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Prostate cancer is where hormone therapy for cancer was invented, in 1941, and where a blood test created an epidemic of diagnoses forty-five years later. This roadmap follows the evidence from castration to the modern androgen receptor drugs, through the screening trials and the argument about overdiagnosis they started, to DNA repair, PSMA and the questions still open in 2032.
In 1941 Charles Huggins and Clarence Hodges castrated men with advanced prostate cancer and watched the disease regress. It was the first demonstration that any human cancer depends on a circulating hormone, and it is still the backbone of treatment: every man who starts androgen deprivation is repeating the experiment. What followed was a long argument about how to do the same thing better, and it turned out that castration resistance is not the cancer ignoring the hormone but adapting to live on less of it. Visakorpi found amplified androgen receptor in a third of recurrent tumours in 1995; Chen showed in 2004 that receptor overexpression alone converts sensitive disease to resistant and turns antagonists into agonists; Attard's 2008 phase 1 of abiraterone proved the point in people, and enzalutamide, built to the specification Chen described, followed.
The other half of the story is detection. Stamey described prostate-specific antigen as a marker in 1987 and Catalona made it a screening test in 1991, with the 4.0 threshold still on laboratory reports today. Testing spread through primary care before any trial had asked whether it saved lives. When the trials reported in 2009 they disagreed: ERSPC found a 20 percent reduction in prostate cancer mortality at a cost of 1,410 men screened and 48 extra cancers treated per death prevented, and PLCO found nothing, largely because half its control group was being screened anyway. Welch and Albertsen counted what had happened in the meantime: 1.3 million extra American men diagnosed and about a million treated. The United States task force recommended against screening in 2012 and partly reversed itself in 2018.
Treatment moved in the 2000s and then very fast in the 2010s. Docetaxel in 2004 was the first drug to extend survival in castration-resistant disease; cabazitaxel opened the second line in 2010; abiraterone and enzalutamide moved from post-chemotherapy to pre-chemotherapy and then, through CHAARTED, STAMPEDE, LATITUDE, TITAN, ENZAMET, ARASENS and PEACE-1, to the first day of metastatic diagnosis. The genome was mapped in parallel: the TMPRSS2-ERG fusion in 2005, the TCGA taxonomy and the SU2C metastatic cohort in 2015, and the finding that made the biggest practical difference, DNA repair gene alterations in about a fifth of advanced tumours, with 11.8 percent of men carrying an inherited one whatever their family history. PARP inhibitors followed, and PSMA, a protein on the surface of almost every prostate cancer cell, became first an imaging target and then a way of delivering radiation to it.
What has not been solved is stated plainly in the open problems on the prostate cancer page. Overdiagnosis is real and unquantified to within a factor of thirty. Nobody knows in what order to give the treatments that now exist. Resistance arrives for all of them, and in a minority the cancer stops being prostate cancer in any recognisable sense and becomes neuroendocrine, for which there is nothing. And a disease that mostly affects older men has its biggest remaining mortality gap in the causes of death that are not cancer.
UK and NHS specifics (the National Screening Committee position, NICE technology appraisals and their recommendation numbers, Cancer Drugs Fund status, magnetic resonance imaging and radiotherapy capacity, National Prostate Cancer Audit indicators and trial access) belong on the UK and NHS page for prostate cancer and are not restated here.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
Every era's records, trial outcomes and papers, and every watch item, as JSON.
Probability ranges are named estimates that the claim is borne out on roughly a five-year horizon. They are meant to be argued with: propose a revision with your name and reasoning via a pull request to src/data/confidence.ts.
Readouts, decisions and registry completion dates ahead. Each date is quoted from its source, not inferred; a missing date means no source states one.
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The 48 most recent of 72 papers; see them all →
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.
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.
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.
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.
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.
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.
This is the paper Europe PMC returns for registry id ISRCTN94604465 with the most citations, so it is the natural first reading for anyone following the 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.
One pairing 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.
Shares Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate, SWOG 9916: docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer, Abiraterone in metastatic prostate cancer without previous chemotherapy, USPSTF 2012: screening for prostate cancer, recommendation statement (grade D).
Shares In vivo amplification of the androgen receptor gene and progression of human prostate cancer, Huggins and Hodges 1941: the effect of castration, of oestrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate, SWOG 9916: docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer, Abiraterone in metastatic prostate cancer without previous chemotherapy.
Shares In vivo amplification of the androgen receptor gene and progression of human prostate cancer, Huggins and Hodges 1941: the effect of castration, of oestrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate, Destroy the truncated androgen receptor that hormone drugs cannot touch, Abiraterone in metastatic prostate cancer without previous chemotherapy.
Shares A 16-yr Follow-up of the European Randomized study of Screening for Prostate Cancer, Prostate Cancer Screening with PSA and MRI Followed by Targeted Biopsy Only, Measurement of prostate-specific antigen in serum as a screening test for prostate cancer, Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context.
Shares Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction, Association of Black race with prostate cancer-specific and other-cause mortality, SPCG-4: radical prostatectomy or watchful waiting in prostate cancer, 29-year follow-up, SWOG 9346: intermittent versus continuous androgen deprivation in metastatic prostate cancer.
Shares PRECISION: MRI-targeted or standard biopsy for prostate cancer diagnosis, Prostate Cancer Screening with PSA and MRI Followed by Targeted Biopsy Only, Prostate active surveillance without scheduled biopsies: MRI and blood tests decide, MRI-first prostate screening with genetic pre-selection.
Shares USPSTF 2012: screening for prostate cancer, recommendation statement (grade D), Measurement of prostate-specific antigen in serum as a screening test for prostate cancer, Prostate cancer diagnosis and treatment after the introduction of prostate-specific antigen screening, 1986 to 2005, Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context.
Shares USPSTF 2012: screening for prostate cancer, recommendation statement (grade D), Prostate cancer diagnosis and treatment after the introduction of prostate-specific antigen screening, 1986 to 2005, Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context, SPCG-4: radical prostatectomy or watchful waiting in prostate cancer, 29-year follow-up.