Matching-adjusted indirect comparisons of PARP inhibitor combinations in metastatic castration-resistant prostate cancer across key populations

BACKGROUND: Without head-to-head trials comparing talazoparib plus enzalutamide (TALA+ENZA), olaparib plus abiraterone acetate and prednisone (OLAP+AAP), and niraparib plus abiraterone acetate and prednisone (NIRA+AAP) as first-line treatments for metastatic castration-resistant prostate cancer (mCRPC), treatment selection remains challenging. This study estimated the relative efficacy of TALA+ENZA vs OLAP+AAP and NIRA+AAP in unselected, homologous recombination repair (HRR)-deficient, and BRCA-mutated (BRCAm) populations. METHODS: Unanchored matching-adjusted indirect comparisons (MAICs) were conducted using individual patient data from TALAPRO-2 (TALA+ENZA) and published summary-level data from PROpel (OLAP+AAP) and MAGNITUDE (NIRA+AAP). TALAPRO-2 patients meeting PROpel/MAGNITUDE eligibility criteria were included; remaining patients were reweighted to align on key baseline characteristics. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for radiographic progression-free survival (rPFS) and overall survival (OS). RESULTS: In unselected patients, TALA+ENZA significantly prolonged rPFS vs OLAP+AAP (HR: 0.747; 95% CI, 0.583, 0.957), with no OS difference (HR: 0.821; 95% CI, 0.649, 1.039). In HRR-deficient patients, TALA+ENZA significantly prolonged rPFS vs OLAP+AAP (HR: 0.648; 95% CI, 0.423, 0.992), with no OS difference (HR: 0.834; 95% CI, 0.569, 1.223). Comparisons with OLAP+AAP in BRCAm were infeasible. Compared with NIRA+AAP, TALA+ENZA significantly prolonged rPFS and OS in HRR-deficient (HR: 0.406; 95% CI, 0.251, 0.655; HR: 0.554; 95% CI, 0.340, 0.902) and BRCAm patients (HR: 0.394; 95% CI, 0.222, 0.698; HR: 0.472; 95% CI, 0.247, 0.902). CONCLUSIONS: MAICs showed improved clinical benefit with TALA+ENZA vs OLAP+AAP and NIRA+AAP across multiple mCRPC populations and endpoints. Despite limitations of indirect comparisons, findings support TALA+ENZA as a first-line treatment option for mCRPC.