Patients with with metastatic castration-resistant prostate cancer continued to derive notable benefit from treatment with first-line olaparib plus abiraterone acetate and prednisone or prednisolone compared with abiraterone monotherapy.
Treatment with olaparib (Lynparza) plus abiraterone acetate (Zytiga) and prednisone or prednisolone resulted in continued overall survival (OS) benefit compared with single-agent abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC), according to updated findings from the phase 3 PROpel trial (NCT03732820).1
Updated findings presented during the 2022 European Society for Medical Oncology Congress (ESMO), which had a data cutoff date of March 14, 2022, showed that the olaparib plus abiraterone (n = 399) produced a radiologic progression-free survival (rPFS) benefit that was 8.6 months longer than that achieved with abiraterone alone (n = 397). The median rPFS in the investigative arm was 25.0 months vs 16.4 months in the control arm (HR, 0.67; 95% CI, 0.56-0.81; P < .0001).
Moreover, the time to first subsequent therapy or death (TFST) and time to second progression or death (PFS2) data also supported a trend toward longer-term benefit with the olaparib regimen. Specifically, the TFST with olaparib plus abiraterone was 25.4 months vs 19.5 months with abiraterone alone (HR, 0.76; 95% CI, 0.63-0.90; P = .0032). The PFS2 had not yet been reached in either arm (HR, 0.71; 95% CI, 0.54-0.94; P = .019).
At the time of this analysis, a continued trend toward OS was observed in the investigative arm vs the control arm. After approximately 22 months prior to extensive censoring, Kaplan-Meier curves showed a clear separation between the arms. At 40.1% maturity, the median OS in the intention-to-treat (ITT) population had not yet been reached in either arm (HR, 0.83; 95% CI, 0.66-1.03; P = .11).
“Updated results [from the] second interim analysis were consistent with the results from [the first analysis] and showed a continuing trend toward an OS benefit in the ITT population. The safety and tolerability results were generally consistent with the primary analysis and the known profiles for abiraterone and olaparib,” lead study author Fred Saad, MD, FRCS, of the Centre Hospitalier de l’Université de Montreal/CRCHUM, Université de Montreal, said in a presentation on the data. “Results from PROpel continue to support a superior clinical benefit with abiraterone plus olaparib vs abiraterone plus placebo as first-line therapy for patients with mCRPC.”
The global, randomized, double-blind, phase 3 PROpel trial enrolled those with mCRPC who had an ECOG performance status of 0 or 1. Docetaxel during neoadjuvant or adjuvant treatment for localized prostate cancer and metastatic hormone-sensitive disease was permitted, but receipt of previous abiraterone was not. Other next-generation hormonal agents were allowed if they were stopped at least 12 months before study enrollment.
Study participants were randomly assigned 1:1 to receive either olaparib at a twice-daily dose of 300 mg or placebo in combination with abiraterone at a daily dose of 1000 mg.
Key stratification factors included site of distant metastases (bone only vs visceral vs other) and prior taxane at mHSPC (yes vs no).
Investigator-assessed rPFS served as the primary end point of the trial, and OS served as a key secondary end point. Additional end points comprised TFST, PFS2, objective response rate, homologous recombination repair (HRR) gene mutation status by tissue and circulating tumor DNA (ctDNA) testing, as well as safety and tolerability.
The baseline patient characteristics were noted to be well balanced between the treatment arms. The prevalence of patients with HRR mutations, including those with BRCA mutations, was consistent with prior studies that have been conducted, according to Saad.
The median age in the olaparib/abiraterone arm was 69.0 years (range, 43-91) vs 70.0 years (range, 46-88) in the control arm. In the investigative arm, 87.5% of patients had metastases in the bone, 33.3% in the distant lymph nodes, 20.6% in the locoregional lymph nodes, 10.0% in the lung, and 3.8% in the liver; these rates were 85.4%, 30.0%, 22.4%, 10.6%, and 4.5%, respectively, in the control arm.
Regarding HRR mutational status in the olaparib/abiraterone arm, 27.8% of patients had HRR-mutated disease, 69.9% had non–HRR-mutated disease, and 2.3% had unknown HRR mutational status; in the abiraterone-alone arm, 29.0% had HRR-mutated disease, 68.8% had non–HRR-mutated disease, and 2.3% had unknown status. In the investigative arm, 2.3% of patients harbored BRCA1 mutations, and 9.5% harbored BRCA2 mutations; these rates were 0.8% and 8.8%, respectively, in the control arm.
In August 2022, the FDA granted a priority review to a supplemental new drug application (sNDA) seeking the approval of olaparib plus abiraterone acetate and prednisone or prednisolone in adult patients with mCRPC.2,3 The sNDA was supported by earlier findings from PROpel.
The first data cutoff date for the primary analysis of the trial was July 30, 2021. At this time point, the addition of olaparib to abiraterone resulted in a 34% reduction in the risk of rPFS vs abiraterone alone in the ITT population. The median rPFS was 24.8 months in the investigative arm and 16.6 months in the control arm (HR, 0.66; 95% CI, 0.54-0.81; P < .001).
Notably, a rPFS benefit was noted across all patients subgroups analyzed, including the HRR-mutated and BRCA-mutated subgroups.
Archival tumor tissue and blood samples were collected at baseline and tested using the FoundationOne CDx and FoundationOne Liquid CDx, respectively. By aggregating both sets of data, participants were assigned to the following subgroups: 226 had HRR-mutated disease, 552 had non–HRR-mutated disease, and 18 had unknown status.
At the time of the primary analysis, a benefit was noted with the olaparib regimen across the HRR-mutated and non–HRR-mutated subgroups. Specifically, among those with HRR-mutated disease who received olaparib plus abiraterone (n = 111), the median rPFS was not yet reached per investigator assessment vs 13.9 months in those who were given abiraterone alone (n = 115; HR, 0.50; 95% CI, 0.34-0.73). In the non–HRR-mutated subgroup, those who received the investigative regimen (n = 279) had a median rPFS of 24.1 months vs 19.0 months in those who were given the control regimen (n = 273; HR, 0.76; 95% CI, 0.60-0.97).
Data from a sensitivity analysis by blinded independent central review (BICR) showed that in the HRR-mutated subgroup, the median rPFS was 28.8 months with the olaparib regimen vs 13.8 months with abiraterone alone (HR, 0.45; 95% CI, 0.31-0.65). In the non–HRR-mutated subgroup, those who were given the investigative regimen experienced a median rPFS of 27.6 months vs 19.1 months in those who received the control regimen (HR, 0.72; 95% CI, 0.56-0.93).
Notably, a benefit with olaparib plus abiraterone was observed across the following subgroups: those with BRCA mutations, those with non–BRCA-mutated disease, those with BRCA2 mutations, and those with non–BRCA2-mutated disease.
Specifically, within the BRCA-mutated subgroup, the median rPFS was not yet reached in those given the investigative regimen (n = 47) vs 8.4 months in those who received the control regimen (n = 38; HR, 0.23; 95% CI, 0.12-0.43). In the non–BRCA-mutated subgroup, those who received olaparib plus abiraterone (n = 343) experienced a median rPFS of 24.1 months vs 19.0 months with abiraterone alone (n = 350; HR, 0.76; 95% CI, 0.61-0.94).
Data from the sensitivity analysis by BICR showed that in the BRCA-mutated subgroup, the median rPFS with the investigative and control regimens was not yet reached and 8.4 months, respectively (HR, 0.18; 95% CI, 0.09-0.34); in the non–BRCA-mutated subgroup, the median rPFS was 27.6 months and 16.6 months, respectively (HR, 0.72; 95% CI, 0.58-0.90).
“In the assessed biomarker subgroup analyses, there was an improvement of at least 5 months [with olaparib plus abiraterone vs abiraterone alone], which was most pronounced in the BRCA-mutated subgroup,” Saad said.
Updated safety findings proved to be consistent with that had been reported in the primary analysis.
One case of myelodysplastic syndrome/acute myeloid leukemia was identified during hospital admission for fatal COVID-19 pneumonia, Saad noted. The incidence of new primary malignancies and pneumonitis were balanced between the olaparib/abiraterone and abiraterone-alone arms. Additionally, the incidence of pulmonary embolism and cardiovascular events were comparable between the first and second data cutoff dates, according to Saad.
The most common grade 3 or higher adverse effects occurring in at least 10% of patients in the investigative and control arms included anemia (15.8% vs 3.3%, respectively), fatigue or asthenia (2.3% vs 1.5%), nausea (0.3% vs 0.3%), back pain (1.0% vs 1.0%), diarrhea (1.0% vs 0.3%), constipation (0% vs 0.3%), decreased appetite (1.0% vs 0%), hypertension (3.8% vs 3.5%), arthralgia (0% vs 0.5%), vomiting (1.3% vs 0.3%), peripheral edema (0% vs 0.3%), and urinary tract infection (2.3% vs 1.0%).