Sequencing Strategies in mCRPC

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Treatment sequencing in mCRPC requires careful consideration of prior therapies and patient characteristics, with the PEACE III combination of radium-223 and enzalutamide offering a valuable option for specific patient populations. This combination demonstrates particular efficacy in patients who received only androgen deprivation therapy (ADT) or ADT plus docetaxel in the hormone-sensitive setting, though many current patients have already received androgen receptor pathway inhibitors (ARPIs) before reaching mCRPC status. For patients without prior ARPI exposure and no homologous recombination repair (HRR) mutations, the PEACE III combination represents an effective and well-tolerated treatment option superior to enzalutamide monotherapy.

The COMRADE trial, presented at the 2024 American Society of Clinical Oncology Annual Meeting, explored combining radium-223 with olaparib vs radium alone in an unselected patient population. The theoretical rationale involved radium-induced DNA damage that could be enhanced by PARP inhibition, potentially creating synergistic antitumor effects. Results showed improved radiographic progression-free survival with combination therapy (8.6 months versus 4 months), but importantly, no overall survival benefit was observed, and adverse event rates were concerning in the combination vs control arm.

Clinical implementation of these findings suggests that although the radium-olaparib combination showed radiographic benefits, the lack of overall survival advantage combined with increased toxicity limits its practical application. The combination approach may not warrant adoption beyond research settings, particularly in unselected populations. For patients with HRR mutations, established PARP inhibitor regimens remain preferred, potentially in combination with ARPIs rather than radium-223. These studies highlight the importance of patient selection and the need for overall survival benefits to justify combination therapy approaches in advanced prostate cancer treatment.