The phase 3 PROpel clinical trial has achieved its primary end point of improvement in radiographic progression-free survival in men with metastatic castration resistant prostate cancer using the novel combination of olaparib and abiraterone.
In patients with metastatic castration-resistant prostate cancer (mCRPC) with or without homologous recombination repair (HRR) gene mutations, frontline treatment with olaparib (Lynparza) combined with abiraterone (Zytiga) achieved a statistically significant and clinically meaningful improvement in radiographic progression-free survival (PFS) compared with abiraterone alone, meeting the primary end point of the phase 3 PROpel clinical trial.1
The findings are from the planned interim analysis from the study announced in a joint press release by AstraZeneca and Merck and Co, Inc (MSD). These findings also showed a trend toward overall survival (OS) improvement with olaparib/abiraterone, and the combination demonstrated a safety profile consistent with the known profiles of each drug individually.
“We are encouraged by the PROpel results and the clinical benefit Lynparza in combination with abiraterone demonstrated versus abiraterone alone as a first-line treatment option for men with metastatic castration-resistant prostate cancer. Today’s results build on MSD and AstraZeneca’s commitment to bring Lynparza earlier in lines of treatment and to more patients with advanced prostate cancer,” stated Roy Baynes, senior vice president and head of Global Clinical Development, chief medical officer, MSD Research Laboratories, in the press release.
PROpel is a randomized, double-blinded, placebo-controlled, multicenter study (NCT03732820) with a targeted enrollment of 904 males with mCRPC. In addition to rPFS, the study is investigating the secondary end points of OS, time to subsequent anticancer therapy, time to pain progression, time to opiate use, time to a symptomatic skeletal-related event, time to second progression or death, quality of life, and HRR gene status and various changes in disease status from baseline.2
Prior to this study, a phase 2 study of olaparib 300 mg twice daily in combination with abiraterone 100 mg once daily plus the combination prednisone and prednisolone 5 mg twice daily showed significant improvement in rPFS compared with abiraterone monotherapy when administered in the second-line setting to patients with mCRPC.3
A total 142 patients enrolled and randomly assigned to received either the olaparib combination or single-agent abiraterone in the phase 2 study. The median rPFS observed was 13.8 months (95% CI, 10.8-20.4) with the experimental combination versus 8.2 months (95% CI, 5.5-9.7) with abiraterone alone (HR, 0.65; 95% CI, 0.44-0.97; P =.034).
In terms of safety, many of the adverse events (AEs) were low grade and the majority of the serious AEs occurred in the olaparib combination arm. The most common grade 1/2 AEs observed in the experimental arm versus the control arm were nausea (37% vs 18%, respectively), constipation (25% vs 11%), back pain (24% vs 18%), respectively. Grade 3 AEs in the experimental and control arms respectively were commonly anemia (21% vs 0), pneumonia (6% vs 4%, and myocardial infarction (6% vs 0).
Exploration of the ability of olaparib plus abiraterone as frontline treatment is ongoing in the PROpel study. Patients who meet certain the study’s criteria are being actively recruited at 176 locations throughout the United States and in Canada, South America, Europe, Asia, and the Oceania.2
To be eligible for inclusion in the study, patients are required to be 18 years of age or older with historically or cytologically confirmed and previously untreated prostate adenocarcinoma that is metastatic with at least 1 documents lesion. Patients must receive ongoing androgen deprivation therapy with gonadotropin-releasing hormone analogue or bilateral orchiectomy, and be candidates to received abiraterone with documents evidence of progressive disease.
Further requirements to be enrolled in PROpel include having a normal organ function and bone marrow function, an ECOG performance status of 0 or 1m and a life expectancy of at least 6 months.
“Today, men with metastatic castration-resistant prostate cancer have limited options in the first-line setting, and sadly often the disease progresses after initial treatment with current standards of care. These exciting results demonstrate the potential for Lynparza with abiraterone to become a new first-line option for patients regardless of their biomarker status and reach a broad population of patients living with this aggressive disease. We look forward to discussing the results with global health authorities as soon as possible, said Susan Galbraith, executive vice president, Oncology R&D at AstraZeneca, in a press release.1
1. Lynparza in combination with abiraterone significantly delayed disease progression in all-comers in PROpel Phase III trial in 1st-line metastatic castration-resistant prostate cancer. News release. AstraZeneca. September 24, 2021. Accessed September 24, 2021. https://bit.ly/2XYeo3V
2. Study on olaparib plus abiraterone as first-line therapy in men with metastatic castration-resistant prostate cancer. Clinicaltrials.gov. Accessed September 24, 2021.
3. Clarke N, Wiechno P, Alekseev B, et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2018;19(7):975-986. doi: 10.1016/S1470-2045(18)30365-6