Results from the PROpel Phase III trial showed that olaparib in combination with abiraterone significantly improved radiographic progression-free survival (rPFS) versus abiraterone alone as a 1st-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) with or without homologous recombination repair (HRR) gene mutations.
The results, showing the combination reduced the risk of disease progression or death by 34% versus abiraterone alone (based on a hazard ratio [HR] of 0.66; 95% confidence interval [CI] 0.54-0.81; p<0.0001), are now published in the New England Journal of Medicine (NEJM).
Prostate cancer is the second most common cancer in male patients, causing approximately 375,000 deaths in 2020.1 In clinical trial settings, overall survival for patients with mCRPC is approximately 3 years, while in the real-world setting this is shorter.
Approximately half of patients with mCRPC may receive only one line of active treatment, with diminishing benefit of subsequent therapies.
HRR gene mutations occur in approximately 20-30% of patients with mCRPC.
Noel Clarke, Urological Surgeon and Professor of Urological Oncology at The Christie/Salford Royal Hospitals and University of Manchester; the PROpel trial joint Chief Investigator and joint lead author of the NEJM Evidence manuscript, said: “It is critically important that we identify new first-line treatment options for patients with metastatic castration-resistant prostate cancer.
The data published in NEJM Evidence emphasise the therapeutic potential of combining olaparib with abiraterone and prednisone and demonstrate efficacy in a wider group of patients beyond those with documented DNA repair deficiency.”
Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, said: “These data demonstrate that the combination of olaparib with abiraterone and prednisone afforded patients a median radiographic progression-free survival of over two years, regardless of biomarker status.
If approved, the combination will offer patients with and without HRR gene mutations a much-needed new treatment option.”
Dr Eliav Barr, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: “Publication of the PROpel data in NEJM Evidence reflects the benefit seen with the combination of olaparib plus abiraterone and prednisone in the first-line setting of metastatic castration-resistant prostate cancer, and we are pleased that these data have been selected for one of the first issues of this new journal."
In September 2021, at a planned interim analysis, the Independent Data Monitoring Committee concluded that the PROpel trial met the primary endpoint of rPFS.
The results were presented in February 2022 during 2022 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium and additional data on Safety and Tolerability as well as Pharmacokinetics were presented at ASCO 2022 on 6 June 2022.
In the PROpel Phase III trial, on the primary endpoint, olaparib in combination with abiraterone improved median rPFS to 24.8 months versus 16.6 for abiraterone alone.
Results also showed that olaparib in combination with abiraterone extended median rPFS by BICR (blinded independent central review) analysis by almost a year, with a median rPFS of 27.6 months versus 16.4 with abiraterone alone.
Results also showed a favourable trend towards improved overall survival (OS) with olaparib plus abiraterone versus abiraterone alone, however the difference did not reach statistical significance at the time of this data cut-off (28.6% maturity; based on a HR of 0.86; 95% CI 0.66-1.12; P=0.29).
Data from the additional secondary efficacy endpoints of time to first subsequent therapy (TFST) (HR, 0.74; 95% CI, 0.61-0.90) and second progression-free survival (PFS2) (HR, 0.69; 95% CI, 0.51-0.94); and exploratory endpoints including objective response rate (ORR) (odds ratio, 1.60; 95% CI,1.02-2.53) as well as prostate-specific antigen levels, determining the time to PSA progression (HR, 0.55; 95% CI, 0.45-0.68), further support the treatment benefit of olaparib and abiraterone compared to abiraterone alone in the overall trial population.
The safety and tolerability of olaparib in combination with abiraterone was in line with that observed in prior clinical trials and the known profiles of the individual medicines.
There was no increase in the rate of discontinuation of abiraterone in patients treated with olaparib in combination with abiraterone, and no detrimental effect on health-related quality of life versus those treated with abiraterone alone (FACT-P (Functional Assessment of Cancer Therapy-Prostate) questionnaire).
Olaparib is approved in the US for patients with HRR gene-mutated mCRPC (BRCA-mutated and other HRR gene mutations) who have progressed following prior treatment with enzalutamide or abiraterone; and in the EU, Japan and China for patients with BRCA-mutated mCRPC who have progressed following prior therapy that included a new hormonal agent (NHA).
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