darolutamide in non-metastatic castration-resistant prostate cancer","route":"/key-papers/paper-aramis-nejm-2019/","tldr":"Darolutamide, an androgen receptor inhibitor that barely enters the brain, delayed metastases by nearly two years in men with non-metastatic castration-resistant prostate cancer with side effects close to placebo, and later showed a survival benefit."}],"trials":[],"papers":[{"id":"paper-gravis-getug-afu-15-docetaxel-lancet-oncol-2013","name":"GETUG-AFU 15: androgen deprivation alone or with docetaxel in non-castrate metastatic prostate cancer","route":"/key-papers/paper-gravis-getug-afu-15-docetaxel-lancet-oncol-2013/","journal":"The Lancet Oncology","year":2013,"whatItMeans":"A negative trial that was later overturned, and a standing argument for pooling individual trials rather than acting on the first one to report. It is also the reason the distinction between high-volume and low-volume metastatic disease is written into guidelines."},{"id":"paper-chaarted-nejm-2015","name":"CHAARTED: chemohormonal therapy in metastatic hormone-sensitive prostate cancer","route":"/key-papers/paper-chaarted-nejm-2015/","journal":"New England Journal of Medicine","year":2015,"whatItMeans":"Docetaxel with androgen deprivation is a standard for high-volume metastatic hormone-sensitive prostate cancer, now usually combined with an androgen receptor pathway inhibitor as triplet therapy."},{"id":"paper-stampede-lancet-2016","name":"Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial","route":"/key-papers/paper-stampede-lancet-2016/","journal":"The Lancet","year":2016,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT00268476 with the most citations, so it is the natural first reading for anyone following the STAMPEDE trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-vale-stopcap-docetaxel-bisphosphonates-lancet-oncol-2016","name":"STOpCaP: docetaxel or bisphosphonates added to standard of care in hormone-sensitive prostate cancer, a systematic review and meta-analysis","route":"/key-papers/paper-vale-stopcap-docetaxel-bisphosphonates-lancet-oncol-2016/","journal":"The Lancet Oncology","year":2016,"whatItMeans":"The answer to a question three individual trials could not answer on their own, and the reason docetaxel with androgen deprivation became standard for metastatic hormone-sensitive disease. It also stopped a widely used bone drug being credited with a survival effect it does not have."},{"id":"paper-latitude-nejm-2017","name":"LATITUDE: abiraterone plus prednisone in newly diagnosed high-risk metastatic castration-sensitive prostate cancer","route":"/key-papers/paper-latitude-nejm-2017/","journal":"New England Journal of Medicine","year":2017,"whatItMeans":"Abiraterone with androgen deprivation is a standard first-line doublet for metastatic hormone-sensitive prostate cancer, consistent with the STAMPEDE result."},{"id":"paper-stampede-abiraterone-nejm-2017","name":"STAMPEDE: adding abiraterone to hormone therapy at diagnosis of advanced prostate cancer","route":"/key-papers/paper-stampede-abiraterone-nejm-2017/","journal":"New England Journal of Medicine","year":2017,"whatItMeans":"Men diagnosed with prostate cancer that has already spread, or that is locally advanced and high risk, should start abiraterone (or another androgen-receptor pathway inhibitor) at the same time as testosterone suppression rather than waiting for resistance. This roughly halves the risk of death over several years. The same platform later showed that docetaxel chemotherapy and, in high-volume metastatic disease, triple therapy also help, and that abiraterone benefits men with high-risk disease treated with radiotherapy."},{"id":"paper-nct02489318-n-engl-j-med-2019","name":"Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer","route":"/key-papers/paper-nct02489318-n-engl-j-med-2019/","journal":"New England Journal of Medicine","year":2019,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT02489318 with the most citations, so it is the natural first reading for anyone following the TITAN trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-enzamet-n-engl-j-med-2019","name":"Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer","route":"/key-papers/paper-enzamet-n-engl-j-med-2019/","journal":"New England Journal of Medicine","year":2019,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT02446405 with the most citations, so it is the natural first reading for anyone following the ENZAMET trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-arasens-nejm-2022","name":"ARASENS: darolutamide added to androgen deprivation and docetaxel in metastatic hormone-sensitive prostate cancer","route":"/key-papers/paper-arasens-nejm-2022/","journal":"New England Journal of Medicine","year":2022,"whatItMeans":"Triplet therapy with darolutamide is a standard for fit men with metastatic hormone-sensitive prostate cancer, particularly high-volume disease; PEACE-1 showed the same with abiraterone."},{"id":"paper-peace-1-lancet-2022","name":"Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design","route":"/key-papers/paper-peace-1-lancet-2022/","journal":"The Lancet","year":2022,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT01957436 with the most citations, so it is the natural first reading for anyone following the PEACE-1 trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-parker-lancet","name":"Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial","route":"/key-papers/paper-parker-lancet/","journal":"The Lancet","year":2018,"whatItMeans":"One trial page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand."},{"id":"paper-spartan-nejm-2018","name":"SPARTAN: apalutamide for non-metastatic castration-resistant prostate cancer","route":"/key-papers/paper-spartan-nejm-2018/","journal":"New England Journal of Medicine","year":2018,"whatItMeans":"Apalutamide, enzalutamide or darolutamide are standard for high-risk non-metastatic castration-resistant prostate cancer, a setting largely defined by conventional imaging."},{"id":"paper-prosper-nejm-2018","name":"PROSPER: enzalutamide in men with non-metastatic castration-resistant prostate cancer","route":"/key-papers/paper-prosper-nejm-2018/","journal":"New England Journal of Medicine","year":2018,"whatItMeans":"Enzalutamide is one of three androgen receptor inhibitors standard for high-risk non-metastatic castration-resistant prostate cancer."},{"id":"paper-aramis-nejm-2019","name":"ARAMIS: darolutamide in non-metastatic castration-resistant prostate cancer","route":"/key-papers/paper-aramis-nejm-2019/","journal":"New England Journal of Medicine","year":2019,"whatItMeans":"Darolutamide is often preferred in older men or those with fall or cognitive concerns because of its favourable tolerability among the three approved agents."}]},{"era":"2015 to 2026","title":"DNA repair: the first molecular subset of prostate cancer with a drug of its own","description":"TOPARP-A treated 50 unselected heavily pre-treated men with olaparib and biopsied all of them: 33 percent responded, and 14 of the 16 men with DNA repair defects did, including all 7 with BRCA2 loss, at a biomarker specificity of 94 percent. PROfound made it randomised, TRITON2 got rucaparib approved on response rate and TRITON3 confirmed it, with imaging-based progression-free survival of 11.2 against 6.4 months in the BRCA subgroup and a hazard ratio of 0.95 in the ATM subgroup, which is no effect at all. PROpel, TALAPRO-2 and MAGNITUDE then combined PARP inhibitors with androgen receptor drugs in first-line castration-resistant disease, and TALAPRO-3 and AMPLITUDE have moved the combination into hormone-sensitive disease. The recurring lesson is that homologous recombination repair is not one biomarker: BRCA2 is not ATM and neither is CDK12.","status":"current","refs":[{"id":"paper-mateo-toparp-a-olaparib-dna-repair-nejm-2015","kind":"paper","name":"TOPARP-A: DNA-repair defects and olaparib in metastatic prostate cancer","route":"/key-papers/paper-mateo-toparp-a-olaparib-dna-repair-nejm-2015/","tldr":"Fifty men whose prostate cancer had exhausted every standard treatment were given a PARP inhibitor and biopsied. A third responded, and almost all the responders were the ones with a broken DNA repair gene, including every man who had lost BRCA2."},{"id":"paper-profound-nejm-2020","kind":"paper","name":"PROfound: olaparib for metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations","route":"/key-papers/paper-profound-nejm-2020/","tldr":"In men with metastatic castration-resistant prostate cancer carrying BRCA1, BRCA2 or ATM alterations who had progressed on hormonal therapy, the PARP inhibitor olaparib delayed progression and lengthened survival compared with another hormonal agent."},{"id":"paper-abida-triton2-rucaparib-brca-jco-2020","kind":"paper","name":"TRITON2: rucaparib in men with metastatic castration-resistant prostate cancer harbouring a BRCA1 or BRCA2 alteration","route":"/key-papers/paper-abida-triton2-rucaparib-brca-jco-2020/","tldr":"The trial that got rucaparib approved for prostate cancer. In 115 men with a BRCA fault whose cancer had already been through hormone drugs and chemotherapy, around half had their tumours shrink or their PSA halve."},{"id":"paper-fizazi-triton3-rucaparib-nejm-2023","kind":"paper","name":"TRITON3: rucaparib or physician's choice in metastatic castration-resistant prostate cancer","route":"/key-papers/paper-fizazi-triton3-rucaparib-nejm-2023/","tldr":"The randomised confirmation that a PARP inhibitor beats the alternatives in men with a BRCA fault, nearly doubling the time before the cancer grew on scans. In men with an ATM fault instead, it did nothing."},{"id":"paper-propel-lancet-oncol-2023","kind":"paper","name":"Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial","route":"/key-papers/paper-propel-lancet-oncol-2023/","tldr":"Published report from the PROpel trial registered as NCT03732820, in The Lancet Oncology (2023), chosen as the most cited paper whose own text cites the registry id."},{"id":"paper-talapro-2-lancet-2023","kind":"paper","name":"Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial","route":"/key-papers/paper-talapro-2-lancet-2023/","tldr":"Published report from the TALAPRO-2 trial registered as NCT03395197, in The Lancet (2023), chosen as the most cited paper whose own text cites the registry id."},{"id":"paper-magnitude-j-clin-oncol-2023","kind":"paper","name":"Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer","route":"/key-papers/paper-magnitude-j-clin-oncol-2023/","tldr":"Published report from the MAGNITUDE trial registered as NCT03748641, in Journal of Clinical Oncology (2023), chosen as the most cited paper whose own text cites the registry id."},{"id":"paper-nct04497844-nat-med-2025","kind":"paper","name":"Niraparib and abiraterone acetate plus prednisone for HRR-deficient metastatic castration-sensitive prostate cancer: a randomized phase 3 trial","route":"/key-papers/paper-nct04497844-nat-med-2025/","tldr":"Published report from the AMPLITUDE trial registered as NCT04497844, in Nature Medicine (2025), chosen as the most cited paper whose own text cites the registry id."},{"id":"paper-nct04821622-n-engl-j-med-2026","kind":"paper","name":"PARP and Androgen-Signaling Inhibition plus ADT in Metastatic Prostate Cancer","route":"/key-papers/paper-nct04821622-n-engl-j-med-2026/","tldr":"Published report from the TALAPRO-3 trial registered as NCT04821622, in New England Journal of Medicine (2026), chosen as the most cited paper whose own text cites the registry id."},{"id":"paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019","kind":"paper","name":"Prospective comprehensive genomic profiling of 3,476 primary and metastatic prostate tumours","route":"/key-papers/paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019/","tldr":"The largest routine-practice picture of what is broken in prostate tumours. Across 3,476 samples sent for commercial sequencing, TP53 was altered in 44 percent and PTEN in 32 percent, and just over half carried something a drug is being developed against."},{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/","tldr":"Targeted drugs switch off the specific broken protein a cancer depends on. The first ones turned a leukaemia into a chronic condition; the field then learned that resistance is the rule, designed drugs around it, and has now reached the drivers that were called impossible to target."}],"trials":[],"papers":[{"id":"paper-mateo-toparp-a-olaparib-dna-repair-nejm-2015","name":"TOPARP-A: DNA-repair defects and olaparib in metastatic prostate cancer","route":"/key-papers/paper-mateo-toparp-a-olaparib-dna-repair-nejm-2015/","journal":"New England Journal of Medicine","year":2015,"whatItMeans":"The first molecularly stratified treatment in prostate cancer, and the proof that the synthetic lethality that works in ovarian and breast cancer works here too. Every PARP inhibitor now licensed in prostate cancer traces back to this trial."},{"id":"paper-profound-nejm-2020","name":"PROfound: olaparib for metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations","route":"/key-papers/paper-profound-nejm-2020/","journal":"New England Journal of Medicine","year":2020,"whatItMeans":"Germline and tumour testing for homologous recombination repair genes is now standard in metastatic prostate cancer, and olaparib is approved for BRCA-mutated disease after a hormonal agent."},{"id":"paper-abida-triton2-rucaparib-brca-jco-2020","name":"TRITON2: rucaparib in men with metastatic castration-resistant prostate cancer harbouring a BRCA1 or BRCA2 alteration","route":"/key-papers/paper-abida-triton2-rucaparib-brca-jco-2020/","journal":"Journal of Clinical Oncology","year":2020,"whatItMeans":"The trial behind the second PARP inhibitor licensed in prostate cancer, and the evidence that a somatic BRCA alteration predicts response as well as an inherited one. Together with TOPARP-A it is why tumour as well as germline sequencing is recommended in metastatic disease."},{"id":"paper-fizazi-triton3-rucaparib-nejm-2023","name":"TRITON3: rucaparib or physician's choice in metastatic castration-resistant prostate cancer","route":"/key-papers/paper-fizazi-triton3-rucaparib-nejm-2023/","journal":"New England Journal of Medicine","year":2023,"whatItMeans":"The randomised proof for PARP inhibition in BRCA-altered prostate cancer, and the clearest evidence that the homologous recombination repair gene list should not be used as a single yes-or-no test. ATM-altered disease needs a different answer, and does not yet have one."},{"id":"paper-propel-lancet-oncol-2023","name":"Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial","route":"/key-papers/paper-propel-lancet-oncol-2023/","journal":"The Lancet Oncology","year":2023,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT03732820 with the most citations, so it is the natural first reading for anyone following the PROpel trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-talapro-2-lancet-2023","name":"Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial","route":"/key-papers/paper-talapro-2-lancet-2023/","journal":"The Lancet","year":2023,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT03395197 with the most citations, so it is the natural first reading for anyone following the TALAPRO-2 trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-magnitude-j-clin-oncol-2023","name":"Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer","route":"/key-papers/paper-magnitude-j-clin-oncol-2023/","journal":"Journal of Clinical Oncology","year":2023,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT03748641 with the most citations, so it is the natural first reading for anyone following the MAGNITUDE trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-nct04497844-nat-med-2025","name":"Niraparib and abiraterone acetate plus prednisone for HRR-deficient metastatic castration-sensitive prostate cancer: a randomized phase 3 trial","route":"/key-papers/paper-nct04497844-nat-med-2025/","journal":"Nature Medicine","year":2025,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT04497844 with the most citations, so it is the natural first reading for anyone following the AMPLITUDE trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-nct04821622-n-engl-j-med-2026","name":"PARP and Androgen-Signaling Inhibition plus ADT in Metastatic Prostate Cancer","route":"/key-papers/paper-nct04821622-n-engl-j-med-2026/","journal":"New England Journal of Medicine","year":2026,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT04821622 with the most citations, so it is the natural first reading for anyone following the TALAPRO-3 trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019","name":"Prospective comprehensive genomic profiling of 3,476 primary and metastatic prostate tumours","route":"/key-papers/paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019/","journal":"JCO Precision Oncology","year":2019,"whatItMeans":"What a prostate cancer sequencing report looks like in practice, and the numerical basis for two clinical rules: do not expect checkpoint immunotherapy to work unless the tumour is mismatch repair deficient, and do not treat a CDK12 alteration as if it were a BRCA alteration."}]},{"era":"2017 to 2026","title":"PSMA: the same molecule used to see the cancer and then to irradiate it","description":"Prostate-specific membrane antigen sits on the surface of almost every prostate cancer cell, which makes it both a camera target and a delivery address. proPSMA showed PSMA positron emission tomography beats conventional imaging for staging high-risk disease, changing management in a substantial minority. TheraP compared lutetium-177 PSMA-617 against cabazitaxel and VISION added it to standard care after an androgen receptor drug and a taxane. PSMAfore moved it in front of the taxane and PSMAddition into hormone-sensitive disease. It is the clearest example in any solid tumour of a single molecule carrying both the diagnostic and the therapeutic, and the open question is dosing: the amount of radiation delivered is not currently measured per patient, and the schedule is fixed rather than adapted to response.","status":"current","refs":[{"id":"paper-propsma-hofman-lancet-2020","kind":"paper","name":"proPSMA: PSMA PET-CT versus conventional imaging for staging high-risk prostate cancer","route":"/key-papers/paper-propsma-hofman-lancet-2020/","tldr":"PSMA PET-CT was 27 percentage points more accurate than CT and bone scan for finding spread in men with high-risk prostate cancer before treatment, with less radiation and more influence on management, and it has replaced conventional imaging where available."},{"id":"paper-psma-prerp-hope-jama-oncol-2021","kind":"paper","name":"Diagnostic accuracy of 68Ga-PSMA-11 PET for pelvic nodal metastasis detection prior to radical prostatectomy and pelvic lymph node dissection: a multicenter prospective phase 3 imaging trial","route":"/key-papers/paper-psma-prerp-hope-jama-oncol-2021/","tldr":"In 277 men whose prostate and pelvic lymph nodes were removed after a gallium PSMA scan, the scan correctly flagged 40 percent of the men with cancer in their nodes and was right 95 percent of the time when it called the nodes clear."},{"id":"paper-therap-lancet-2021","kind":"paper","name":"[ 177 Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial","route":"/key-papers/paper-therap-lancet-2021/","tldr":"Published report from the TheraP trial registered as NCT03392428, in The Lancet (2021), chosen as the most cited paper whose own text cites the registry id."},{"id":"paper-vision-nejm-2021","kind":"paper","name":"VISION: lutetium-177 PSMA-617 radioligand therapy extends survival in advanced prostate cancer","route":"/key-papers/paper-vision-nejm-2021/","tldr":"A radioactive drug that homes to the PSMA protein on prostate cancer cells helped men with heavily pretreated metastatic prostate cancer live about four months longer, launching radioligand therapy as a mainstream treatment."},{"id":"paper-psmafore-lancet-2024","kind":"paper","name":"177 Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial","route":"/key-papers/paper-psmafore-lancet-2024/","tldr":"Published report from the PSMAfore trial registered as NCT04689828, in The Lancet (2024), chosen as the most cited paper whose own text cites the registry id."},{"id":"paper-psmaddition-lancet-2026","kind":"paper","name":"[ 177 Lu]Lu-PSMA-617 in patients with PSMA-positive metastatic androgen pathway modulator-naive/sensitive prostate cancer (PSMAddition): a phase 3 randomised, controlled trial","route":"/key-papers/paper-psmaddition-lancet-2026/","tldr":"Published report from the PSMAddition trial registered as NCT04720157, in The Lancet (2026), chosen as the most cited paper whose own text cites the registry id."},{"id":"radiopharma-roadmap","kind":"roadmap","name":"Radiopharmaceutical roadmap: iodine → lutetium → actinium","route":"/roadmaps/radiopharma-roadmap/","tldr":"The radiopharmaceutical roadmap runs eighty years from radioactive iodine for thyroid cancer to alpha-emitting drugs for prostate and neuroendocrine cancers, with isotope supply as the limiting factor."},{"id":"molecular-imaging-roadmap","kind":"roadmap","name":"Molecular imaging roadmap: FDG → PSMA → FAP → antigen and immune PET","route":"/roadmaps/molecular-imaging-roadmap/","tldr":"From a sugar tracer that lights up most cancers to tracers that show a single protein, a stromal cell type, or the immune cells inside a tumour."}],"trials":[],"papers":[{"id":"paper-propsma-hofman-lancet-2020","name":"proPSMA: PSMA PET-CT versus conventional imaging for staging high-risk prostate cancer","route":"/key-papers/paper-propsma-hofman-lancet-2020/","journal":"The Lancet","year":2020,"whatItMeans":"PSMA PET-CT is the preferred staging investigation for high-risk prostate cancer and for biochemical recurrence, though most treatment trials were designed with conventional imaging."},{"id":"paper-psma-prerp-hope-jama-oncol-2021","name":"Diagnostic accuracy of 68Ga-PSMA-11 PET for pelvic nodal metastasis detection prior to radical prostatectomy and pelvic lymph node dissection: a multicenter prospective phase 3 imaging trial","route":"/key-papers/paper-psma-prerp-hope-jama-oncol-2021/","journal":"JAMA Oncology","year":2021,"whatItMeans":"This academic programme is what the FDA approved 68Ga-PSMA-11 on in December 2020, and the Illuccix and Locametz kits rest on it for the staging indication. Its message for a man being staged before surgery is that a positive PSMA PET node is very likely real, but a negative scan does not rule out small nodal deposits, so the lymph node dissection still matters."},{"id":"paper-therap-lancet-2021","name":"[ 177 Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial","route":"/key-papers/paper-therap-lancet-2021/","journal":"The Lancet","year":2021,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT03392428 with the most citations, so it is the natural first reading for anyone following the TheraP trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-vision-nejm-2021","name":"VISION: lutetium-177 PSMA-617 radioligand therapy extends survival in advanced prostate cancer","route":"/key-papers/paper-vision-nejm-2021/","journal":"New England Journal of Medicine","year":2021,"whatItMeans":"Men with metastatic castration-resistant prostate cancer that has progressed after hormonal therapy and chemotherapy, and whose tumours show PSMA on a PET scan, can now receive lutetium-PSMA, which extends life, controls pain and is usually better tolerated than further chemotherapy. It has established a new treatment class in which a scan decides who gets the matching radioactive drug, and it is now being tested earlier in the disease (PSMAfore, PSMAddition)."},{"id":"paper-psmafore-lancet-2024","name":"177 Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial","route":"/key-papers/paper-psmafore-lancet-2024/","journal":"The Lancet","year":2024,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT04689828 with the most citations, so it is the natural first reading for anyone following the PSMAfore trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."},{"id":"paper-psmaddition-lancet-2026","name":"[ 177 Lu]Lu-PSMA-617 in patients with PSMA-positive metastatic androgen pathway modulator-naive/sensitive prostate cancer (PSMAddition): a phase 3 randomised, controlled trial","route":"/key-papers/paper-psmaddition-lancet-2026/","journal":"The Lancet","year":2026,"whatItMeans":"This is the paper Europe PMC returns for registry id NCT04720157 with the most citations, so it is the natural first reading for anyone following the PSMAddition trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand."}]},{"era":"2014 to 2026","title":"What the androgen receptor era created: splice variants, lineage switching and a cold tumour","description":"Antonarakis showed in 2014 that men whose circulating tumour cells carry AR-V7, an androgen receptor missing the part the drugs bind, have a zero percent prostate-specific antigen response rate to enzalutamide and abiraterone. Mu and Ku then showed the more complete escape: losing TP53 and RB1 lets the cell switch on SOX2 and change identity from a luminal cell that needs the androgen receptor to a basal or neuroendocrine cell that does not, and restoring the tumour suppressors reverses it in the laboratory. Aggarwal found treatment-emergent small-cell neuroendocrine carcinoma in 17 percent of metastatic biopsies. Immunotherapy, which might have been the answer, is not: KEYNOTE-199 gave response rates of 5 and 3 percent and PD-L1 expression predicted nothing, which is consistent with a median tumour mutational burden of 2.6 mutations per megabase and mismatch repair deficiency in 4 percent.","status":"emerging","refs":[{"id":"paper-antonarakis-ar-v7-resistance-nejm-2014","kind":"paper","name":"AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer","route":"/key-papers/paper-antonarakis-ar-v7-resistance-nejm-2014/","tldr":"A short form of the androgen receptor, missing the part that the hormone drugs grab onto, can be detected in tumour cells circulating in the blood. Not one man whose cells carried it responded to either enzalutamide or abiraterone."},{"id":"paper-mu-sox2-lineage-plasticity-science-2017","kind":"paper","name":"SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer","route":"/key-papers/paper-mu-sox2-lineage-plasticity-science-2017/","tldr":"Some prostate cancers escape hormone drugs not by changing the receptor but by becoming a different kind of cell that does not need it. This paper showed how: losing two tumour suppressors lets the cell switch on SOX2 and change identity, and restoring them reverses it."},{"id":"paper-ku-science","kind":"paper","name":"Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance","route":"/key-papers/paper-ku-science/","tldr":"Paper cited by one pathway page, indexed on Europe PMC as PubMed record 28059767 and published in Science; the citing page links this DOI, which is how the record was matched."},{"id":"paper-beltran-nepc-divergent-evolution-nat-med-2016","kind":"paper","name":"Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer","route":"/key-papers/paper-beltran-nepc-divergent-evolution-nat-med-2016/","tldr":"Sequencing showed that neuroendocrine prostate cancer arises from the same cells as ordinary prostate adenocarcinoma but diverges through loss of RB1 and TP53 and changes in DNA methylation rather than new mutations, explaining how the cancer escapes hormone therapy by changing identity."},{"id":"paper-aggarwal-t-sccpc-jco-2018","kind":"paper","name":"Clinical and genomic characterisation of treatment-emergent small-cell neuroendocrine prostate cancer","route":"/key-papers/paper-aggarwal-t-sccpc-jco-2018/","tldr":"Biopsying metastases in men progressing on modern hormone therapy found small-cell neuroendocrine prostate cancer in 17 percent, with a median survival under three years, showing how commonly the lineage switch occurs and why biopsy at progression matters."},{"id":"paper-antonarakis-keynote-199-pembrolizumab-jco-2020","kind":"paper","name":"KEYNOTE-199: pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer","route":"/key-papers/paper-antonarakis-keynote-199-pembrolizumab-jco-2020/","tldr":"Checkpoint immunotherapy transformed several cancers and did almost nothing here. In 258 men with advanced prostate cancer, about 1 in 20 had a response, and whether the tumour expressed PD-L1 made no difference."},{"id":"paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019","kind":"paper","name":"Prospective comprehensive genomic profiling of 3,476 primary and metastatic prostate tumours","route":"/key-papers/paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019/","tldr":"The largest routine-practice picture of what is broken in prostate tumours. Across 3,476 samples sent for commercial sequencing, TP53 was altered in 44 percent and PTEN in 32 percent, and just over half carried something a drug is being developed against."}],"trials":[],"papers":[{"id":"paper-antonarakis-ar-v7-resistance-nejm-2014","name":"AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer","route":"/key-papers/paper-antonarakis-ar-v7-resistance-nejm-2014/","journal":"New England Journal of Medicine","year":2014,"whatItMeans":"The first predictive resistance biomarker in prostate cancer, and a mechanism rather than a correlation: a receptor with no ligand-binding domain cannot be blocked by a drug that binds the ligand-binding domain. It is also the origin of the case for androgen receptor degraders, which destroy the protein rather than blocking a site the protein no longer has."},{"id":"paper-mu-sox2-lineage-plasticity-science-2017","name":"SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer","route":"/key-papers/paper-mu-sox2-lineage-plasticity-science-2017/","journal":"Science","year":2017,"whatItMeans":"A mechanism for the most feared form of treatment resistance in prostate cancer, and the reason combined TP53 and RB1 loss is worth knowing about before a man starts an androgen receptor drug rather than after his biopsy comes back neuroendocrine. Reversibility in the laboratory is also an argument that the switch is a target and not just a prognosis."},{"id":"paper-ku-science","name":"Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance","route":"/key-papers/paper-ku-science/","journal":"Science","year":2017,"whatItMeans":"One pathway page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand."},{"id":"paper-beltran-nepc-divergent-evolution-nat-med-2016","name":"Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer","route":"/key-papers/paper-beltran-nepc-divergent-evolution-nat-med-2016/","journal":"Nature Medicine","year":2016,"whatItMeans":"Treatment-emergent neuroendocrine prostate cancer is understood as lineage plasticity under androgen receptor blockade; EZH2, DLL3 and Aurora kinase are the targets under investigation."},{"id":"paper-aggarwal-t-sccpc-jco-2018","name":"Clinical and genomic characterisation of treatment-emergent small-cell neuroendocrine prostate cancer","route":"/key-papers/paper-aggarwal-t-sccpc-jco-2018/","journal":"Journal of Clinical Oncology","year":2018,"whatItMeans":"Biopsy of progressing lesions, especially with low PSA or visceral spread, is recommended to detect neuroendocrine transformation and switch to platinum-based therapy or trials."},{"id":"paper-antonarakis-keynote-199-pembrolizumab-jco-2020","name":"KEYNOTE-199: pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer","route":"/key-papers/paper-antonarakis-keynote-199-pembrolizumab-jco-2020/","journal":"Journal of Clinical Oncology","year":2020,"whatItMeans":"The measured size of the immunotherapy problem in prostate cancer: a response rate in the low single figures, no signal from PD-L1 expression, and durable benefit in a small subgroup nobody can yet identify prospectively. Any claim that immunotherapy is coming to prostate cancer has to explain this trial."},{"id":"paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019","name":"Prospective comprehensive genomic profiling of 3,476 primary and metastatic prostate tumours","route":"/key-papers/paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019/","journal":"JCO Precision Oncology","year":2019,"whatItMeans":"What a prostate cancer sequencing report looks like in practice, and the numerical basis for two clinical rules: do not expect checkpoint immunotherapy to work unless the tumour is mismatch repair deficient, and do not treat a CDK12 alteration as if it were a BRCA alteration."}]},{"era":"2018 to 2030","title":"Reversing the adaptation instead of blocking it, and asking what order to give things in","description":"RESTORE gave supraphysiological testosterone to men who had progressed on enzalutamide: 30 percent responded, and 52 percent of those who then went back on enzalutamide responded to the drug that had failed them. TRANSFORMER randomised the approach and found the primary endpoint flat at 5.7 months in both arms, but progression-free survival through crossover of 28.2 months for testosterone-then-enzalutamide against 19.6 for the reverse, with quality of life favouring testosterone throughout. SWOG 9346 had already shown that taking planned breaks from androgen deprivation is not clearly safe, with a hazard ratio of 1.10 whose confidence interval crossed the non-inferiority boundary. Between them these three trials make the same point from different directions: in a disease with six active treatment classes and no head-to-head sequencing data, the order is itself an untested intervention.","status":"emerging","refs":[{"id":"paper-teply-restore-bipolar-androgen-therapy-lancet-oncol-2018","kind":"paper","name":"RESTORE: bipolar androgen therapy after progression on enzalutamide in metastatic castration-resistant prostate cancer","route":"/key-papers/paper-teply-restore-bipolar-androgen-therapy-lancet-oncol-2018/","tldr":"Prostate cancer adapts to having almost no testosterone. This trial did the opposite of what the textbook says and gave men large doses of testosterone. Three in ten responded, and more than half responded again to the hormone-blocking drug that had stopped working."},{"id":"paper-denmeade-transformer-bipolar-androgen-therapy-jco-2021","kind":"paper","name":"TRANSFORMER: bipolar androgen therapy versus enzalutamide in asymptomatic metastatic castration-resistant prostate cancer","route":"/key-papers/paper-denmeade-transformer-bipolar-androgen-therapy-jco-2021/","tldr":"A randomised comparison of high-dose testosterone against a standard hormone-blocking drug. Neither delayed progression better than the other, but men who had the testosterone first and the drug second lived nearly nine months longer before their second progression, and felt better throughout."},{"id":"paper-hussain-swog-9346-intermittent-androgen-deprivation-nejm-2013","kind":"paper","name":"SWOG 9346: intermittent versus continuous androgen deprivation in metastatic prostate cancer","route":"/key-papers/paper-hussain-swog-9346-intermittent-androgen-deprivation-nejm-2013/","tldr":"Hormone therapy causes hot flushes, loss of libido, loss of muscle and bone, and low mood. This trial asked whether men could take breaks from it. After ten years the answer was uncomfortable: the breaks felt better for three months, and the trial could not rule out a worse chance of survival."},{"id":"paper-zhang-nat-commun","kind":"paper","name":"Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer","route":"/key-papers/paper-zhang-nat-commun/","tldr":"Paper cited by one technology page, one pathway page and one term page, indexed on Europe PMC as PubMed record 29180633 and published in Nature Communications; the citing pages link this DOI, which is how the record was matched."},{"id":"idea-bio1-alternating-schedules","kind":"idea","name":"Rotate between drugs on a fixed schedule instead of waiting for failure","route":"/ideas/idea-bio1-alternating-schedules/","tldr":"Hospitals rotate antibiotics to stop bacteria adapting. Cycling between two cancer drugs on a set schedule, rather than using one until it fails, might work the same way."},{"id":"idea-tr1-adaptive-therapy-randomised-phase-2","kind":"idea","name":"Evolution-guided 'adaptive therapy' dosing tested in randomised phase 2 trials","route":"/ideas/idea-tr1-adaptive-therapy-randomised-phase-2/","tldr":"Adaptive therapy uses just enough drug to keep a tumour in check, pausing when the burden falls and resuming when it rises, so drug-sensitive cells suppress resistant ones. A prostate cancer pilot with abiraterone lengthened time to progression against historical controls on half the drug; randomised phase 2 trials are the next step."}],"trials":[],"papers":[{"id":"paper-teply-restore-bipolar-androgen-therapy-lancet-oncol-2018","name":"RESTORE: bipolar androgen therapy after progression on enzalutamide in metastatic castration-resistant prostate cancer","route":"/key-papers/paper-teply-restore-bipolar-androgen-therapy-lancet-oncol-2018/","journal":"The Lancet Oncology","year":2018,"whatItMeans":"A demonstration that a drug that has stopped working can be made to work again by changing the environment the tumour has adapted to, rather than by changing the drug. It is the strongest clinical evidence in prostate cancer for treating resistance as something reversible."},{"id":"paper-denmeade-transformer-bipolar-androgen-therapy-jco-2021","name":"TRANSFORMER: bipolar androgen therapy versus enzalutamide in asymptomatic metastatic castration-resistant prostate cancer","route":"/key-papers/paper-denmeade-transformer-bipolar-androgen-therapy-jco-2021/","journal":"Journal of Clinical Oncology","year":2021,"whatItMeans":"The first randomised evidence that the order in which prostate cancer treatments are given changes how long they work, independently of which treatments they are. It is also a rare trial in which quality of life pointed one way and the primary endpoint pointed nowhere."},{"id":"paper-hussain-swog-9346-intermittent-androgen-deprivation-nejm-2013","name":"SWOG 9346: intermittent versus continuous androgen deprivation in metastatic prostate cancer","route":"/key-papers/paper-hussain-swog-9346-intermittent-androgen-deprivation-nejm-2013/","journal":"New England Journal of Medicine","year":2013,"whatItMeans":"The reason intermittent androgen deprivation is offered as a choice in metastatic disease rather than recommended, and a case study in what an inconclusive non-inferiority trial should say. For a man weighing the side effects, the honest statement is that the quality-of-life gain is real but brief and the survival question is open."},{"id":"paper-zhang-nat-commun","name":"Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer","route":"/key-papers/paper-zhang-nat-commun/","journal":"Nature Communications","year":2017,"whatItMeans":"One technology page, one pathway page and one term page on OnCo cite this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing pages listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand."}]},{"era":"2026 to 2032","title":"What would have to be true for prostate cancer mortality to fall substantially again","description":"Five things, only one of which is a new drug. A screening pathway judged on metastatic presentation rather than on incidence, invited by risk rather than by birthday, with magnetic resonance imaging in front of the biopsy so the overdiagnosis half of the trade shrinks. DNA repair testing at the moment of metastatic diagnosis rather than three lines later, because the drugs have already moved there. The order of treatment randomised, in a platform that can compare sequences rather than only drugs. Lineage plasticity watched for in the men whose tumours have lost TP53 and RB1, before the biopsy comes back neuroendocrine. And the mortality gap that survives equal access, which is dying of something other than prostate cancer, measured and treated as an outcome of the cancer service rather than someone else's problem.","status":"speculative","refs":[{"id":"idea-prostate-metastatic-presentation-as-the-screening-endpoint","kind":"idea","name":"Judge a prostate screening programme on metastatic presentation, not on incidence or mortality","route":"/ideas/idea-prostate-metastatic-presentation-as-the-screening-endpoint/","tldr":"Screening trials are judged on deaths, which take fifteen years to count, and on cancers found, which is the wrong direction. Preventing a man from turning up with cancer already in his bones happens three times as often as preventing a death, arrives years earlier, and is the outcome he cares about."},{"id":"idea-prostate-hrr-testing-at-metastatic-diagnosis","kind":"idea","name":"Test every man for DNA repair faults on the day his prostate cancer is found to have spread, not three treatments later","route":"/ideas/idea-prostate-hrr-testing-at-metastatic-diagnosis/","tldr":"About one man in eight with prostate cancer that has spread carries an inherited DNA repair fault, and about one in five has one in the tumour. The drugs for those faults have moved to the beginning of treatment, but the test is still usually done near the end, when it is too late to use the result."},{"id":"idea-prostate-randomise-the-sequence-not-only-the-drugs","kind":"idea","name":"Randomise the order of treatment, not only the drugs: a strategy platform for metastatic prostate cancer","route":"/ideas/idea-prostate-randomise-the-sequence-not-only-the-drugs/","tldr":"Metastatic prostate cancer now has six classes of treatment that work, and no trial has ever compared the orders they can be given in. Every trial adds a drug to the front; none asks what should follow it, so the sequence a man receives is decided by habit and by what was licensed first."},{"id":"idea-prostate-plasticity-surveillance-before-it-is-neuroendocrine","kind":"idea","name":"Watch for the cancer changing cell type before the biopsy says neuroendocrine, and act on it","route":"/ideas/idea-prostate-plasticity-surveillance-before-it-is-neuroendocrine/","tldr":"In a minority of men, prostate cancer escapes hormone drugs by becoming a different kind of cell that no longer needs the androgen receptor. By the time a biopsy shows it, the treatment options are almost gone. The genetic changes that allow the switch are detectable years earlier, and nobody is looking for them."},{"id":"idea-prostate-other-cause-mortality-as-a-reported-service-outcome","kind":"idea","name":"Report death from other causes as an outcome of the prostate cancer service, split by deprivation and ethnicity","route":"/ideas/idea-prostate-other-cause-mortality-as-a-reported-service-outcome/","tldr":"When Black and white men in the United States are given the same treatment, the gap in dying of prostate cancer largely closes. The gap in dying of everything else does not. Cancer services measure the first and not the second, which means the surviving disparity is invisible to the people best placed to act on it."},{"id":"idea-prostate-per-lesion-mri-audit-before-focal-treatment","kind":"idea","name":"Publish a per-lesion miss rate for every prostate MRI service before it is allowed to guide focal treatment","route":"/ideas/idea-prostate-per-lesion-mri-audit-before-focal-treatment/","tldr":"Prostate MRI is good at telling you whether a man has a serious cancer and poor at telling you where all of it is. It missed at least one significant tumour in a third of men in the study that checked it against the whole removed prostate. Services that treat part of the gland, or follow men on imaging alone, are relying on the number they do not measure."},{"id":"idea-prostate-bipolar-androgen-therapy-phase-3-on-pfs2","kind":"idea","name":"Take high-dose testosterone to phase 3, with progression-free survival through the second line as the primary endpoint","route":"/ideas/idea-prostate-bipolar-androgen-therapy-phase-3-on-pfs2/","tldr":"Giving men with castration-resistant prostate cancer large doses of the hormone the treatment has spent years removing makes a third of them respond, and makes half of them respond again to the drug that had stopped working. It has never been taken to a definitive trial, partly because the endpoint that shows the benefit is not the one trials usually use."}],"trials":[],"papers":[]}],"watch":[{"item":"ProBio: the biomarker-driven outcome-adaptive platform in metastatic prostate cancer, the first trial designed to compare treatment strategies rather than single drugs in this disease","expected":"Primary completion and study completion December 2026 (estimated, ClinicalTrials.gov NCT03903835)","source":"https://clinicaltrials.gov/study/NCT03903835","refs":[{"id":"idea-prostate-randomise-the-sequence-not-only-the-drugs","kind":"idea","name":"Randomise the order of treatment, not only the drugs: a strategy platform for metastatic prostate cancer","route":"/ideas/idea-prostate-randomise-the-sequence-not-only-the-drugs/","tldr":"Metastatic prostate cancer now has six classes of treatment that work, and no trial has ever compared the orders they can be given in. Every trial adds a drug to the front; none asks what should follow it, so the sequence a man receives is decided by habit and by what was licensed first."}]},{"item":"PSMAddition: lutetium-177 PSMA-617 added to standard care in metastatic hormone-sensitive disease, the earliest setting radioligand therapy has been tested in","expected":"Study completion 11 February 2027 (estimated; primary completion 13 January 2025 actual, ClinicalTrials.gov NCT04720157)","source":"https://clinicaltrials.gov/study/NCT04720157","refs":[{"id":"paper-psmaddition-lancet-2026","kind":"paper","name":"[ 177 Lu]Lu-PSMA-617 in patients with PSMA-positive metastatic androgen pathway modulator-naive/sensitive prostate cancer (PSMAddition): a phase 3 randomised, controlled trial","route":"/key-papers/paper-psmaddition-lancet-2026/","tldr":"Published report from the PSMAddition trial registered as NCT04720157, in The Lancet (2026), chosen as the most cited paper whose own text cites the registry id."},{"id":"psmaddition","kind":"trial","name":"PSMAddition","route":"/trials/psmaddition/","status":"positive","tldr":"PSMAddition moved the radioligand Pluvicto into the first treatment of metastatic hormone-sensitive prostate cancer, given alongside hormone therapy, and the FDA approved this use on 31 July 2026. It delayed progression on scans, but severe side effects were more common and whether it lengthens life is not yet known."}]},{"item":"CAPItello-281: capivasertib with abiraterone in PTEN-deficient metastatic hormone-sensitive disease, the first PI3K-pathway result in a biomarker-selected prostate population","expected":"Study completion 31 March 2027 (estimated; primary completion 7 October 2024 actual, ClinicalTrials.gov NCT04493853)","source":"https://clinicaltrials.gov/study/NCT04493853","refs":[{"id":"paper-capitello-281-ann-oncol-2026","kind":"paper","name":"Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 phase III study","route":"/key-papers/paper-capitello-281-ann-oncol-2026/","tldr":"Published report from the CAPItello-281 trial registered as NCT04493853, in Annals of Oncology (2026), chosen as the most cited paper whose own text cites the registry id."},{"id":"capitello-281","kind":"trial","name":"CAPItello-281","route":"/trials/capitello-281/","status":"positive","tldr":"CAPItello-281 delivered the first AKT inhibitor success in prostate cancer, for the ~25% of men whose tumours have lost PTEN."},{"id":"paper-tcga-molecular-taxonomy-primary-prostate-cell-2015","kind":"paper","name":"TCGA: the molecular taxonomy of primary prostate cancer","route":"/key-papers/paper-tcga-molecular-taxonomy-primary-prostate-cell-2015/","tldr":"The Cancer Genome Atlas classified 333 prostate cancers taken out at surgery and found that three quarters fall into one of seven groups defined by a fusion or a mutation. A quarter had a change that a drug could in principle be aimed at, and one in five had a broken DNA repair gene."}]},{"item":"TALAPRO-3: talazoparib with enzalutamide in DNA damage repair gene-mutated metastatic hormone-sensitive disease, the PARP combination moved to the hormone-sensitive setting","expected":"Study completion 28 August 2027 (estimated; primary completion 18 February 2026 actual, ClinicalTrials.gov NCT04821622)","source":"https://clinicaltrials.gov/study/NCT04821622","refs":[{"id":"paper-nct04821622-n-engl-j-med-2026","kind":"paper","name":"PARP and Androgen-Signaling Inhibition plus ADT in Metastatic Prostate Cancer","route":"/key-papers/paper-nct04821622-n-engl-j-med-2026/","tldr":"Published report from the TALAPRO-3 trial registered as NCT04821622, in New England Journal of Medicine (2026), chosen as the most cited paper whose own text cites the registry id."},{"id":"nct04821622","kind":"trial","name":"Study of Talazoparib With Enzalutamide in Men With DDR Gene Mutated mCSPC","route":"/trials/nct04821622/","status":"active","tldr":"A phase 3 trial of Talazoparib and Enzalutamide in prostate cancer, run by Pfizer, active and no longer recruiting."},{"id":"idea-prostate-hrr-testing-at-metastatic-diagnosis","kind":"idea","name":"Test every man for DNA repair faults on the day his prostate cancer is found to have spread, not three treatments later","route":"/ideas/idea-prostate-hrr-testing-at-metastatic-diagnosis/","tldr":"About one man in eight with prostate cancer that has spread carries an inherited DNA repair fault, and about one in five has one in the tumour. The drugs for those faults have moved to the beginning of treatment, but the test is still usually done near the end, when it is too late to use the result."}]},{"item":"PROTEUS: perioperative apalutamide with androgen deprivation around radical prostatectomy in high-risk localised disease, the largest test of intensification before the operation","expected":"Primary completion 1 December 2026 and study completion 13 October 2028 (both estimated, ClinicalTrials.gov NCT03767244)","source":"https://clinicaltrials.gov/study/NCT03767244","refs":[{"id":"paper-nct03767244-n-engl-j-med-2026","kind":"paper","name":"Perioperative Apalutamide in High-Risk Localized Prostate Cancer","route":"/key-papers/paper-nct03767244-n-engl-j-med-2026/","tldr":"Published report from the PROTEUS trial registered as NCT03767244, in New England Journal of Medicine (2026), chosen as the most cited paper whose own text cites the registry id."},{"id":"nct03767244","kind":"trial","name":"A Study of Apalutamide in Participants With High-Risk, Localized or Locally Advanced Prostate Cancer Who Are Candidates for Radical Prostatectomy","route":"/trials/nct03767244/","status":"active","tldr":"A phase 3 trial of Apalutamide in prostate cancer, run by Janssen Research & Development, LLC, active and no longer recruiting."}]},{"item":"PEACE III: radium-223 with enzalutamide against enzalutamide alone in bone-metastatic castration-resistant disease, and the bone-protecting agent question it raised","expected":"Study completion December 2028 (estimated; primary completion 19 February 2024 actual, ClinicalTrials.gov NCT02194842)","source":"https://clinicaltrials.gov/study/NCT02194842","refs":[{"id":"paper-alsympca-radium-223-nejm-2013","kind":"paper","name":"ALSYMPCA: alpha emitter radium-223 and survival in metastatic prostate cancer with bone metastases","route":"/key-papers/paper-alsympca-radium-223-nejm-2013/","tldr":"Radium-223, an injected alpha-emitting radioisotope that homes to bone, lengthened survival and delayed skeletal complications in men with castration-resistant prostate cancer that had spread to bone but not to organs."},{"id":"paper-lutetium-177-vipivotide-tetrax-prostate-oncol-ther-2025","kind":"paper","name":"Sequencing of Radium-223 and Lutetium-177 Vipivotide Tetraxetan: Maximizing the Benefit of Systemic Targeted Radiation Therapy in Metastatic Castration-Resistant Prostate Cancer","route":"/key-papers/paper-lutetium-177-vipivotide-tetrax-prostate-oncol-ther-2025/","tldr":"Review on Lutetium-177 vipivotide tetraxetan in Prostate cancer, in Oncology and therapy (2025), one of the most cited Europe PMC records with Lutetium-177 vipivotide tetraxetan in its title."}]},{"item":"PSMA-DC: lutetium-177 vipivotide tetraxetan against observation in oligometastatic castration-sensitive disease detected on PSMA imaging, the test of whether a systemic radioligand can replace metastasis-directed treatment","expected":"Primary completion 25 April 2028 and study completion 3 October 2031 (both estimated, ClinicalTrials.gov NCT05939414)","source":"https://clinicaltrials.gov/study/NCT05939414","refs":[{"id":"nct05939414","kind":"trial","name":"An Open-label Study Comparing Lutetium (177Lu) Vipivotide Tetraxetan Versus Observation in PSMA Positive OMPC.","route":"/trials/nct05939414/","status":"recruiting","tldr":"A phase 3 trial of FAP-2286 in prostate cancer, run by Novartis Pharmaceuticals, now recruiting."},{"id":"paper-phillips-jama-oncol","kind":"paper","name":"Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial","route":"/key-papers/paper-phillips-jama-oncol/","tldr":"Paper cited by one idea page, indexed on Europe PMC as PubMed record 32215577 and published in JAMA Oncology; the citing page links this DOI, which is how the record was matched."},{"id":"idea-psma-pet-guided-mdt","kind":"idea","name":"PSMA-PET-guided metastasis-directed therapy as a curative strategy in oligorecurrent prostate cancer","route":"/ideas/idea-psma-pet-guided-mdt/","tldr":"When PSMA PET finds only a few spots after surgery, zap each spot with focused radiation and delay or avoid lifelong hormone therapy."}]},{"item":"STAMPEDE2: the successor platform, testing stereotactic radiotherapy to metastases, lutetium-177 PSMA-617 and niraparib with abiraterone against contemporary standard care, with 3,360 men planned","expected":"Primary completion April 2031 and study completion March 2032 (both estimated, ClinicalTrials.gov NCT06320067)","source":"https://clinicaltrials.gov/study/NCT06320067","refs":[{"id":"stampede","kind":"trial","name":"STAMPEDE","route":"/trials/stampede/","status":"positive","tldr":"STAMPEDE is the longest-running platform trial in oncology, and showed that both docetaxel and abiraterone extend life when started at first diagnosis of metastatic disease."},{"id":"paper-stampede-abiraterone-high-risk-attard-lancet-2022","kind":"paper","name":"STAMPEDE: abiraterone with or without enzalutamide added to androgen deprivation for high-risk non-metastatic prostate cancer","route":"/key-papers/paper-stampede-abiraterone-high-risk-attard-lancet-2022/","tldr":"Adding two years of abiraterone to hormone therapy and radiotherapy for high-risk localised or node-positive prostate cancer halved the risk of metastases and cut deaths by 40 percent, while adding enzalutamide on top brought only extra toxicity."},{"id":"idea-prostate-randomise-the-sequence-not-only-the-drugs","kind":"idea","name":"Randomise the order of treatment, not only the drugs: a strategy platform for metastatic prostate cancer","route":"/ideas/idea-prostate-randomise-the-sequence-not-only-the-drugs/","tldr":"Metastatic prostate cancer now has six classes of treatment that work, and no trial has ever compared the orders they can be given in. Every trial adds a drug to the front; none asks what should follow it, so the sequence a man receives is decided by habit and by what was licensed first."}]}]}