Treating itProstate cancer

Active surveillance, prostatectomy, or radiation ± ADT (duration guided by risk/ArteraAI).

ADT + ARPI ± docetaxel; PSMA PET staging; capivasertib if PTEN-deficient.

ARPI switch, PARP inhibitor combinations (HRR+), 177Lu-PSMA-617, docetaxel/cabazitaxel, radium-223.

Shared-decision PSA testing from 50 (45 if Black or family history/BRCA), risk-adapted intervals; MRI before biopsy; avoid biopsy if MRI negative and PSA density low.

Active surveillance (PSA, MRI, repeat biopsy) for Grade Group 1 and many favourable GG2; genomic classifier or ArteraAI to refine.

Radical prostatectomy (robotic) or radiotherapy (hypofractionated IMRT, SBRT, or brachytherapy boost) with 4-6 months (intermediate) to 18-36 months (high risk) of ADT; abiraterone added for very high risk (STAMPEDE); ArteraAI predicts ADT benefit.

PSMA PET to localise; salvage radiotherapy ± ADT after prostatectomy; metastasis-directed SBRT for oligorecurrence (investigational for survival); enzalutamide ± ADT for high-risk BCR (EMBARK).

ADT (GnRH agonist/antagonist, e.g., relugolix) + ARPI (abiraterone, enzalutamide, apalutamide, or darolutamide); add docetaxel for high-volume de novo disease (ARASENS, PEACE-1); add 177Lu-PSMA-617 if PSMA-positive (PSMAddition, approved 31 Jul 2026); capivasertib + abiraterone if PTEN-deficient (2026); prostate RT for low-volume disease.

Apalutamide, enzalutamide, or darolutamide (SPARTAN, PROSPER, ARAMIS); PSMA PET usually reclassifies as metastatic.

ARPI (if not used earlier); PARP inhibitor + ARPI for BRCA/HRR-mutant (olaparib-abiraterone, talazoparib-enzalutamide, niraparib-abiraterone); docetaxel; 177Lu-PSMA-617 after one ARPI before chemotherapy (PSMAfore); pembrolizumab if MSI-high.

177Lu-PSMA-617 post-taxane (VISION); cabazitaxel (CARD); radium-223 for bone-only symptomatic disease (with bone protection); 225Ac-PSMA, xaluritamig, pasritamig, mevrometostat in trials; platinum-etoposide for neuroendocrine transformation; tarlatamab/I-DXd trials for DLL3/B7-H3.

This is the decision the whole of prostate cancer turns on, and it is unusual because the three options are not ranked. NICE NG131 (1.3.8 to 1.3.12) writes one recommendation per Cambridge Prognostic Group: active surveillance is offered first at CPG 1, a choice between all three is offered at CPG 2, radical treatment is offered at CPG 3 with surveillance kept open for men who choose not to be treated immediately, and surveillance is not offered at CPG 4 and 5. If you were given a risk band instead of a number, the bridge is that CPG 1 is low risk, CPG 2 and 3 are intermediate risk and CPG 4 and 5 are high risk; the group is worked out from your Gleason score or grade group, your PSA and your T stage, and a UK pathology report carries the Gleason score and the grade group together. For CPG 1 to 3, NICE (1.3.7) sends the conversation to its box 2, which is a table of what happened to 100 men offered each option in the UK ProtecT trial, and the honest summary of that table is that survival was the same and the harms were not. On survival, box 2 reports that at 10 years, 98 out of 100 men offered monitoring, 99 out of 100 offered prostatectomy and 99 out of 100 offered radiotherapy had not died of prostate cancer, and that the evidence does not show a difference between them. At a median of 15 years the trial found death from prostate cancer in 17 of 545 men (3.1 percent) on monitoring, 12 of 553 (2.2 percent) after prostatectomy and 16 of 545 (2.9 percent) after radiotherapy, with the overall comparison not significant. What treatment changed was spread: metastases in 51 men (9.4 percent) on monitoring against 26 (4.7 percent) and 27 (5.0 percent), and clinical progression in 141 (25.9 percent) against 58 (10.5 percent) and 60 (11.0 percent). A quarter of the monitoring group, 133 men, were alive at the end of follow-up with no prostate cancer treatment of any kind. On continence, box 2 reports moderate to severe incontinence at 6 months in 19 out of 100 men offered prostatectomy against 4 on monitoring and 6 after radiotherapy, and at 6 years in 13, 8 and 5. The trial's own patient-reported figures are blunter: pad use went from 1 percent before treatment to 46 percent at 6 months after surgery, against 4 percent and 5 percent in the other two groups, and was still 17 percent at 6 years and 18 to 24 percent through years 7 to 12. On sexual function, box 2 reports moderate or severe erectile dysfunction at 6 months in 66 out of 100 men offered prostatectomy, 48 after radiotherapy and 29 on monitoring, and at 6 years in 50, 36 and 40. Of the men in the trial, 67 percent could get an erection firm enough for intercourse before anything was done; at 6 months that was 12 percent after surgery, 22 percent after radiotherapy and 52 percent on monitoring, and by year 12 all three groups had converged at a low level. On bowels, radiotherapy is the one that costs: moderate to severe impact of bowel habits on quality of life at 6 months in 10 out of 100 men offered radiotherapy against 3 in each other group, and faecal leakage in 12 percent of the radiotherapy group against 6 percent of the others by year 12. Nothing in this row is a prediction about one man. It is what happened to 1,643 UK men aged 50 to 69 with mostly CPG 1 to 3 disease, and the reason to read it is that it names the trade-off rather than gesturing at it. NICE surrounds the choice with process: a decision aid in the clinic (1.1.6), nomograms with their limits explained (1.1.7), all relevant options discussed even when the local service does not offer them (1.1.9), an assessment by both a specialist surgical oncologist and a specialist clinical oncologist (1.3.5), and an explicit conversation about sexual function, physical appearance, continence and other aspects of masculinity with the man and, if he wishes, his partner (1.1.12).

Choosing radiotherapy is choosing a schedule and a course of hormone therapy at the same time, and men are often surprised by the second part. On the schedule, NICE NG131 (1.3.19) says to offer hypofractionated radiotherapy, 60 Gy in 20 fractions, using image-guided intensity modulated radiation therapy unless contraindicated, with conventional radiotherapy, 74 Gy in 37 fractions, reserved for people who cannot have the shorter course. Twenty visits over four weeks is therefore the standard rather than a lesser version of it. NG131 (1.3.24) says to consider adding a brachytherapy boost, where radioactive sources are placed in the prostate itself, for CPG 2 to 5, and (1.3.25) not to offer brachytherapy alone at CPG 4 and 5, so whether a boost is available is a question about the centre. On the hormone therapy, NG131 (1.3.21) says to offer radical radiotherapy combined with androgen deprivation therapy rather than either alone for CPG 2, 3, 4 and 5, (1.3.22) six months of it before, during or after the radiotherapy, and (1.3.23) to consider continuing for up to 3 years at CPG 4 and 5 while discussing the benefits and risks of that with the person. This matters because almost everything men describe afterwards as the effect of radiotherapy is the effect of the hormone therapy: the hot flushes, the loss of sex drive, the weight around the waist, the tiredness. The radiotherapy's own signature is in the bowel and the bladder in the weeks around treatment, and in the small late risks: NG131 (1.3.6) asks that people are told about the small increase in the risk of colorectal cancer after radical external beam radiotherapy, and (1.3.42) that anyone with signs of radiation-induced enteropathy is cared for by a team with expertise in it. For high-risk disease starting long-term hormone therapy, NG131 (1.3.26) asks for a separate discussion about adding six cycles of docetaxel, with box 3 setting out both sides plainly: clear evidence that progression is delayed by about a year, a five-year survival difference of 84 against 80 out of 100 that might be chance, and 15 out of 100 developing a fever from a low white count with 1 in 100 dying of an infection they might not otherwise have had.

Hormone therapy is the longest part of this illness for most men and the least well covered. It works by taking testosterone away, and testosterone was doing a great many other things. The effects last for as long as the treatment does, and Prostate Cancer UK says that after stopping it can take several months to several years for them to settle, while an orchidectomy cannot be reversed at all. Hot flushes are the commonest complaint: NICE NG131 (1.4.3) says to offer medroxyprogesterone 20 mg a day for an initial 10 weeks and to evaluate the effect at the end, and (1.4.4) to consider cyproterone acetate 50 mg twice a day for 4 weeks if that fails or is not tolerated; in a randomised trial of 309 men the median daily hot-flush score fell by 83.7 percent on medroxyprogesterone and 94.5 percent on cyproterone at one month, against 47.2 percent on venlafaxine. NG131 (1.4.5) also says plainly that there is no good-quality evidence for complementary therapies here. Bone thinning starts in the first year and increases with time on treatment: in 50,613 men, 19.4 percent of those on androgen deprivation surviving at least five years had a fracture against 12.6 percent of those not on it. NICE's four bone sentences run in a specific order: (1.4.12) do not routinely offer bisphosphonates to prevent osteoporosis, (1.4.13) consider assessing fracture risk, (1.4.14) offer bisphosphonates to those who have osteoporosis, and (1.4.15) consider denosumab where bisphosphonates are contraindicated or not tolerated. A DEXA scan is how the question is answered. On the heart and the metabolism, in 73,196 Medicare enrollees GnRH agonist use carried adjusted hazard ratios of 1.44 for new diabetes, 1.16 for coronary heart disease, 1.11 for myocardial infarction and 1.16 for sudden cardiac death; in the HERO trial, major adverse cardiovascular events occurred in 2.9 percent of 622 men on oral relugolix against 6.2 percent of 308 on leuprolide over 48 weeks. Prostate Cancer UK suggests general health checks roughly every six months: weight, blood pressure, cholesterol and a diabetes check. Body composition changes: muscle goes, fat arrives, particularly at the waist, and joint and muscle aches follow. NICE NG131 (1.4.18) says to tell people that fatigue is a recognised effect of the therapy and might not be the cancer, and (1.4.19) to offer supervised resistance and aerobic exercise at least twice a week for 12 weeks to reduce fatigue and improve quality of life, which is the single most concrete offer in this section. On mood, Prostate Cancer UK says hormone therapy itself can cause tearfulness, mood swings, low mood, anxiety and depression, and a meta-analysis of 18 studies in 168,756 men found a 41 percent higher risk of depression on androgen deprivation. Memory and concentration change too, though the evidence for a direct cause is weak. Gynaecomastia has its own answer: NG131 (1.4.16) says to offer prophylactic radiotherapy to both breast buds within the first month for people starting long-term bicalutamide monotherapy, a single 8 Gy fraction, with weekly tamoxifen considered if that does not work. And where treatment is long-term and not adjuvant, NG131 (1.4.1) says to consider intermittent therapy, discussing the limited evidence for a reduction in side effects and the effect on progression, with PSA measured every 3 months and treatment restarted at 10 nanogram/ml or above.

These are the two things men do not raise, so this page raises them first. On continence: most men leak when the catheter comes out after a prostatectomy, usually seven to ten days after the operation, because the operation disturbs the sphincter and the pelvic floor. It improves. In ProtecT, pad use after surgery was 46 percent at six months and 17 percent at six years; radiotherapy barely touched continence at 4 to 5 percent. What helps, in the order the guideline puts it: pelvic floor muscle exercises, started four to six weeks before the operation and restarted as soon as the catheter is out; absorbent pads and pants, sheaths, bed protectors and clamps while things settle; bladder retraining for urgency; and, where it does not settle, medicines, an internal male sling for men leaking two to three pads a day at a year, or an artificial urinary sphincter for men still leaking heavily six months on. NICE NG131 (1.3.39) requires access to specialist continence services, (1.3.40) referral for consideration of an artificial urinary sphincter for intractable stress incontinence, and (1.3.41) rules out bulking agent injections. On sexual function: the numbers are in the first row of this page and they are not gentle. What is worth knowing is that the services exist and that starting early works better. NICE NG131 (1.3.36) says to offer access to specialist erectile dysfunction services after radical treatment, (1.3.37) to offer PDE5 inhibitor tablets, and (1.3.38) to offer vacuum devices, intraurethral inserts, penile injections or a penile prosthesis where tablets fail or are contraindicated; (1.4.8) extends the same access to men starting hormone therapy and (1.4.10, 1.4.11) repeats the ladder for them. All of it is free on the NHS whether the erection is wanted for sex or for masturbation, and there is no age limit. Prostate Cancer UK says to try each type of tablet at least eight times before moving on, that injections work within 5 to 10 minutes and often work even when desire is low, that about 3 in 100 implants get infected and roughly 5 in 100 inflatable implants need replacing within ten years, and that an erection lasting more than four hours is priapism and means going straight to accident and emergency. Two other things men are rarely told: the penis can become shorter or curved after surgery, and using a vacuum pump early, alone or with tablets, may help preserve it; and orgasm survives even when ejaculation does not, though it feels different, and some men leak urine at orgasm, which pelvic floor exercises help. Beside all of this NICE NG131 (1.1.13) offers the man and his partner the chance to talk to a healthcare professional experienced in psychosexual issues at any stage, and (1.4.9) considers psychosexual counselling for couples on long-term hormone therapy. Taking that offer is not an admission of anything.

After radical treatment the PSA becomes the thing everyone watches, and the waiting for each result has its own name in the clinic. NICE NG131 (1.3.47) says to check it no earlier than 6 weeks after treatment, then at least every 6 months for the first 2 years and at least once a year after that, and (1.3.48) not to do a routine rectal examination while it stays at baseline; (1.3.49) allows remote follow-up after the first 6 months for people with a stable PSA and no significant complications, which for many men means a blood test locally and a phone call. The most useful sentence in the guideline for anyone watching a number go up is (1.3.55): a rising PSA alone should not mean an immediate change in treatment. What matters is the speed, so (1.3.56) asks for the doubling time to be estimated from at least three measurements over at least six months. After a prostatectomy with no known metastases the standard answer is radiotherapy to the prostate bed (1.3.57), often still given with the aim of cure. NG131 (1.3.54) says not to offer routine MRI before salvage radiotherapy but to offer an isotope bone scan if symptoms or PSA trends suggest metastases, and (1.3.58) to consider entry to a clinical trial; in practice a PSMA PET scan is now what localises the disease, and this record covers that in its imaging rows. Hormone therapy is deliberately held back: (1.3.59) says not to offer it routinely for biochemical relapse unless there is symptomatic local progression, proven metastases, or a doubling time of less than three months, which is the guideline protecting men from years of side effects for a number rather than a disease. Where the risk is high, the EMBARK trial is the evidence for adding enzalutamide at this point, and that is a conversation for the multidisciplinary team rather than a default.

Prostate cancer goes to bone more reliably than almost any other cancer, and the emergency that follows is the one men are least often warned about. Metastatic spinal cord compression happens when deposits in or near the spine press on the spinal cord, and Prostate Cancer UK says about 4 in 100 people with prostate cancer develop it, with the risk highest once the cancer has reached the spine. Untreated it causes nerve damage and can cause paralysis; treated quickly, the risk of that being permanent falls. The signs are worth learning by heart: new, severe or progressive back or neck pain, pain worse on coughing, straining, lying down or at night, tenderness over the spine, a band of pain around the chest or abdomen, pain running down an arm or leg, weakness or unsteadiness in the legs, numbness or pins and needles that does not go away, and any loss of control of the bladder or bowel. NICE NG234 (1.3.2) says to immediately contact the metastatic spinal cord compression coordinator for anyone with a past or current cancer diagnosis and those signs, and to treat it as an oncological emergency; (1.3.3) asks for advice within 24 hours for the pain pattern alone; (1.5.2) asks for an MRI as soon as possible and always within 24 hours; and (1.4.1 to 1.4.3) ask for immobilisation and nursing flat while that is arranged. Prostate Cancer UK adds the practical instruction: do not wait to see if it settles, do not worry that it is the evening or the weekend, ask the team in advance to write down who to contact during the day, at night and at weekends, and if you cannot reach anyone, go to A and E and tell them you have prostate cancer and symptoms of spinal cord compression, because not everyone who sees you will be familiar with it. Alongside the emergency sits the ordinary work of protecting a skeleton. NICE NG131 (1.5.19) says to consider zoledronic acid to prevent or reduce skeletal-related events in hormone-relapsed metastatic disease and (1.5.20) bisphosphonates for pain where painkillers and palliative radiotherapy have not been enough; (1.3.35) says not to offer bisphosphonates to prevent bone metastases developing, and (1.4.12) not to offer them routinely to prevent osteoporosis on hormone therapy. Those are three different questions and NICE gives them three different answers, which is why a single yes or no about bone drugs usually means the wrong question was asked. Radium-223 remains an option for symptomatic bone-only disease that is no longer responding to hormone therapy, with bone protection alongside. A word about words: NICE calls that state hormone-relapsed prostate cancer, many hospitals and papers call it castration-resistant or castrate-resistant, and the three mean the same thing, which is prostate cancer that has started growing again despite testosterone being switched off.

Prostate cancer has an unusually full trial landscape, because the number of things worth testing keeps growing: radioligands moving earlier in the disease, PARP inhibitor and AR-pathway combinations selected by genetics, T-cell engagers against STEAP1 and KLK2, and, at the other end, trials of how to monitor low-risk disease with fewer biopsies. NICE NG131 names trials at several points rather than as a last resort: (1.3.28) says high-intensity focused ultrasound and cryotherapy should be used for localised disease only in controlled trials comparing them with established treatments, which is the answer to give when a focal treatment is offered privately; (1.3.32 and 1.3.33) say the same about immediate post-operative radiotherapy and adjuvant hormone therapy after prostatectomy; (1.3.58) says to consider trial entry for biochemical relapse; and (1.2.5) restricts mapping transperineal template biopsy at initial assessment to trials. The practical questions are the ordinary ones. The NHS says you can ask your doctor or a patient organisation about trials you may be eligible to join, that you would usually be randomly assigned to the new treatment or to a control group, and that you can leave at any point without giving a reason and without it affecting your care. Worth asking as well: whether taking part means travelling, how many extra scans and biopsies it involves, whether the trial covers travel costs, and what happens to your treatment when the trial ends.

Palliative care in prostate cancer is often needed for years rather than weeks, because men live a long time with metastatic disease, and the guideline treats it that way. NICE NG131 (1.5.4) says to ensure palliative care is available when needed and is not limited to the end of life, and that care should not be restricted to being associated with hospice care. NG131 (1.5.1) asks for tailored information and access to specialist urology and palliative care teams from the point of a metastatic diagnosis, (1.5.2) for palliative interventions to be integrated at any stage into coordinated care with smooth transitions between settings, (1.5.3) for personal preferences and the preferred place of care to be discussed as early as possible with the man, his partner and his carers, and (1.5.5) for a regular assessment of needs rather than waiting to be asked. In practice this is the team that manages bone pain, fatigue, bowel and bladder symptoms, the fear that arrives with each PSA result, and the conversations nobody else starts. Marie Curie says palliative care can be given alongside treatments aimed at controlling the illness, which is the sentence to quote if a referral feels like a verdict. Alongside it sit the things that keep a life working: Maggie's centres, which are free and need no appointment; Prostate Cancer UK's specialist nurses, one-to-one peer support and online community; a carer's assessment, which is free and is for the person doing the caring rather than the patient; and help with money and work, which is easier to arrange early than late.

Active surveillance, with PSA, multiparametric MRI and repeat biopsy, is the standard and not a compromise. ProtecT randomised 1,643 men with PSA-detected localised disease and found prostate cancer mortality at 15 years of 3.1 percent under monitoring, 2.2 percent after prostatectomy and 2.9 percent after radiotherapy (p=0.53), while 24.4 percent of monitored men were alive at the end of follow-up having never had any treatment. Treatment halves metastasis (9.4 percent monitored against 4.7 and 5.0 percent) but the base rate is low. PIVOT, in a largely PSA-detected United States population, found no significant mortality benefit from surgery over observation at nearly 20 years and more incontinence and erectile dysfunction through 10 years. Padeliporfin vascular-targeted photodynamic therapy is licensed for this population but NICE TA546 does not recommend it.

Radical prostatectomy and radical radiotherapy give the same cancer outcome and different side-effect shapes; ProtecT's patient-reported outcomes are the best guide to which. If radiotherapy is chosen, moderate hypofractionation is standard: CHHiP found 60 Gy in 20 fractions non-inferior to 74 Gy in 37 (5-year freedom from failure 90.6 against 88.3 percent), PROFIT found 60 Gy in 20 non-inferior to 78 Gy in 39 (85 percent in both arms) and RTOG 0415 found 70 Gy in 28 non-inferior to 73.8 Gy in 41 in low-risk disease. Five-fraction stereotactic body radiotherapy is non-inferior again (PACE-B, 5-year freedom from failure 95.8 against 94.6 percent) at the price of more late grade 2 or higher genitourinary toxicity (26.9 against 18.3 percent). Four to six months of androgen deprivation is added: RTOG 94-08 found 4 months raised 10-year overall survival from 57 to 62 percent, with the benefit confined to intermediate-risk men, and EORTC 22991 found 6 months halved biochemical failure at every radiation dose tested.

Radiotherapy plus long-course androgen deprivation, not either alone. SPCG-7 halved 10-year prostate cancer mortality by adding radiotherapy to hormones (11.9 against 23.9 percent) and the NCIC PR.3/MRC PR07 intergroup trial confirmed it in 1,205 men (overall survival hazard ratio 0.70). EORTC 22863 showed the reverse addition works too, raising 10-year overall survival from 39.8 to 58.1 percent. Duration is three years, not six months: EORTC 22961 failed to show non-inferiority for 6 months (5-year mortality 19.0 against 15.2 percent, hazard ratio 1.42), RTOG 92-02 found 28 months better than 4 on every endpoint and better for survival in Gleason 8 to 10 disease (45.1 against 31.9 percent at 10 years), and DART 01/05 GICOR found the same even at radiation doses above 76 Gy. A low-dose-rate brachytherapy boost doubles freedom from biochemical failure at 9 years (83 against 62 percent, ASCENDE-RT) without a survival difference. Adding abiraterone for two years improved 6-year metastasis-free survival from 69 to 82 percent in the STAMPEDE non-metastatic comparison; adding docetaxel improved 4-year overall survival from 89 to 93 percent in RTOG 0521.

An observation policy with early salvage radiotherapy triggered by a rising PSA, not adjuvant radiotherapy. RADICALS-RT (1,396 men), RAVES (333) and GETUG-AFU 17 (424) all found the same, and the prospectively planned ARTISTIC meta-analysis of all 2,153 gave an event-free survival hazard ratio of 0.95 (95 percent confidence interval 0.75 to 1.21), a 1 percentage point difference at 5 years. The gain is in what is avoided: only 33 percent of the RADICALS-RT observation group needed radiotherapy within 8 years, and adjuvant treatment caused more incontinence at 1 year and more grade 3 to 4 urethral stricture (6 against 4 percent). GETUG-AFU 17 measured the same harm larger: late grade 2 or worse genitourinary toxicity 27 against 7 percent and erectile dysfunction 28 against 8 percent. When salvage radiotherapy is given, add androgen deprivation: GETUG-AFU 16 raised 120-month progression-free survival from 49 to 64 percent with 6 months of goserelin, SPPORT raised 5-year freedom from progression from 70.9 to 81.3 percent by adding short-term androgen deprivation and to 87.4 percent by adding pelvic nodal radiotherapy as well, and RADICALS-HD found 24 months better than 6 (10-year metastasis-free survival 78.1 against 71.9 percent) at the cost of more grade 3 toxicity (19 against 14 percent).

Androgen deprivation plus at least one of an androgen receptor pathway inhibitor and docetaxel. Docetaxel: CHAARTED found median overall survival 57.6 against 44.0 months (hazard ratio 0.61) with the benefit concentrated in high-volume disease, and the STAMPEDE docetaxel comparison agreed; GETUG-AFU 15, with 385 men, was the underpowered exception. Androgen receptor pathway inhibitors: abiraterone in LATITUDE and STAMPEDE (hazard ratio for death 0.63 in STAMPEDE's 1,917 men), apalutamide in TITAN (24-month overall survival 82.4 against 73.5 percent, hazard ratio 0.67), enzalutamide in ARCHES and ENZAMET, darolutamide in ARANOTE. Triplets for fit men with de novo high-volume disease: ARASENS added darolutamide to docetaxel and androgen deprivation, PEACE-1 added abiraterone. For low-volume metastatic disease, radiotherapy to the prostate improved survival in the prespecified subgroup of the STAMPEDE radiotherapy comparison. Castration itself can be delivered orally with relugolix (NICE TA995) or, in trials, by transdermal oestradiol patches, which give fewer hot flushes (35 against 86 percent) and better bone density with no excess cardiovascular events. Continuous, not intermittent: SWOG 9346 could not exclude a 20 percent higher risk of death with treatment breaks.

Apalutamide or darolutamide added to continuing androgen deprivation, for men whose PSA doubling time is 10 months or less. SPARTAN (1,207 men) found median metastasis-free survival 40.5 against 16.2 months with apalutamide (hazard ratio 0.28), and PROSPER and ARAMIS found the same size of effect with enzalutamide and darolutamide. The cost is measurable: in SPARTAN, rash 23.8 against 5.5 percent, hypothyroidism 8.1 against 2.0 percent and fracture 11.7 against 6.5 percent. In England NICE TA740 recommends apalutamide and TA660 darolutamide here; NICE TA580 does not recommend enzalutamide, so one of the three licensed options is not routinely funded. The whole setting is shrinking: men called non-metastatic on CT and bone scan are frequently metastatic on PSMA PET, and the three trials that defined it used conventional imaging.

An androgen receptor pathway inhibitor if none has been used (COU-AA-302, PREVAIL before chemotherapy; COU-AA-301, AFFIRM after docetaxel); docetaxel with prednisone (TAX 327, median survival 18.9 against 16.5 months against mitoxantrone, with pain relief in 35 against 22 percent); cabazitaxel after docetaxel (TROPIC, 15.1 against 12.7 months; PROSELICA showed 20 mg/m2 is non-inferior to 25 with grade 3 or 4 events in 39.7 against 54.5 percent); olaparib for BRCA-mutated disease after a newer hormonal treatment (NICE TA887; TRITON3 shows the effect is BRCA-dependent and absent in ATM-altered disease); lutetium-177 PSMA radioligand therapy (VISION, TheraP, PSMAfore, but NICE TA930 does not recommend it in England); radium-223 for symptomatic bone-predominant disease without visceral metastases (ALSYMPCA, NICE TA412, only after or instead of docetaxel), now with an overall survival benefit in combination with enzalutamide when bone-protecting agents are given (PEACE-3, 38.2 against 32.6 months). The one hard sequencing rule comes from CARD: after rapid failure of one androgen receptor pathway inhibitor, cabazitaxel beats switching to the other (imaging-based progression-free survival 8.0 against 3.7 months, overall survival 13.6 against 11.0 months).

Checkpoint inhibitors in unselected men do not work: IMbassador250, KEYNOTE-641, KEYNOTE-921, KEYNOTE-991 and CA184-043 between them randomised more than 5,000 men and none improved survival. Anti-angiogenic drugs do not work: CALGB 90401 with bevacizumab and COMET-1 with cabozantinib both improved progression endpoints and neither improved survival, and bevacizumab quadrupled treatment-related deaths (4.0 against 1.2 percent). Endothelin A antagonists do not work: SWOG S0421 and ENTHUSE M1 were both flatly negative. Radium-223 must not be combined with abiraterone without bone protection: ERA 223 found fractures in 29 against 11 percent and no benefit. Two drugs improved radiographic progression-free survival substantially and did nothing for survival, orteronel in ELM-PC 4 and tasquinimod in 10TASQ10, which is why an imaging endpoint alone is not accepted here.