ASCO GU 2022: PROpel: Phase III Trial of Olaparib and Abiraterone Versus Placebo and Abiraterone as First-Line Therapy for Patients with mCRPC

(UroToday.com) The 2022 GU ASCO Annual meeting included a prostate cancer oral abstract session featuring Dr. Fred Saad and colleagues presenting results of the PROpel phase 3 trial of olaparib and abiraterone versus placebo and abiraterone as first-line therapy for patients with metastatic castration resistant prostate cancer (mCRPC). Patients treated in the first line mCRPC setting have a median survival of approximately 3 years in clinical trial settings. In clinical practice, approximately half of these patients receive only one line of active therapy with median survivals of less than 2 years. As such, there is a major unmet need to improve patient outcomes in the first-line mCRPC treatment setting. A Phase II trial (NCT01972217) in patients with mCRPC unselected by homologous recombination repair (HRR) status who previously received docetaxel demonstrated improved radiographic progression-free survival (rPFS) for patients treated with olaparib + abiraterone vs placebo + abiraterone.1 At GU ASCO 2022, Dr. Saad presented results of the Phase III PROpel study (NCT03732820) evaluating the efficacy and safety of olaparib + abiraterone in the first-line mCRPC setting, irrespective of HRR mutation status.


PROpel is a randomized, double-blind, placebo-controlled Phase III trial in patients with mCRPC undergoing first-line treatment after failure of primary androgen deprivation therapy, enrolled independent of HRR status. Patients were randomized 1:1 to receive olaparib (300 mg twice daily) or placebo, and abiraterone (1000 mg once daily) + prednisone or prednisolone (5 mg twice daily). The primary endpoint was investigator-assessed rPFS with multiple secondary endpoints, including overall survival. The trial design for PROpel is as follows:

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There were 796 patients randomized to olaparib + abiraterone (n=399) or placebo + abiraterone (n=397). The baseline characteristics between the two arms were well-balanced between the treatment arms as highlighted in the following table:

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In this planned interim analysis, first-line treatment with olaparib + abiraterone significantly prolonged rPFS vs placebo + abiraterone in patients with mCRPC irrespective of HRR status (24.8 vs 16.6 months; HR 0.66, 95% CI 0.54–0.81; p <0.0001):

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Predefined subgroup analyses showed rPFS improvement across all subgroups, including patients with (HR 0.50, 95% CI 0.34–0.73) and without (HR 0.76, 95% CI 0.60–0.97) HRR mutations detected by circulating tumor DNA testing:

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A sensitivity analysis of rPFS by blinded independent central review was consistent with the primary analysis (HR 0.61, 95% CI 0.49–0.74; p =0.004). Overall survival is currently immature, with 228 deaths (28.6%) observed to date; however, a trend in overall survival favoring olaparib + abiraterone was noted (HR 0.86, 95% CI 0.66–1.12):

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Secondary endpoints of time to first subsequent treatment (HR 0.74, 95% CI 0.61–0.90) and time to second progression-free survival or death (HR 0.69, 95% CI 0.51–0.94) were supportive of long-term benefits:

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Among patients with measurable disease, the objective response rate showed a 10% improvement with olaparib + abiraterone:

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The most common grade ≥3 adverse event reported was anemia (15.1 vs 3.3%) for olaparib + abiraterone vs placebo + abiraterone; 13.8 vs 7.8% patients, respectively, discontinued olaparib/placebo because of an adverse event. The rate of adverse events leading to abiraterone discontinuation was similar in both arms (8.5 vs 8.8%):

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Specifically, cardiac failure and arterial thromboembolic events were well balanced between the two arms. Numerically higher venous thromboembolic events were reported for olaparib + abiraterone; pulmonary embolism was the most commonly reported venous thromboembolic event, however, pulmonary embolism events were mostly incidental findings on CT scan and did not lead to discontinuation of olaparib or abiraterone:

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Quality of life, as assessed by FACT-P, was also comparable between the treatment arms: 

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Dr. Saad concluded his presentation of the PROpel phase 3 trial of olaparib and abiraterone versus placebo and abiraterone as first-line therapy for patients with mCRPC with the following take-home messages:

  • At the interim analysis, PROpel met its primary objective, demonstrating significant improvement in rPFS for olaparib + abiraterone vs placebo + abiraterone (HR 0.66, 95% CI 0.54-0.81) in patients with newly detected mCRPC who had not received prior first-line therapy, irrespective of HRR status
    • This benefit led to a median rPFS beyond 2 years
    • The rPFS benefit was observed irrespective of HRR mutation status
  • Secondary and exploratory endpoints support the treatment benefit of olaparib + abiraterone over placebo + abiraterone in the overall survival patient population
  • The safety and tolerability profile of olaparib + abiraterone was consistent with the known safety profiles of the individual drugs
  • These results demonstrate the benefit of olaparib + abiraterone without the need for HRR stratification in first-line treatment of mCRPC
  • Patient follow-up is ongoing for the planned overall survival analysis
  • The phase III PROpel study is the first combination approach to deliver consistent clinical benefits for patients in the first-line mCRPC setting, irrespective of HRR mutation status

Presented by: Fred Saad, MD, FRCS, Centre Hospitalier de l’Université de Montréal/CRCHUM, Montreal, Quebec, Canada

Co-Authors: Andrew J. Armstrong, Antoine Thiery-Vuillemin, Mototsugu Oya, Eugenia Loredo, Giuseppe Procopio, Juliana Menezes, Gustavo Girotto, Cagatay Arslan, Niven Mehra, Francis Parnis, Emma Brown, Friederike Schlürmann, Jae Young Joung, Mikio Sugimoto, Christian Heinrich Poehlein, Elizabeth Harrington, Chintu Desai, Jinyu Kang, Noel Clarke

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 2022 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, Thursday, Feb 17 – Saturday, Feb 19, 2022 

References:

  1. Clarke N, Wiechno P, Alekseev B, et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: A randomized, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2018 Jul;19(7):975-986.
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