Results from the pivotal phase 3 PROpel trial demonstrating that addition of olaparib (Lynparza) to frontline abiraterone acetate (Zytiga) significantly improved radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (mCRPC) are published in the New England Journal of Medicine†1.2
The data, previously presented at the ASCO Genitourinary Cancers Symposium in 2022, showed that the median investigator-assessed rPFS was 24.8 months with olaparib/abiraterone versus 16.6 months with placebo/abiraterone, translating into a reduction of 34% in risk of radiographic disease progression or death (HR 0.66; 95% CI 0.54-0.81; p <.0001). The 1- and 2-year rPFS rates were 71.8% and 51.4% in the olaparib/abiraterone arm, respectively; these rates were 63.4% and 33.6%, respectively, with placebo/abiraterone.
When evaluated by blinded independent central review, the median rPFS with olaparib/abiraterone was 27.6 months versus 16.4 months with placebo/abiraterone, leading to a 39% reduction in the risk of disease progression or death on radiography ( HR 0.61, 95% CI, 0.49-0.74; p <.0001). The 1- and 2-year rPFS rates with olaparib plus abiraterone were 73.8% and 53.7%, respectively. In the placebo/abiraterone arm these percentages were 60.6% and 34.1%, respectively.
“It is critical that we identify new first-line treatment options for patients with metastatic castration-resistant prostate cancer. The data published in NEJM proof highlight the therapeutic potential of combining olaparib with abiraterone and prednisone and demonstrate efficacy in a broader group of patients than those with documented DNA repair deficiency,” Noel Clarke, MBBS, FRCS, ChM, urological surgeon and professor of Urological Oncology at The Christie/ Salford Royal Hospitals and University of Manchester; the joint principal investigator of the PROpel study and the joint lead author of the NEJM Evidence manuscript, stated in a press release.
In the international, double-blind, phase 3 PROpel study (NCT03732820), investigators randomized patients with mCRPC in the first-line setting 1:1 to olaparib 300 mg twice daily plus abiraterone 1000 mg daily (n = 399) or placebo and abiraterone 1000 mg daily (n=397). Patients could have received docetaxel in the setting of metastatic hormone-sensitive prostate cancer (mHSPC), but prior abiraterone was not allowed. Other NHAs were allowed if they were discontinued at least 12 months prior to study enrollment. Patients also had ongoing androgen deprivation therapy and an ECOG performance status of 0 or 1.
Stratification factors included the site of distant metastases (bone only vs. visceral vs. others) and prior taxane in the mHSPC setting (yes vs. no).
The primary endpoint was investigator-assessed rPFS, with OS as the secondary endpoint. Additional outcome measures included time to first subsequent therapy or death (TFST), time to second progression or death (PFS2), objective response rate (ORR), prevalence of HRR mutations (retrospective testing), health-related quality of life and safety and tolerability.
Baseline characteristics were well balanced between the 2 arms. The median age was 69.5 years (range, 43-91), and most patients had an ECOG performance status of 0 (70.1%). Note that symptomatic patients (short-form pain inventory 4 and/or opiate use) were 25.8% and 20.2% of olaparib and placebo-treated patients, respectively; 22.5% of patients had received docetaxel at the mHSPC stage.
In addition, patients had either HRR mutations (27.8% with olaparib vs 29.0% with placebo), non-HRR mutations (69.9% vs 68.8%, respectively), or unknown HRR mutation status (2 each .3%). The median PSA was 17.90 µg/L (interquartile range [IQR], 6.09-67.00) with olaparib/abiraterone and 16.81 µg/L (IQR, 6.26-53.30) with placebo/abiraterone. Most metastases occurred in bone in 87.5% and 85.4% of patients, respectively.
Additional findings showed that the rPFS benefit was observed in all pre-specified subgroups, including age (<65 years, HR, 0.51; 95% CI, 0.35-0.75; ≥65 years, HR, 0, 78; 95% CI, 0.62-0.98), distant metastasis site (bone only, HR 0.73; 95% CI 0.54-0.98; visceral HR 0.62; 95% CI 0 .39-0.99; other HR 0.62; 95% CI 0.44-0.85) prior docetaxel (yes, HR 0.61; 95% CI 0.40-0.92; no HR 0.71 95% CI 0.56-0.89) and HRR mutation status (HRR mutant, HR 0.50; 95% CI 0.34-0.73; non-HRR mutant, HR, 0.76, 95 %CI, 0.60-0.97).
OS data, which had a maturity of 28.6%, showed that median OS was not achieved in either arm, but showed a trend towards improved survival with olaparib/abiraterone versus placebo/abiraterone (HR 0, 86, 95% CI 0.66-1.12, pre-specified 2-sided alpha p = .29).
TFST was also favored with the addition of olaparib. The median TFST was 25.0 months in the olaparib/abiraterone arm compared to 19.9 months in placebo/abiraterone (HR 0.74; 95% CI 0.61-0.90; p = .004). In addition, the median PFS2 was not achieved in either arms, but supported the long-term benefit with olaparib/abiraterone (HR 0.69; 95% CI 0.51-0.94; p = .0184).
When evaluated for response, the ORR with olaparib plus abiraterone was 58.4% with a 4.3% complete response rate (CR) and a 54.0% partial response rate (PR). The rate of stable disease (SD) was 26.1% and the rate of progressive disease (PD) was 13.7%. In the placebo/abiraterone arm, the ORR was 48.1%, consisting of a CR rate of 6.3% and a PR rate of 41.9%; the SD and PD rates were 28.1% and 19.4%, respectively. The odds ratio in ORR between olaparib/abiraterone and placebo/abiraterone was 1.60 (95% CI: 1.02-2.53; p = .0409).
Overall, 40.3% of the total study population had measurable disease according to RECIST v1.1 criteria at baseline.
In terms of safety, adverse events (AEs) occurred in 97.2% and 94.9% of olaparib/abiraterone and placebo/abiraterone-treated patients, respectively; Grade 3 or higher adverse reactions occurred in 47.2% and 38.4% of patients, respectively. AE-related deaths occurred in 4.0% (n = 16) of those in the olaparib arm compared to 4.3% (n = 17) of patients in the placebo arm.
Dose interruptions and reductions occurred in 44.7% and 20.1% of patients who received the addition of olaparib; these rates were 25.3% and 5.6% for those in the placebo arm.
In addition, more patients discontinued olaparib due to an AE (13.8%) compared to 7.8% of patients receiving placebo. Overall, 8.5% and 8.8% of patients in each arm discontinued abiraterone due to an adverse event, respectively.
No cases of myelodysplastic syndrome or acute myeloid leukemia have been reported, and the incidence of new primary cancers and pneumonitis was evenly distributed between the two arms.
The AE profiles were consistent with the known toxicity profiles of the individual agents. The most common adverse reaction of all grades and grade 3 or greater with olaparib was anemia (46.0% and 15.1%, respectively). In the placebo arm, this occurred in 16.4% and 3.3% of patients, respectively.
Heart failure occurred at comparable rates between the 2 arms in 1.5% with olaparib and 1.3% with placebo; arterial thromboembolic events were also comparable at 2.0% and 2.5%, respectively. However, numerically higher venous thromboembolic events were reported for olaparib/abiraterone (7.3%) vs placebo/abiraterone (3.3%), with pulmonary embolism being the most commonly reported venous thromboembolic event (6.5% vs. 1.8%). Pulmonary embolism events were mostly incidental findings via CT scans, and this did not lead to discontinuation of olaparib or abiraterone.
Quality of life was also found to be comparable between the 2 groups.
1. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al. Abiraterone and olaparib for metastatic castration-resistant prostate cancer [published online June 21, 2022]† NEJM proof† doi: 10.1056/EVIDoa2200043
2. Positive results of PROpel Phase III trial of Lynparza plus abiraterone in first-line metastatic castration-resistant prostate cancer published in New England Journal of Medicine. Published online June 21, 2022. Accessed June 22, 2022. https://bit.ly/3yawhf2