Systemic treatment options for metastatic castration resistant prostate cancer: A living systematic review

BackgroundOptimal treatment selection for metastatic castration resistant prostate cancer (mCRPC) remains challenging due to evolving standards of care in castration sensitive setting. PurposeTo synthesize and appraise evidence on systemic therapy for mCRPC patients stratified by prior therapy and HRR alterations informing a clinical practice guideline. Data SourcesMEDLINE and EMBASE (inception to 5 March 2025) using living search. Study SelectionRandomized clinical trials assessing systemic therapy in mCRPC. Data ExtractionPrimary outcomes assessed were progression free survival (PFS) and overall survival (OS). Data SynthesisThis report of the living systematic review (LSR) includes 143 trials with 17,523 patients (59 phase III/IV trials, 8,941 patients; 84 phase II, 8,582 patients). In the setting of prior androgen deprivation therapy (ADT) alone or ADT+docetaxel, treatment benefit was observed with poly (ADP-ribose) polymerase inhibitors (PARPi) in combination with androgen receptor pathway inhibitors (ARPI) for BRCA+ subgroup. In the setting of prior ADT+ARPI or ADT+ARPI+docetaxel, treatment benefit was observed with PARPi monotherapy for BRCA+ subgroup. Treatment benefit with PARPi may be observed for select non-BRCA homologous recombination repair (HRR) alterations (CDK12, PALB2). Treatment benefit was observed with abiraterone, enzalutamide, cabazitaxel, docetaxel (if no prior docetaxel), and Lu177 (if PSMA+) for patients without HRR alterations. LimitationsStudy-level data and indirectness in evidence. ConclusionFindings from the current LSR suggest that optimal treatment for mCRPC should be individualized based on prior therapy and HRR alterations. Current evidence favors PARPi alone (ARPI exposed) or in combination with ARPI (ARPI naive) for patients with BRCA alterations, while ARPI alone, chemotherapy, and Lu177 remain potential options for patients without HRR alterations. Registrationhttps://osf.io/46tjm Primary Funding SourceNIH U24 grant (U24CA265879-01-1).