At the European Association of Urology (EAU) Annual Meeting 2025, Dr. Bertrand Tombal explored a challenging clinical scenario faced by many oncologists: managing metastatic castration-resistant prostate cancer (mCRPC) progression after initial triplet therapy for metastatic hormone-sensitive prostate cancer (mHSPC). Specifically, the presentation discussed whether a second androgen receptor pathway inhibitor (ARPI), such as abiraterone or enzalutamide, should be considered when initial therapy fails.

Currently, ARPIs are central in prostate cancer management, but responses to a second ARPI after initial progression are generally limited and transient. The PLATO trial notably showed that combining abiraterone and enzalutamide after progression yielded minimal responses, with only 1-2% of patients achieving significant PSA reductions.

Further research indicates that treatment sequencing matters. A phase II trial suggested modest improvements when abiraterone was followed by enzalutamide compared to the opposite sequence, although overall responses remained limited regardless of order. Consequently, current clinical guidelines advise against routinely using a second ARPI upon progression due to limited effectiveness.

Instead, recommended treatments include chemotherapy (cabazitaxel), PARP inhibitors, ¹⁷⁷Lu-PSMA-617 (LuPSMA), or radium-223. These alternatives typically offer more robust responses and survival benefits.

However, Dr. Tombal discussed intriguing results from the PSMAfore trial, revealing what he termed the “PSMAfore paradox.” The trial compared LuPSMA therapy with an ARPI switch in chemotherapy-naïve mCRPC patients, finding improved progression-free survival but no significant overall survival difference. This outcome suggests that, in specific cases, transitioning to a second ARPI might delay the need for more aggressive treatments without significantly compromising patient outcomes.

In conclusion, while second ARPIs generally offer limited efficacy following triplet therapy failure, carefully selected patients—especially those initially treated with abiraterone—may benefit from temporarily switching to a second ARPI. This approach could potentially extend the interval before initiating more aggressive treatment strategies.

Source.