ASCO GU 2023: Final Overall Survival in PROpel: Abiraterone and Olaparib Versus Abiraterone and Placebo as First-Line Therapy for mCRPC

(UroToday.com) The 2023 GU ASCO annual meeting included a session on advanced prostate cancer, specifically new targets, new drugs, and new victories, featuring a presentation by Dr. Noel Clarke discussing the final overall survival results in PROpel, a phase 3 trial assessing abiraterone and olaparib versus abiraterone and placebo as first-line therapy for mCRPC. There is preclinical rationale for a combined effect of PARP and androgen receptor inhibition, given that PARP and the androgen receptor are important for DNA repair in prostate cancer, and inhibition of PARP and the androgen receptor in combination results in more DNA damage:

PROpel (NCT03732820) met its primary endpoint showing significant investigator-assessed radiographic progression-free survival benefit for patients with mCRPC treated with abiraterone and olaparib versus abiraterone and placebo in the first line setting (HR 0.66, 95% CI 0.54–0.81, p < 0.001, data cut-off: July 30, 2021):¹

Additionally, sensitivity analysis by blinded independent central review were consistent. A trend toward OS benefit with abiraterone and olaparib was observed at the time of the primary radiographic progression-free survival analysis (28.6% maturity, HR 0.86, 95% CI 0.66–1.12) and a subsequent interim analysis (40.1% maturity, HR 0.83, 95% CI 0.66–1.03). At the 2023 GU ASCO annual meeting, Dr. Clarke and colleagues reported OS and safety from the pre-planned final analysis (data cut-off: October 12, 2022).

PROpel is a randomized, double-blind phase 3 trial of first line therapy for patients with mCRPC eligible for abiraterone. Patients were prospectively assessed for homologous recombination repair (HRR) mutation status using tumor tissue (FoundationOneCDx) and/or circulating tumor DNA (ctDNA; FoundationOneLiquid CDx) tests after randomization 1:1 to olaparib (300 mg twice daily [bid]) or placebo, and abiraterone (1000 mg once daily) plus prednisone/prednisolone (5 mg bid). Treatment continued until radiographic disease progression, unacceptable toxicity or withdrawal of consent. OS was a key secondary endpoint (2-sided boundary for significance 0.0377). Aggregate results from tumor tissue and ctDNA tests were used to assign patients to HRR mutation/BRCA mutation subgroups. The trial design for PROpel is as follows: 

 Patient (n = 796) characteristics (including prior docetaxel, site of metastasis, symptom score and HRR mutation status) were generally balanced. There was a consistent trend toward OS benefit in the intention-to-treat (ITT) population with abiraterone and olaparib versus abiraterone and placebo (maturity 47.9%, HR 0.81, 95% CI 0.67–1.00, p = 0.0544), with median OS 42.1 months vs 34.7 months, respectively:

 OS medians and HRs for HRR mutation, non-HRR mutation, BRCA mutation, and non-BRCA mutation subgroups all favored abiraterone and olaparib versus abiraterone and placebo:

 Additionally, there was a benefit for abiraterone and olaparib for time to next subsequent therapy (HR 0.76, 95% CI 0.64-0.90) and PFS2 (HR 0.76, 95% CI 0.59-0.99):

 The most common subsequent therapies were cytotoxic chemotherapy (n = 242) or hormonal therapy (n = 113), with 3 patients in the abiraterone and placebo arm receiving a PARP inhibitor has their first subsequent therapy. With regards to safety, there were no new safety signals with longer treatment duration and follow-up. In the abiraterone and olaparib arm the most common Grade ≥3 adverse event was anemia (16.1%):

Additionally, health-related quality of life was similar between the two arms, indicating no detriment with the addition of olaparib:

 Dr. Clarke concluded his presentation discussing the final overall survival results in PROpel with the following take-home messages:

• At the prespecified final analysis in PROpel, abiraterone and olaparib prolonged OS by > 7 months vs standard-of-care abiraterone (abiraterone and placebo) in the ITT population 
• The median OS of > 42 months is the longest median reported to date in a phase 3 trial in first line mCRPC 
• Consistent with radiographic progression-free survival results, a trend toward OS benefit was observed in HRR mutation, non-HRR mutation, BRCA mutation and non-BRCA mutation subgroups with greatest benefit in the BRCA mutation (HR 0.29, 95% CI 0.14-0.56) subgroup 
• No new long-term safety issues were identified. These results support the use of abiraterone + olaparib in first line mCRPC 

Presented by: Noel W. Clarke, MBBS, FRCS, ChM, The Christie and Salford Royal NHS Foundation Trusts, Manchester, UK

Co-Authors: Andrew J. Armstrong, Antoine Thiery-Vuillemin, Mototsugu Oya, Neal D. Shore, Giuseppe Procopio, João Daniel Cardoso Guedes, Cagatay Arslan, Niven Mehra, Francis Parnis, Emma Brown, Friederike Schlürmann, Jae Young Joung, Mikio Sugimoto, A. Oliver Sartor, Yu-Zhen Liu, Christian Heinrich Poehlein, Laura Barker, Paula Michelle del Rosario, Fred Saad 

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, Thurs, Feb 16 – Sat, Feb 18, 2023. 

 References: 

1. Clarke N, Armstrong AJ, Thiery-Vuillemin A, et al. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evidence 2022.EVIDoa2200043.