The PARP inhibitor olaparib in combination with abiraterone demonstrated a statistically significant and clinically meaningful improvement in radiographic progression-free survival vs current standard-of-care abiraterone as a first-line treatment for patients with metastatic castration-resistant prostate cancer with or without homologous recombination repair (HRR) gene mutations, according to results from the PROpel phase III trial presented at the 2022 ASCO Genitourinary (GU) Cancers Symposium.1
Patients randomly assigned to olaparib plus abiraterone had a 34% reduced risk of disease progression vs standard treatment with abiraterone alone as first-line treatment for metastatic castration-resistant prostate cancer. Thus, the study met its primary endpoint at the first interim analysis. The combination of olaparib plus abiraterone was well tolerated compared with abiraterone alone.
“It is clear to me that the prognosis for metastatic castration-resistant prostate cancer is extremely poor, and many patients are able to receive only one line of effective therapy,” said Fred Saad, MD, Professor and Chairman of Urology and Director of Genitourinary Oncology at the University of Montreal Hospital Center. “The results of the PROpel trial, which showed that olaparib in combination with abiraterone significantly delayed disease progression vs abiraterone by more than 8 months, demonstrate the potential for this combination to become a new standard-of-care option in metastatic castration-resistant prostate cancer if approved.”
Fred Saad, MD
Dr. Saad added: “The benefit of olaparib plus abiraterone in this trial led to what I think is the longest radiographic progression-free survival in patients with metastatic castration-resistant prostate cancer—beyond 2 years—irrespective of HRR status.”
Olaparib is approved by the U.S. Food and Drug Administration for patients with HRR gene–mutated metastatic castration-resistant prostate cancer (BRCA-mutated and other HRR gene mutations) and in the European Union, Japan, and China for patients with BRCA-mutated metastatic castration-resistant prostate cancer.
The positive results of the PROpel trial in patients with and without HRR gene alterations are distinct from the results of MAGNITUDE, another phase III trial reported at the 2022 ASCO Genitourinary Cancers Symposium,2 evaluating a different poly (ADP-ribose) polymerase (PARP) inhibitor—niraparib—plus abiraterone and prednisone vs abiraterone alone in men with metastatic castration-resistant prostate cancer. MAGNITUDE showed robust results in patients with HRR-positive disease using niraparib plus abiraterone and prednisone. In contrast, the combination did not benefit those with HRR-negative disease, and the findings suggest that this particular PARP inhibitor–based combination should be reserved for mutation-positive disease.
Prostate cancer is the second most common cancer in male patients, and advanced prostate cancer has a poor prognosis, with low 5-year survival rates. About half of these patients are treated with only one line of treatment, and median survival is about 2 years. Patients treated with more than one line of treatment at disease progression experience diminishing effectiveness with each subsequent treatment. HRR gene mutations occur in approximately 20% to 30% of patients with metastatic castration-resistant prostate cancer.
The double-blind, placebo-controlled, phase III PROpel trial randomly assigned 399 patients who had disease progression on treatment with androgen-deprivation therapy to receive olaparib plus abiraterone and 397, abiraterone alone. Of these patients, 111 and 115, respectively, had HRR mutations, whereas 279 and 273 did not.
“This is the first phase III trial to evaluate the combined effects of a PARP inhibitor and abiraterone as first-line treatment of metastatic castration-resistant prostate cancer irrespective of HRR status,” Dr. Saad stated.
In a predefined interim analysis, olaparib in combination with abiraterone reduced the risk of disease progression or death by 34% vs abiraterone alone, according to investigator assessment. Median radiographic progression-free survival was 24.8 months for olaparib plus abiraterone vs 16.6 months for abiraterone alone (P < .0001). “This is a statistically significant and clinically meaningful difference,” Dr. Saad said.
Predefined subgroup analysis showed radiographic progression-free survival improvement for 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).
There was a favorable trend toward improved overall survival with olaparib plus abiraterone vs abiraterone alone; however, the difference did not reach statistical significance at the time of this early data cutoff. Overall survival will be followed at future time points.
In the overall study population, olaparib plus abiraterone was superior to abiraterone alone for the following secondary endpoints: time to first subsequent therapy, second progression-free survival, objective response rate, as well as prostate-specific antigen levels and circulating tumor cell counts. Among the approximately 43% of patients with measurable disease, objective response rates were 58.4% for the combination and 48.1% for the control arm.
The safety and tolerability of the olaparib combination with abiraterone were consistent with those reported in other clinical trials as well as the established side-effect profiles of each agent. No increase in the rate of discontinuation of abiraterone was observed in patients who received the combination, and there was no detrimental effect on health-related quality of life vs those treated with abiraterone alone, according to the results of the Functional Assessment of Cancer Therapy–-Prostate questionnaire.
The most common adverse events (experienced by ≥ 20% of patients) were anemia (45%), nausea (28%), and fatigue (28%). Grade 3 or higher adverse events 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 in combination with abiraterone who experienced adverse events remained on treatment at the time of data cutoff.
In a previous phase II trial, there was a signal of potential cardiac toxicity using olaparib plus abiraterone,3 Dr. Saad noted. In PROpel, there was no difference in cardiac events or arterial thrombotic events between the two treatment arms. There were more venous thromboembolic events in the olaparib-containing arm, mostly pulmonary embolism, but these events were incidental findings on CT scan and did not lead to treatment discontinuation.
DISCLOSURE: Dr. Saad has received honoraria from AbbVie, Advanced Accelerator Applications, Astellas Pharma, AstraZeneca, Bayer, BMS, Janssen Oncology, Knight Therapeutics, Merck, Myovant Sciences, Novartis, Pfizer, and Sanofi; has served as a consultant or advisor to AbbVie, Advanced Accelerator Applications, Astellas Pharma, AstraZeneca/MedImmune, Bayer, Janssen Oncology, Knight Therapeutics, Myovant Sciences, Novartis, Pfizer, and Sanofi; and has received institutional research funding from Advanced Accelerator Applications, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen Oncology, Merck, Novartis, Pfizer, and Sanofi.
1. Saad F, Armstrong A, Thiery-Vuillemin T, et al: PROpel: Phase III trial of olaparib and abiraterone versus placebo and abiraterone as first-line therapy for patients with metastatic castration-resistant prostate cancer. 2022 ASCO Genitourinary Cancers Symposium. Abstract 11. Presented February 17, 2022.
2. Chi KN, Rathkopf DE, Smith MR, et al: Phase 3 MAGNITUDE study: First results of niraparib with abiraterone acetate and prednisone as first-line therapy in patients with metastatic castration-resistant prostate cancer with and without homologous recombination repair gene alterations. 2022 ASCO Genitourinary Cancers Symposium. Abstract 12. Presented February 17, 2022.
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 19:975-986, 2018.
Celestia S. Higano, MD
Formal discussant Celestia S. Higano, MD, Adjunct Professor in the Department of Urologic Sciences at the University of British Columbia, Vancouver, had the task of reviewing the results of both the MAGNITUDE and PROpel trials, which were presented at the same session....