Olaparib Demonstrates Significant PFS Benefit in Phase III mCRPC Trial

Jose Baselga, MD, PhD

Jose Baselga, MD, PhD,

Olaparib (Lynparza) demonstrated a statistically significant improvement in radiographic progression-free survival (rPFS) compared with enzalutamide (Xtandi) or abiraterone acetate (Zytiga) in men with metastatic castration-resistant prostate cancer (mCRPC) who have a homologous recombination repair (HRR) mutation and have progressed on prior treatment with new hormonal anticancer treatments, according to early findings from the PROfound trial.

The clinically meaningful benefit in rPFS with olaparib in men withBRCA1/2orATMmutations met the primary endpoint of the phase III clinical trial, AstraZeneca and Merck (MSD), the companies jointly developing and commercializing the PARP inhibitor, announced in a press release. The safety profile for olaparib was also found to be consistent with prior reports of the agent from previous studies.

The companies are planning to present further findings from the PROfound trial at an upcoming medical meeting.

“For men with metastatic castration-resistant prostate cancer the disease remains deadly, especially in those who have failed on a new hormonal anticancer treatment. This trial is the only positive phase III trial of any PARP inhibitor in metastatic castration-resistant prostate cancer, where the need for new, effective therapies is high. The PROfound trial also demonstrates the potential value of genomic testing in this at-risk patient population. We look forward to discussing these results with global health authorities soon,” said José Baselga, MD, PhD, executive vice president, Oncology Research & Development, AstraZeneca, in the press release.

PROfound is an ongoing randomized, multinational, open-label phase III trial investigating olaparib versus enzalutamide or abiraterone in previously treated men with mCRPC who have HRR mutations (NCT02987543). About 340 patients have been enrolled in the trial and were randomized 2:1 to olaparib or the investigator’s choice of enzalutamide or abiraterone acetate. The patients in the trial were also divided into 2 cohorts based on their HRR mutation status: cohort A includes men with aBRCA1/2orATMmutation (approximately 240 men) and cohort B includes men with a mutation in one of the 12 other HRR genes (approximately 100 men).

Patients who have received prior treatment with a PARP inhibitor or DNA-damaging cytotoxic chemotherapy were not eligible for enrollment, as well as patients with other malignancies within the past 5 years or known brain metastases.

Olaparib is given at 300 mg twice daily, enzalutamide at 160 mg once daily, and abiraterone acetate at 1000 mg once daily in combination with prednisone 5 mg twice daily. Treatment in both arms is to be continued until radiographic progression assessed by blinded independent central review or unacceptable toxicity.

The primary endpoint of the trial is rPFS by RECIST 1.1 and the Prostate Cancer Clinical Trials Working Group 3 criteria in cohort A, and secondary endpoints include objective response rate, time to pain progression, overall survival, rPFS in cohort B, and safety.

“Metastatic castration-resistant prostate cancer is a deadly disease and represents an area of critical unmet medical need. The phase III PROfound trial is another example of MSD and AstraZeneca’s shared commitment to improving long-term outcomes for people living with cancer. These results represent the potential for a new, oral targeted treatment option for this patient population,” Roy Baynes, senior vice president, head of global clinical development, and chief medical officer, MSD Research Laboratories, said in the press release.

Olaparib has received a breakthrough therapy designation from the FDA for the treatment of patients withBRCA1/2orATM-mutated mCRPC who have received prior taxane-based chemotherapy and at least either hormonal agent enzalutamide or abiraterone acetate. The designation was based on findings from the phase II TOPARP-A trial.

The PARP inhibitor is also being investigated in the ongoing phase III PROpel trial as a first-line treatment regimen in combination with abiraterone acetate compared with abiraterone acetate and placebo in men with mCRPC (NCT03732820).

Reference:

Lynparza Phase III PROfound trial in HRR* mutation-selected metastatic castration-resistant prostate cancer met primary endpoint [press release]. Kenilworth, NJ: AstraZeneca and MSD Inc; August 7, 2019. https://bit.ly/2YNczoS. Accessed August 7, 2019.