The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended the approval of olaparib in combination with abiraterone acetate and prednisone or prednisolone for use in adult patients with metastatic castration-resistant prostate cancer in whom chemotherapy is not indicated.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of olaparib (Lynparza) in combination with abiraterone acetate (Zytiga) and prednisone or prednisolone for use in adult patients with metastatic castration-resistant prostate cancer (mCRPC) in whom chemotherapy is not indicated.1
The positive opinion is supported by data from the phase 3 PROpel trial (NCT03732820), in which the olaparib regimen (n = 399) significantly improved radiographic progression-free survival (rPFS) over abiraterone/placebo (n = 397) in this patient population.2
At the time of the first data cutoff date of July 30, 2021 for the primary analysis of the trial, the median rPFS in the olaparib arm was 24.8 months vs 16.6 months in the placebo arm (HR, 0.66; 95% CI, 0.54-0.81; P < .001); this translated to a 34% reduction in the risk of disease progression or death in this population.
“Patients with mCRPC in the European Union have limited treatment options. This form of advanced prostate cancer has a poor prognosis, and the treatment decisions after initial diagnosis are critical,” Noel Clarke, PROpel joint senior investigator, as well as urological surgeon and professor of urological oncology at the Christie/Salford Royal Hospitals and University of Manchester, stated in a press release. “If approved in the European Union for prostate cancer of this type, olaparib in combination with abiraterone will provide a much-needed new treatment option for the many men with this condition.”
The double-blind, global, randomized phase 3 trial enrolled patients with mCRPC who had an ECOG performance status of 0 or 1. Although neoadjuvant or adjuvant treatment with docetaxel for localized disease and metastatic hormone-sensitive disease was permitted, prior receipt of abiraterone was not. Patients were able to have previously received next-generation hormonal agents if they stopped at least 1 year before enrollment to the trial.
Patients were randomly assigned 1:1 to receive olaparib at 300 mg twice daily or placebo in combination with abiraterone acetate at 1000 mg daily. Randomization was stratified based on site of distant metastases (bone only vs visceral vs other) and previous taxane for metastatic hormone-sensitive prostate cancer (yes vs no).
The primary end point of the trial was investigator-assessed rPFS, and a key secondary end point was overall survival (OS). Investigators also evaluated time to first subsequent therapy or death (TFST), time to second progression or death (PFS2), objective response rate, homologous recombination repair (HRR) gene mutational status testing, safety, and tolerability.
Patient characteristics at baseline were noted to be well balanced across the treatment arms. Moreover, the prevalence of patients whose tumors harbored HRR mutations, including BRCA mutations, was in line with previous studies.
The median age in the investigative arm was 69.0 years (range, 43-91); in the control arm, the median age was 70.0 years (range, 46-88). Moreover, in the olaparib arm, 87.5% had metastases in the bone, 33.3% had them in the distant lymph nodes, 20.6% in the locoregional lymph nodes, 10.0% in the lung, and 3.8% in the liver; in the control arm, these rates were 85.4%, 30.0%, 22.4%, 10.6%, and 4.5%, respectively.
In the olaparib arm, 27.8% of patients had tumors harboring HRR mutations, 69.9% did not, and 2.3% had unknown mutational status; in the placebo arm, these rates were 29.0%, 68.8%, and 2.3%, respectively. Moreover, 2.3% and 9.5% of patients in the investigative arm had tumors harboring BRCA1 or BRCA2mutations, respectively; these rates were 0.8% and 8.8%, respectively, in the control arm.
Additional data from the PROpel trial, which had a cutoff date of March 14, 2022, were shared during the 2022 ESMO Congress.2 At this timepoint, the median rPFS was 25.0 months with the addition of olaparib to abiraterone vs 16.4 months with abiraterone alone (HR, 0.67; 95% CI, 0.56-0.81; P < .0001).
The TFST and PFS2 findings were noted to support a trend toward longer-term benefit with the olaparib combination vs abiraterone alone, at 25.4 months vs 19.5 months, respectively (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).
Additionally, a continued trend toward OS improvement was also observed with the investigative regimen vs the control. After about 22 months before extensive censoring, Kaplan-Meier curves showed a clear separation between the treatment arms. At 40.1% maturity, the median OS in the intention-to-treat population was not yet reached in either arm (HR, 0.83; 95% CI, 0.66-1.03; P = .11).
The safety of the olaparib combination was in line with what has been reported in previous clinical trials and in line with the known toxicity profiles of the individual agents.
The most frequent adverse effects (AEs) experienced by at least 20% of patients included anemia (46%), fatigue (37%), and nausea (28%). Grade 3 or higher AEs observed with the regimen included anemia (15%), hypertension (4%), urinary tract infection (2%), fatigue (2%), reduced appetite (1%), vomiting (1%), back pain (1%), diarrhea (1%), and nausea (0.3%).
Moreover, about 14% of patients who received the olaparib regimen discontinued treatment because of a toxicity.
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 based on earlier findings from PROpel.3 The regulatory agency will decide on the sNDA in the fourth quarter of 2022.