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. 2024 Jun 8;24(1):706.
doi: 10.1186/s12885-024-12388-2.

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 Zhu #  1 , Junru Chen #  1 , Haoyang Liu #  1 , Jinge Zhao  1 , Chenhao Xu  1 , Guangxi Sun  2 , Hao Zeng  3
Affiliations

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 Zhu et al. BMC Cancer. .

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.

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: Adverse events; Homologous recombination deficiency; Metastatic castration-resistance prostate cancer; Poly (ADP- ribose) polymerase inhibitors; Progression-free survival.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Literature search and study selection process according to PRISMA flow diagram for systematic reviews
Fig. 2
Fig. 2
Network plot of the efficacy comparisons among different poly (ADP- ribose) polymerase inhibitors and androgen receptor-axis-targeted therapy (ARAT) regarding radiographic progression-free survival. Abbreviation: CED: cediranib; OLA: olaparib; AAP: abiraterone acetate plus prednisone; RUCA: rucaparib
Fig. 3
Fig. 3
Pairwise comparison and SUCRA for radiographic progression-free survival in HRR-mutated population based on Bayesian network meta-analysis. (A): Pairwise comparison for radiographic progression-free survival in HRR-mutated population; (B): SUCRA for radiographic progression-free survival in HRR-mutated population. Abbreviation: SUCRA: surface under cumulative ranking; HRR: homologous recombination repair; ARAT: androgen receptor-axis-targeted therapy; CED: cediranib; OLA: olaparib; AAP: abiraterone acetate plus prednisone; RUCA: rucaparib
Fig. 4
Fig. 4
Pairwise comparison and SUCRA for radiographic progression-free survival in subgroup analysis based on genetic mutation. (A): Pairwise comparison for radiographic progression-free survival in BRCA 1/2-mutated population; (B): SUCRA for radiographic progression-free survival in BRCA 1/2-mutated population; (C): Pairwise comparison for radiographic progression-free survival in BRCA-2-mutated population; (D): SUCRA for radiographic progression-free survival in BRCA-2-mutated population; (E): Pairwise comparison for radiographic progression-free survival in ATM-mutated population; (F): SUCRA for radiographic progression-free survival in ATM-mutated population. Abbreviation: SUCRA: surface under cumulative ranking; ARAT: androgen receptor-axis-targeted therapy; CED: cediranib; OLA: olaparib; RUCA: rucaparib
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