Abstract Background: The landscape of metastatic castration-resistant prostate cancer (mCRPC) treatment has evolved greatly; however, limited data are available regarding its relative efficacy and safety. We conducted a systematic review and network meta-analysis to analyze and compare the effectiveness and safety of first-line therapies for mCRPC, particularly doublet therapy and monotherapy. Methods: The PubMed, Embase, and Cochrane Library databases were searched from their inception until June 6, 2023. ClinicalTrials.gov and congress abstracts were also searched. We selected randomized controlled trials (RCTs) in English that reported the first-line treatment outcomes of mCRPC. The primary efficacy outcomes included radiographic progression-free survival (rPFS), overall survival (OS), and safety outcomes included any adverse events (AEs) and grade 3 or higher AEs (grade ≥3 AEs). Considering only trials that used therapies without docetaxel (Doc) assess rPFS and no common arm between therapies with or without Doc in terms of OS and safety outcomes, two separate pairwise meta-analyses were conducted. We performed subgroup, metaregression, and sensitivity analyses to identify moderators and account for heterogeneity. The Cochrane risk-of-bias assessment tool was used to evaluate the quality of each study. Results: Thirty-five RCTs with 24,400 patients comparing 30 treatments were analyzed. In the non-Doc group, poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) doublet with androgen receptor signaling inhibitor (ARSI) conferred rPFS and OS improvements in patients with mCRPC, especially with alterations in homologous recombination repair (HRR) genes. In the Doc group, combination therapies showed no significant difference in OS compared to Doc. Regarding safety outcomes, ra-223 plus abiraterone and estramustine plus docetaxel showed the lowest risks of AEs in the non-Doc and Doc groups, respectively. The PARPi doublet with the ARSI had a relatively low ranking. Conclusion: While raising concerns about safety profiles, our findings highlight that the PARPi doublet with ARSI probably has the greatest benefit in mCRPC patients with HRR gene alterations. Registration: PROSPERO, No. CRD42023400452.
Guo et al. (Mon,) studied this question.
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