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Once prostate cancer stops responding to standard hormone therapy there are six or seven things left to try, and the order matters. The one rule proved by a trial is that swapping one hormone tablet for another, after the first stopped working quickly, is a waste of time.
The drugs available after castration resistance, each with the trial that established it: an androgen receptor pathway inhibitor if none has been used (COU-AA-302 for abiraterone before chemotherapy, PREVAIL for enzalutamide, COU-AA-301 and AFFIRM after docetaxel); docetaxel (TAX 327 and SWOG 9916); cabazitaxel after docetaxel (TROPIC, and PROSELICA for the lower dose); a PARP inhibitor if there is a BRCA alteration (PROfound, TRITON3, and PROpel, MAGNITUDE and TALAPRO-2 in combination); lutetium-177 PSMA radioligand therapy (VISION after taxane, TheraP against cabazitaxel, PSMAfore before taxane); radium-223 for bone-predominant disease (ALSYMPCA, and PEACE-3 in combination with enzalutamide); and pembrolizumab for the roughly 3 percent with mismatch repair deficiency.
The one hard rule. CARD randomised 255 men who had received docetaxel and progressed within 12 months on abiraterone or enzalutamide to cabazitaxel or to the other androgen receptor pathway inhibitor. Cabazitaxel gave imaging-based progression-free survival of 8.0 against 3.7 months (hazard ratio 0.54, 95 percent confidence interval 0.40 to 0.73, p<0.001) and overall survival of 13.6 against 11.0 months (0.64, 0.46 to 0.89, p=0.008), with PSA response in 35.7 against 13.5 percent. Grade 3 or higher adverse events were 56.3 against 52.4 percent, so the chemotherapy was not materially more toxic. After rapid failure of one androgen receptor pathway inhibitor, do not switch to the other.
TheraP makes the same point for the radioligand: in men selected by PSMA PET and FDG PET after docetaxel, lutetium-177 PSMA-617 beat cabazitaxel on PSA response. VISION beat standard care after both a taxane and an androgen receptor pathway inhibitor. PSMAfore moved the radioligand before chemotherapy against an androgen receptor pathway inhibitor switch, which CARD had already shown to be a weak comparator.
What decides the order in practice: whether the cancer has a BRCA alteration, whether the disease is PSMA-avid enough on a PET scan, whether the man is fit for chemotherapy, whether disease is confined to bone, and in England whether the drug is funded. That last constraint is real and is not the same as the label; see `prostate-uk-drug-approvals`.
What is not known. Nobody has run a randomised trial of PARP inhibitor before against after a taxane, or of radioligand therapy before against after chemotherapy in the same men, or of what to do after lutetium-177 PSMA fails. Actinium-225 PSMA agents, PSMA-directed T-cell engagers and EZH2 inhibitors are the candidates being tested for that last slot.
Showing the technology this term belongs to: Androgen deprivation & AR pathway inhibitors.
Shares PROSELICA, TROPIC, TAX 327, Cabazitaxel.
Shares ALSYMPCA, PEACE-3 (EORTC 1333), Radium-223 dichloride, Targeted alpha therapy.
Shares ALSYMPCA, PSMAfore, VISION, Lutetium-177 vipivotide tetraxetan.
Shares PROSELICA, COU-AA-301, PREVAIL, AFFIRM.
Shares ALSYMPCA, Radium-223 dichloride, Cabazitaxel, Androgen receptor pathway inhibitor (ARPI).
Shares PREVAIL, AFFIRM, Androgen receptor pathway inhibitor (ARPI), Castration-resistant prostate cancer (CRPC).
Shares COU-AA-302, Androgen receptor pathway inhibitor (ARPI), Castration-resistant prostate cancer (CRPC), Androgen deprivation & AR pathway inhibitors.
Shares PSMAfore, VISION, Lutetium-177 vipivotide tetraxetan, PSMA PET.