The addition of olaparib to abiraterone acetate resulted in numerically higher prostate-specific antigen response rates and prolonged time to PSA progression vs abiraterone alone when used in the frontline treatment of patients with metastatic castration-resistant prostate cancer.
The addition of olaparib (Lynparza) to abiraterone acetate (Zytiga) resulted in numerically higher prostate-specific antigen (PSA) response rates and prolonged time to PSA progression vs abiraterone alone when used in the frontline treatment of patients with metastatic castration-resistant prostate cancer (mCRPC), according to data from an exploratory analysis of the phase 3 PROpel trial (NCT03732820) presented during the 2023 AUA Annual Meeting.1
In the intention-to-treat (ITT) population, 79.3% of those who received the doublet (n = 397) experienced at least a 50% decline in PSA concentration from baseline (PSA50) vs 69.2% of those who received abiraterone alone (n = 396), equating to a difference of 10.1%.
The improvement in PSA50 response rates with olaparib plus abiraterone was observed across all subgroups analyzed but the effect was most pronounced in those with BRCA-mutated disease. In this group, the PSA50response rate in the investigative arm (n = 47) was 85.1% vs 51.4% in the control arm (n = 37), translating to a difference of 33.7%.
Moreover, the median time to PSA progression in the ITT population was 24.18 months with olaparib plus abiraterone (n = 399) vs 12.02 months with abiraterone alone (n = 397; HR, 0.59; 95% CI, 0.49-0.71). This benefit with the doublet was observed in both the BRCA-mutated and non–BRCA-mutated populations, with the most pronounced difference between treatment arms observed in the mutated population.
Specifically, in the BRCA-mutated subset, the median time to PSA progression was 40.61 with the investigative regimen (n = 47) vs 5.59 months with the control regimen (n = 38; HR, 0.14; 95% CI, 0.08-0.25). Those in the non–BRCA-mutated group who received olaparib (n = 343) had a median time to PSA progression of 22.01 months vs 13.08 months in those who did not (n = 350; HR, 0.67; 95% CI, 0.55-0.82).
“The PSA results are consistent with the primary and secondary results of PROpel, and support olaparib plus abiraterone as an important new first-line treatment option for patients with mCRPC,” lead study author Fred Saad, MD, of the Centre Hospitalier de l’Université de Montréal/CRCHUM, Université de Montreal, Montreal, Canada, said in a moderated poster presentation on the data.
The double-blind, placebo-controlled, phase 3 PROpel trial enrolled patients with histologically or cytologically confirmed prostate adenocarcinoma with at least 1 documented metastatic lesion who were at least 18 years of age and had an ECOG performance status of 0 or 1.1,2 Patients could not have previously received abiraterone. Other next-generational hormonal agents were permitted if they were stopped at least 1 year prior to study enrollment.
Study participants were randomly assigned 1:1 to receive olaparib at a twice-daily dose of 300 mg and abiraterone at a daily dose of 1000 mg (n = 399) or placebo plus abiraterone alone at the same dose and schedule (n = 397). All patients were given prednisone or prednisolone at a twice-daily dose of 5 mg per the abiraterone label requirement. Treatment was continued until progressive disease, intolerable toxicity, or withdrawn consent. After progression, further treatment was decided based on investigator discretion.
Patients were stratified based on site of distant metastasis (bone only vs visceral vs other) and whether they previously received a taxane for metastatic hormone-sensitive prostate cancer (yes vs no).
Radiographic progression-free survival (rPFS) by investigator assessment served as the primary end point of the trial, and overall survival (OS) was a key secondary end point.
Baseline characteristics were noted to be balanced between the olaparib and placebo arms. The median age was 69.5 years (range, 43-91), and most patients had an ECOG performance status of 0 (71.7% vs 68.5%, respectively) and the bone as their site of metastases (87.5% vs 85.4%). In the olaparib arm, 27.8% of patients had homologous recombination repair (HRR) mutations, 69.9% did not, and 2.3% had unknown status; in the placebo arm, these rates were 29.0%, 68.8%, and 2.3%, respectively. Moreover, 11.8% of those in the investigative arm had BRCA-mutated disease and 86.0% did not; these rates were 9.6% and 88.2%, respectively, in the control arm.
Earlier data from the trial showed that the median rPFS with the addition of olaparib to abiraterone was 24.8 months vs 16.6 months with abiraterone alone, translating to a 34% reduction in the risk of disease progression or death that met the primary end point of the trial (HR, 0.66; 95% CI, 0.54-0.81; P < .0001). The rPFS benefit achieved with olaparib over placebo was observed across prespecified subsets.
Moreover, findings from a post-hoc analysis of aggregate HRR-mutated, non–HRR-mutated, BRCA-mutated, and non–BRCA-mutated subgroups revealed favorable rPFS with olaparib plus abiraterone compared with abiraterone alone for those with and without an HRR mutation and/or a BRCA mutation. For those who were positive for HRR mutations, the HR for rPFS was 0.50 (95% CI, 0.34-0.73); the HR was 0.76 (95% CI, 0.60-0.97) for those who were without such mutations. The HR for rPFS in those who had BRCA-positive disease was 0.23 (95% CI, 0.12-0.43); in those without BRCA mutations, the HR was 0.76 (95% CI, 0.61-0.94).
The median OS with olaparib plus abiraterone was 42.1 months vs 34.7 months with abiraterone alone, translating to a 7.4-month difference between the arms (HR, 0.81; 95% CI, 0.67-1.00; P = .0544); however, the trial was not powered to demonstrate statistical significance for OS.
Investigators evaluated PSA levels at baseline, at the time of the first treatment, and every 4 weeks thereafter until treatment was discontinued. They defined PSA50 response rate as the proportion of patients who achieved at least a 50% reduction in PSA from baseline to lowest post-baseline result; this was confirmed by a second consecutive PSA result at least 3 weeks later.
Time to PSA progression was defined as the time from randomization to first PSA progression in accordance with Prostate Cancer Working Group 3 (PCWG3) criteria. Those who did not meet the criteria for progression were censored at their last assessment for PSA. If they had no evaluable or post-baseline assessments, they were censored at day 1. If they received subsequent treatment, findings were only included until the subsequent treatment was initiated.
Additional data from the analysis presented at the meeting showed that in the non–BRCA-mutated group, the PSA50 response rates were 78.6% with olaparib (n = 341) and 71.4% without olaparib (n = 350). In the homologous recombination repair (HRR)–mutated group, these rates were 78.2% in the investigative arm (n = 110) and 63.2% in the control arm (n = 114). In the non–HRR-mutated group, these rates were 79.9% with olaparib (n = 276) and 72.2% without (n = 273).
The time to PSA progression was prolonged with olaparib plus abiraterone in the HRR-mutated group, as well as the non–HRR-mutated group. For those with HRR mutations who received olaparib (n = 111), the median time to PSA progression was 25.10 months vs 9.17 months in those who did not (n = 115; HR, 0.41; 95% CI, 0.29-0.59). Those in the non–HRR-mutated group who received olaparib (n = 115) experienced a median time to PSA progression of 23.10 months vs 13.83 months in those who did not (n = 273; HR, 0.67; 95% CI, 0.53-0.84).
“The delay in time to PSA progression per PCWG3 observed for patients receiving olaparib plus abiraterone in each biomarker subgroup, including the non–BRCA-mutated and non–HRR-mutated subgroups, supports the proposed mode of action for combination olaparib plus abiraterone treatment in a biomarker-unselected population,” the study authors wrote in the poster.
In August 2022, the FDA granted priority review to a supplemental new drug application (sNDA) seeking the approval of olaparib plus abiraterone and prednisone or prednisolone for the treatment of patients with mCRPC based on data from PROpel.3
Although the regulatory agency initially expected to rule on the application in the fourth quarter of 2022, in December 2022, they opted to extend the Prescription Drug User Fee Act decision date by 3 months to provide further time for a full review of the application.4
In March 2023, it was announced that an Oncologic Drugs Advisory Committee meeting will take place on April 28, 2023 to discuss the sNDA for this patient population.