Combining the PARP inhibitor olaparib (Lynparza) with abiraterone acetate (Zytiga) led to a statistically significant and clinically meaningful improvement in radiographic progression-free survival (PFS) versus abiraterone alone in patients with metastatic castration-resistant prostate cancer (mCRPC), regardless of homologous recombination repair (HRR) status, according to results of the phase 3 PROpel trial, presented at the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium.
Patients randomized to receive first-line treatment with olaparib plus abiraterone had a 34% reduced risk for disease progression versus those who received abiraterone alone, fulfilling the primary end point of the study.
“It is clear to me that the prognosis for mCRPC is extremely poor, and many patients are only able to receive 1 line of effective therapy. The results of the PROpel trial, which showed that olaparib in combination with abiraterone significantly delayed disease progression versus abiraterone by more than 8 months, demonstrate the potential for this combination to become a new standard-of-care option in mCRPC if approved,” said lead investigator Fred Saad, MD, FRSC, Professor and Chief, Urology, and Director of Genitourinary Oncology, Centre hospitalier de l’Université de Montréal, Quebec, Canada.
“The benefit of olaparib plus abiraterone in this trial led to what I think is the longest radiographic PFS in patients with mCRPC—beyond 2 years—irrespective of HRR status,” he added.
In the international, double-blind, placebo-controlled, phase 3 PROpel trial, investigators randomized patients with mCRPC who had disease progression while receiving treatment with androgen deprivation therapy to abiraterone 1000 mg daily plus olaparib 300 mg twice daily (N = 399) or abiraterone 1000 mg daily plus placebo (N = 397). Patients could have received docetaxel in the metastatic hormone-sensitive prostate cancer setting, but no prior abiraterone was allowed. Other next-generation hormonal agents were permitted if they were stopped at least 12 months prior to study enrollment.
Baseline characteristics were well-balanced between the 2 arms of the study. Median age was 69.5 years (range, 43-91 years), and most patients had an Eastern Cooperative Oncology Group performance status of 0 (70.1%). Patients either had HRR mutations (27.8% in the combination arm vs 29.0% in the abiraterone-alone arm), non-HRR mutations (69.9% vs 68.8%, respectively), or unknown HRR mutation status (2.3% each).
In a predefined interim analysis, treatment with olaparib plus abiraterone reduced the risk for disease progression or death by 34% versus abiraterone alone, according to investigator assessment. Median radiographic PFS was 24.8 months for olaparib plus abiraterone versus 16.6 months for abiraterone alone (P <.0001).
Predefined subgroup analysis demonstrated improved radiographic PFS with the combination across all subgroups, including patients with and without HRR gene alterations detected by circulating tumor DNA testing (46% reduction for those with HRR gene alterations and 24% reduction for those without).
Dr Saad noted that the overall survival data are currently immature, with 228 deaths (28.6%). However, a trend toward improved overall survival was observed with the addition of olaparib (hazard ratio, 0.86; 95% confidence interval, 0.66-1.12).
In the overall study population, olaparib plus abiraterone was superior to abiraterone alone for the following secondary end points: time to first subsequent therapy, second PFS, objective response rate, prostate-specific antigen levels, and circulating tumor cell counts. In the approximately 43% of patients with measurable disease, objective response rates were 58.4% for the combination regimen versus 48.1% for abiraterone alone.
The safety and tolerability associated with the olaparib plus abiraterone regimen were consistent with the established side-effect profiles of each agent. No increase in the rate of discontinuation of abiraterone was observed in patients treated with the combination, and there were no detrimental effects on health-related quality of life versus those treated with abiraterone alone, according to results of a Functional Assessment of Cancer Therapy-Prostate questionnaire.
The most common (>20%) adverse events (AEs) reported in patients were anemia (45%), nausea (28%), and fatigue (28%). Grade ≥3 AEs were anemia (15%), hypertension (4%), urinary tract infection (2%), fatigue (1%), decreased appetite (1%), vomiting (1%), asthenia (1%), back pain (1%), and diarrhea (1%). Approximately 86% of patients treated with olaparib plus abiraterone who experienced AEs remained on treatment at the time of data cutoff. Deaths due to AEs occurred in approximately 4% of patients in each arm.
“The take-home message from PROpel is that we should wait for overall survival results and a better understanding of which patients benefit the most before using this combination in the clinic for first-line therapy [mCRPC],” said invited discussant Celestia S. Higano, MD, FACP, Medical Director, Prostate Cancer Supportive Care Program, Vancouver Prostate Centre, Canada, and Adjunct Professor, Department of Urologic Sciences, University of British Columbia, Vancouver.
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