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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.
Each of the classes was licensed against placebo or against an older drug, in a population defined by what it had already received: docetaxel against mitoxantrone, cabazitaxel after docetaxel, abiraterone and enzalutamide before and after chemotherapy, radium-223 in bone-predominant disease, lutetium-177 PSMA-617 after an androgen receptor drug and a taxane, and PARP inhibitors after progression on an androgen receptor drug. Intensification trials then moved several of them to the first day of metastatic diagnosis. What no trial has done is randomise the order.
That the order matters is not speculation. TRANSFORMER found identical progression-free survival on its primary endpoint and a difference of 8.6 months in progression-free survival through crossover depending on which arm came first, with a hazard ratio of 0.44. The same trial found prostate-specific antigen progression-free survival on enzalutamide was 3.8 months when it followed abiraterone and 10.9 months when it followed bipolar androgen therapy. CARD showed that switching from one androgen receptor drug to the other is worse than moving to cabazitaxel. The proposal is a standing platform in which the randomisation unit is a strategy rather than an agent, with progression-free survival through the second line as a co-primary endpoint alongside overall survival, and with re-randomisation at each progression. ProBio, which randomises by biomarker signature and adapts on outcome, is the nearest existing design; STAMPEDE2 has the infrastructure.
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.
Two years of abiraterone with androgen deprivation and radiotherapy is the standard for very high-risk and node-positive localised prostate cancer.
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).
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.
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.
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.
Shares Rotate between drugs on a fixed schedule instead of waiting for failure, AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer, TRANSFORMER: bipolar androgen therapy versus enzalutamide in asymptomatic metastatic castration-resistant prostate cancer, Bipolar androgen therapy (BAT) and the tag prostate-evidence.
Shares Rotate between drugs on a fixed schedule instead of waiting for failure, TRANSFORMER: bipolar androgen therapy versus enzalutamide in asymptomatic metastatic castration-resistant prostate cancer, Bipolar androgen therapy (BAT), Too many combinations to test and the tag prostate-evidence.
Shares Metastasis-free survival (MFS), Radiographic progression-free survival (rPFS), Too many combinations to test, Enzalutamide and the tag prostate-evidence.
Shares AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer, Bipolar androgen therapy (BAT), Enzalutamide, 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 and the tag prostate-evidence.
Shares TROPIC: prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel, Radiographic progression-free survival (rPFS), Enzalutamide, 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 and the tag prostate-evidence.
Shares Radiographic progression-free survival (rPFS), Abiraterone acetate, Enzalutamide, 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 and the tag prostate-evidence.
Shares TROPIC: prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel, 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, Acquired resistance to every therapy, Docetaxel and the tag prostate-evidence.
Shares TRANSFORMER: bipolar androgen therapy versus enzalutamide in asymptomatic metastatic castration-resistant prostate cancer, Metastatic hormone-sensitive prostate cancer, 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, Trial design, endpoints and cost and the tag prostate-evidence.