Olaparib Combined with Abiraterone versus Olaparib Monotherapy for Patients with Metastatic Castration-resistant Prostate Cancer Progressing after Abiraterone and Harboring DNA Damage Repair Deficiency: A Multicenter Real-world Study

Jun Xie; Hanxu Guo; Baijun Dong; Wei Chen; Chengqi Jin; Qiufan Xu; Li Ding; Wujianhong Liu; Shengrong Dong; Tingting Zhao; Yang Yu; Changcheng Guo; Xudong Yao; Bo Peng; Bin Yang

doi:10.1016/j.euo.2024.02.005

Olaparib Combined with Abiraterone versus Olaparib Monotherapy for Patients with Metastatic Castration-resistant Prostate Cancer Progressing after Abiraterone and Harboring DNA Damage Repair Deficiency: A Multicenter Real-world Study

Eur Urol Oncol. 2024 Mar 7:S2588-9311(24)00050-6. doi: 10.1016/j.euo.2024.02.005. Online ahead of print.

Authors

Jun Xie¹, Hanxu Guo², Baijun Dong³, Wei Chen⁴, Chengqi Jin⁵, Qiufan Xu², Li Ding², Wujianhong Liu⁶, Shengrong Dong⁶, Tingting Zhao⁷, Yang Yu², Changcheng Guo², Xudong Yao⁸, Bo Peng⁹, Bin Yang¹⁰

Affiliations

¹ Department of Urology, Shanghai Tenth People's Hospital, Shanghai Clinical College, Fifth Clinical Medical College, Anhui Medical University, Shanghai, China.
² Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Urologic Cancer Institute, Tongji University School of Medicine, Shanghai, China.
³ Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁴ Department of Urology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
⁵ Department of Urology, School of Medicine, Anhui University of Science and Technology, Huainan, China.
⁶ Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
⁷ School of Life Sciences and Technology, Tongji University, Shanghai, China; Research Institute, GloriousMed Clinical Laboratory, Shanghai, China.
⁸ Department of Urology, Shanghai Tenth People's Hospital, Shanghai Clinical College, Fifth Clinical Medical College, Anhui Medical University, Shanghai, China; Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Urologic Cancer Institute, Tongji University School of Medicine, Shanghai, China; Department of Urology, School of Medicine, Anhui University of Science and Technology, Huainan, China. Electronic address: yaoxudong1967@163.com.
⁹ Department of Urology, Shanghai Tenth People's Hospital, Shanghai Clinical College, Fifth Clinical Medical College, Anhui Medical University, Shanghai, China; Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Urologic Cancer Institute, Tongji University School of Medicine, Shanghai, China. Electronic address: pengbo6908@163.com.
¹⁰ Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Urologic Cancer Institute, Tongji University School of Medicine, Shanghai, China; Department of Urology, School of Medicine, Anhui University of Science and Technology, Huainan, China. Electronic address: yangbnju@gmail.com.

PMID: 38458891
DOI: 10.1016/j.euo.2024.02.005

Abstract

Background and objective: Olaparib + abiraterone has a combined antitumor effect in metastatic castration-resistant prostate cancer (mCRPC), but the efficacy of this combination in patients with DNA damage repair (DDR)-deficient mCRPC progressing after abiraterone is unknown. Our aim was to compare the efficacy of olaparib + abiraterone versus olaparib monotherapy for patients with DDR-deficient mCRPC progressing after abiraterone.

Methods: The study included 86 consecutive patients with DDR-deficient mCRPC progressing after abiraterone: 34 received olaparib + abiraterone, and 52 received olaparib monotherapy. DDR-deficient status was defined as the presence of a DDR gene with a pathogenic or likely pathogenic variant (DDR-PV), or with a variant of unknown significance (DDR-VUS). We assessed progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method. Potential factors influencing PFS and OS were compared between the treatment arms using Cox proportional-hazards models. The prostate-specific antigen (PSA) response, the treatment effect across subgroups, and adverse events (AEs) were also evaluated.

Key findings and limitations: Median follow-up was 9 mo. In the overall cohort, median PFS and OS were significantly longer in the combination arm than in the monotherapy arm (PFS: 6.0 vs 3.0 mo; hazard ratio [HR] 0.41, 95% confidence interval [CI] 0.25-0.67; p < 0.01; OS: 25.0 vs 12.0 mo; HR 0.30, 95% CI 0.14-0.67; p < 0.01). PSA responses were significantly higher following combination therapy versus monotherapy. Combination therapy had significantly better efficacy in the DDR-PV and DDR-VUS subgroups, and was an independent predictor of better PFS and OS. AE rates were acceptable. The retrospective nature, small sample size, and short follow-up are limitations.

Conclusions: Olaparib + abiraterone resulted in better PFS and OS than olaparib alone for patients with DDR-deficient mCRPC progressing after abiraterone. These results need to be confirmed by a large-scale prospective randomized controlled trial.

Patient summary: Our study shows that the drug combination of olaparib plus abiraterone improved survival over abiraterone alone for patients who have mutations in genes affecting DNA repair and metastatic prostate cancer resistant to hormone therapy. The results provide evidence of a synergistic effect of the two drugs in these patients.

Keywords: Abiraterone; Androgen receptor signaling pathway; DNA damage repair; Homologous recombination repair; Olaparib; PARP inhibitor; Precision medicine; Prostate cancer; Synergistic effect.