The efficacy and safety of PARP inhibitors in mCRPC with HRR mutation in second-line treatment: a systematic review and bayesian network meta-analysis

Zhu et al. BMC Cancer (2024) 24:706 https://doi.org/10.1186/s12885-024-12388-2 BMC Cancer S YS T E M AT I C R E V I E W Open Access The efficacy and safety of PARP inhibitors in mCRPC with HRR mutation in second-line treatment: a systematic review and bayesian network meta-analysis Qiyu Zhu1†, Junru Chen1†, Haoyang Liu1†, Jinge Zhao1, Chenhao Xu1, Guangxi Sun1* and Hao Zeng1* Abstract Background Poly (ADP- ribose) polymerase inhibitors (PARPi) has been increasingly adopted for metastatic castration-resistance prostate cancer (mCRPC) patients with homologous recombination repair deficiency (HRD). However, it is unclear which PARPi is optimal in mCRPC patients with HRD in 2nd -line setting. Method We conducted a systematic review of trials regarding PARPi- based therapies on mCRPC in 2nd -line setting and performed a Bayesian network meta-analysis (NMA). Radiographic progression-free survival (rPFS) was assessed as primary outcome. PSA response and adverse events (AEs) were evaluated as secondary outcomes. Subgroup analyses were performed according to specific genetic mutation. Results Four RCTs comprised of 1024 patients (763 harbored homologous recombination repair (HRR) mutations) were identified for quantitative analysis. Regarding rPFS, olaparib monotherapy, rucaparib and cediranib plus olaparib showed significant improvement compared with ARAT. Olaparib plus cediranib had the highest surface under cumulative ranking curve (SUCRA) scores (87.5%) for rPFS, followed by rucaparib, olaparib and olaparib plus abiraterone acetate prednisone. For patients with BRCA 1/2 mutations, olaparib associated with the highest probability (98.1%) of improved rPFS. For patients with BRCA-2 mutations, olaparib and olaparib plus cediranib had similar efficacy. However, neither olaparib nor rucaparib showed significant superior effectiveness to androgen receptor-axis-targeted therapy (ARAT) in patients with ATM mutations. For safety, olaparib showed significantly lower ≥ 3 AE rate compared with cediranib plus olaparib (RR: 0.72, 95% CI: 0.51, 0.97), while olaparib plus cediranib was associated with the highest risk of all-grade AE. † Qiyu Zhu, Junru Chen and Haoyang Liu contributed equally to this work. *Correspondence: Guangxi Sun Hao Zeng ; Full list of author information is available at the end of the article © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhu et al. BMC Cancer (2024) 24:706 Page 2 of 10 Conclusion PARPi-based therapy showed considerable efficacy for mCRPC patients with HRD in 2nd -line setting. However, patients should be treated accordingly based on their genetic background as well as the efficacy and safety of the selected regimen. Trial registration : CRD42023454079. Keywords Poly (ADP- ribose) polymerase inhibitors, Homologous recombination deficiency, Metastatic castrationresistance prostate cancer, Progression-free survival, Adverse events Introduction Prostate cancer (PCa) is the most commonly diagnosed cancer in men, accounting for over 10% of all cancercaused death in 2023 [1]. Metastatic castration-resistant prostate cancer (mCRPC) was considered as the terminal stage of PCa with a median overall survival of less than 3 years [2–4]. Androgen receptor-axis-targeted (ARAT) regimens and taxane have been widely used as the first-line treatments for mCRPC in recent years [5, 6]. However, patients inevitably experience progression after receiving these agents [7–9], thus the exploration of effective 2nd -line therapy for mCRPC experiencing treatments failure becomes increasingly important. With the rapid development of precision medicine, molecular characterization of PCa has led to the discovery of multiple actionable genomic alterations. Several large-scale studies have revealed that 20-30% of mCRPC patients harbored germline or somatic DNA damage repair (DDR) mutation, including those participating in homologous recombination repair (HRR) pathway, which is targeted by poly (ADP- ribose) polymerase inhibitors (PARPi) [10, 11]. PARPi functions through selectively binding catalytic pocket among PARP1/2 and DNA trapping to achieve DNA damage repair inhibition, and thus induce synthetic lethality specifically in patients with homologous recombination deficiency (HRD) [12–14]. Multiple trials exploring the efficacy of PARPi in 2nd -line mCRPC setting have been carried out and demonstrated promising anti-tumor activity especially in HRD patients [14–18]. Several previous meta-analyses and systematic reviews also confirmed the superior efficacy of PARPi-based therapies in mCRPC patients with HRD [19–21]. However, no head-to-head comparative trials of different PARPis have been conducted, and the optimal PARPi-based treatment for this population remains unknown. Thus, we conducted this systematic review and network meta-analysis (NMA) to assess the efficacy and safety of different PARPis in 2nd -line mCRPC setting with HRD. Method This network meta-analysis adhered to the guidelines of PRISMA for Network Meta-Analyses (PRISMANMA) and adopted the standard methods approved by the Cochrane Collaboration [22, 23]. The protocol of this NMA was registered on PROSPERO in prior (CRD42023454079). Literature research A systematic literature review was conducted based on three databases (PubMed, Cochrane CENTRAL, and Embase), focusing on papers published before August 2, 2023. Detailed search strategy was attached to the protocol published on PROSPERO. Two reviewers (HYL and QYZ) were responsible for the literature scanning process based on title, abstract, and full text. Disagreements were resolved under the guidance of a third reviewer (JRC). Eligibility criteria Studies meeting the following eligibility criteria were included in this NMA: (1) Trials comparing PARPi with androgen receptor axis-targeted (ARAT) agents or combination therapy of PARPi and other anti-tumor regimens (e.g., abiraterone, cediranib). (2) mCRPC patients progressed after (...truncated)