“Overall survival in metastatic castration-resistant prostate cancer has remained extremely challenging to achieve. We are thrilled by these results for Lynparza and we are working with regulatory authorities to bring this medicine to patients as soon as possible.”
The PARP inhibitor olaparib (Lynparza) induced a statistically significant improvement in overall survival (OS) compared with enzalutamide (Xtandi) or abiraterone (Zytiga) as treatment of men with metastatic castration-resistant prostate cancer (mCRPC) who have a homologous recombination repair gene mutation (HRRm), BRCA1/2 or ATM mutation, and previously progressed on a new hormonal agent therapy, meeting the the key secondary end point of the phase III PROfound trial (NCT02987543), announced Merck & Co., Inc..
Olaparib demonstrated a safe and tolerable profile that was consistent with data from previous trials. The findings from the PROfound clinical trial will be presented at an upcoming medical meeting.
“Overall survival in metastatic castration-resistant prostate cancer has remained extremely challenging to achieve,” said José Baselga, executive vice president, Oncology R&D, in a statement. “We are thrilled by these results for Lynparza and we are working with regulatory authorities to bring this medicine to patients as soon as possible.”
The trial met its primary end point with significant improvement of radiographic progression-free survival (rPFS), in and the trial also achieved a key secondary end point of rPFS in patients from the overall HRRm population, according to findings previously reported at the 2019 European Society for Medical Oncology Congress.
The median rPFS for patients with BRCA1/2 or ATM alterations was 7.39 months with olaparib versus 3.55 months in the control arm (HR, 0.34; 95% CI, 0.25-0.47; P <.0001). The 12-month rPFS rate was 40% with olaparib versus 11% in the control arm. The investigators also noted improvements in the objective response rate, pain progression, and OS, but the OS improvement was not statistically significant.
The trial included 2 cohorts of patients; cohort A consisted of patients harboring BRCA1/2 or ATM alterations (n =245), and cohort B included patients with an alteration in BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, PPP2R2A, RAD51B/C/D, or RAD54L (n = 142). Patients in cohort A had more established markers of HRR, while the alterations in cohort B were associated with HRR but not as established.
This prospective, multicenter, open-label clinical trial is evaluating the efficacy and safety of olaparib versus enzalutamide or abiraterone as treatment of patients with mCRPC who previously progressed on prior treatment with a new hormonal agent and have a qualifying tumor mutation in the BRCA1/2, ATM or 1 of 12 other genes in the HRR pathway.
Patients of cohort A received olaparib (n = 162) or abiraterone plus prednisone or enzalutamide (n = 83). Patients of cohort B received either olaparib (n = 94) or abiraterone plus prednisone or enzalutamide (n = 48), as well. Olaparib was given twice daily at a dose of 300 mg, abiraterone was administered at 1000 mg per day with prednisone at 5 mg twice daily, while enzalutamide was given once daily at a dose of 160 mg.
To be included in this clinical trial, patients had to have a histologically confirmed diagnosis of prostate cancer, documented evidence of mCRPC, and have progressed on prior a new hormonal agent, such as abiteraterone or enzalutamide. Patients were also allowed to enroll in the study if they had ongoing therapy with LHRH analog or bilateral orchiectomy, as well as radiographic progression at study entry while on androgen deprivation therapy or following bilateral orchiectomy. They also had to have an HRR mutation in their tumor tissue.
Eligibility criteria included prior treatment with a PARP inhibitor, any previous therapy with DNA-damaging cytotoxic chemotherapy, or another diagnosed malignancy. Patients were also unable to enroll to the study if they had known brain metastases.
In January 2020, olaparib received a Priority Review designation from the FDA as a treatment of patients with HRRm mCRPC. Regulatory reviews remain ongoing in the European Union and other jurisdictions for this indication as well.
Lynparza demonstrated overall survival benefit in Phase III PROfound trial for BRCA1/2 or ATM-mutated metastatic castration-resistant prostate cancer [news release]. Kenilworth, NJ: Merck & Co., Inc.; April 24, 2020. https://bit.ly/2VYmMeL. Accessed April 24, 2020.