PARP inhibitor-based treatment in metastatic, castration-resistant prostate cancer (mCRPC): A systematic review and meta-analysis.

Background: We present a systematic review and meta-analysis of randomized clinical trials (RCTs) with PARPi either as monotherapy or in combination with an androgen receptor-targeted agent (ARTA) in first- and second-line settings.

Methods: Primary endpoints are radiographic progression free survival (rPFS) and overall survival (OS) in patients with mCRPC and either unselected, homologous recombination repair wild-type (HRR-), homologous recombination repair mutated (HRR+) or with BRCA1, BRCA2, or ATM mutation. The effect of PARPi + ARTA in the second-line setting is also explored. Safety is a secondary end-point.

Results: A total of five phase III (first line: MAGNITUDE, PROpel, TALAPRO-2; second line: PROfound, TRITON3) and two phase II RCTs (second line: NCT01972217, NCT01576172) were selected. In the first-line setting, rPFS was significantly improved in PARPi + ARTA arm in all comers (HR 0.70,  < 0.00001), HRR- (HR 0.76,  = 0.005), HRR+ (HR 0.57,  = 0.0003), and BRCA1/2-mutated patients (HR: 0.33,  < 0.00001). OS was improved in the population with HRR+ status (HR 0.76,  = 0.02) but not statistically significant in BRCA1/2-mutated patients (HR 0.57, 95% CI 0.30-1.08,  = 0.08). In the second line, PARPi improves rPFS (HR for BRCA2 0.31,  = 0.002) and OS (HR for BRCA1/2 0.71,  = 0.01) only in such patients. In this setting, no advantage was reported by adding a PARPi to an ARTA. The arm with PARPi either as monotherapy or in combination with ARTA showed a significantly higher toxicity profile.

Conclusions: PARPi-based therapy represents a compelling treatment option for HRR+ mCRPC, mainly BRCA1/2-mutated patients. However, further biomarker analysis are needed in order to identify other responsive patients across the different disease settings.