Final overall survival (OS) in PROpel: Abiraterone (abi) and olaparib (ola) versus abiraterone and placebo (pbo) as first-line (1L) therapy for metastatic castration-resistant prostate cancer (mCRPC).
Noel W. Clarke, Andrew J. Armstrong, Antoine Thiery-Vuillemin, Mototsugu Oya, Neal D. Shore, Giuseppe Procopio, João Daniel Guedes, Cagatay Arslan, Niven Mehra, Francis Parnis, Emma Brown, Friederike Schlürmann, Jae Young Joung, Mikio Sugimoto, Oliver Sartor, Yuzhen Liu, Christian Poehlein, Laura Barker, Paula Michelle del Rosario, Fred Saad
Abstract
LBA16 Background: PROpel (NCT03732820) met its primary endpoint showing significant investigator-assessed radiographic progression-free survival (rPFS) benefit for patients with mCRPC treated with abi + ola vs abi + pbo in the 1L setting (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54–0.81, P< 0.001, data cut-off: 7/30/2021). Sensitivity analysis by blinded independent central review was consistent. A trend toward OS benefit with abi + ola was observed at the time of the primary rPFS 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). We report OS and safety from the pre-planned final analysis (data cut-off: 10/12/2022). Methods: PROpel is a randomized, double-blind phase 3 trial of 1L therapy for patients with mCRPC eligible for abiraterone. Patients were prospectively assessed for homologous recombination repair mutation (HRRm) status using tumor tissue (FoundationOne CDx) and/or circulating tumor DNA (ctDNA; FoundationOne Liquid CDx) tests after randomization 1:1 to ola (300 mg twice daily [bid]) or pbo, and abi (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 HRRm/BRCAm subgroups. Results: Patient (n = 796) characteristics (including prior docetaxel, site of metastasis, symptom score and HRRm status) were generally balanced. There was a consistent trend toward OS benefit in the intention-to-treat (ITT) population with abi + ola vs abi + pbo (maturity 47.9%, HR 0.81, 95% CI 0.67–1.00, P= 0.0544), with median OS 42.1 months (m) vs 34.7 m, respectively. OS medians and HRs for HRRm, non-HRRm, BRCAm and non-BRCAm subgroups all favored abi + ola vs abi + pbo. In the abi + ola arm the most common Grade ≥3 adverse event was anemia (16.1%). Conclusions: At the prespecified final analysis in PROpel, abi + ola prolonged OS by > 7 m vs standard-of-care abiraterone (abi + pbo) in the ITT population. The median OS of > 42 m is the longest median reported to date in a phase 3 trial in 1L mCRPC. Consistent with rPFS results, a trend toward OS benefit was observed in HRRm, non-HRRm, BRCAm and non-BRCAm subgroups with greatest benefit in the BRCAm subgroup. No new long-term safety issues were identified. These results support the use of abi + ola in 1L mCRPC. Clinical trial information: NCT03732820 . [Table: see text]