Olaparib Treatment Leads to Significant Survival Improvement in Patients with mCRPC

Maha Hussain, MD

A significantly longer overall survival (OS) was observed with olaparib (Lynparza) in patients with metastatic castration-resistant prostate cancer (mCRPC) who had tumors with at least 1 alteration in BRCA1, BRCA2, or ATM, compared with those who received enzalutamide (Xtandi) or abiraterone (Zytiga) plus prednisone, according to research presented at the 21st Annual Meeting of the Society of Urologic Oncology.¹

The PROfound study enrolled 387 patients with mCRPC who had disease progression on prior new hormonal agents and an alteration in 1 or more qualifying gene with a direct or indirect role in HRR.

Cohort A was comprised of patients with mutations in BRCA1, BRCA2, or ATM and were considered the primary population for the analysis. Cohort B was comprised of patients with all other HRR mutations.

Overall results of the trial were positive, with patients in cohort A demonstrating higher radiographic progression-free survival (PFS; 7.4 mo vs 3.6 mo, respectively; HR 0.34 0.25-0.47, P<0.001), median time to pain progression (HR 0.44 0.22-0.91, P <0.02), and overall survival (19.1 months vs 14.7 mo, HR 0.69 9.50-0.97 P =0.02) than patients in cohort B.

Additionally, 81% of patients who progressed after receiving the control treatment crossed over to the olaparib arm.

“Olaparib is the first targeted therapy to demonstrate a radiographic PFS and OS benefit in phase 3 trials in metastatic castration-resistant prostate cancer patients with HRR mutations, thus really ushering in the era of precision medicine in prostate cancer,” said PROfound investigator Maha Hussain, MD, deputy director, Robert H. Lurie Comprehensive Cancer Center.

Results of the PROfound study, previously published in the New England Journal of Medicine², resulted in the FDA approval of olaparib for HRR gene-mutated mCRPC in May.

An exploratory gene by gene analysis showed that the benefit of olaparib varied significantly between patients based on their underlying mutation. Patients with BRCA2 appeared to derive the most benefit, with a median overall survival of 24.8 months (95% CI; 17.4-NC) vs 15.2 months (95% CI; 10.7-19.8) for the control group. Survival benefits were also indicated for patients with BRCA1 mutations (11.7 months vs. 9.4 months, respectively), ATM mutations (18.0 months vs. 15.6 months, respectively), CDK12 mutations (14.1 months vs. 11.5 months, respectively) and RAD54L (19.3 months vs. 5.7 months, respectively).

As a caveat, Hussain noted that gene-level analysis is complex, and results may be confounded by multiple factors.

The gene-level breakdown was the subject of a counterpoint presentation from Daniel Spratt, MD, chair of Genitourinary Clinical Research at the University of Michigan Rogel Cancer Center, who noted that the signal of benefit outside of BRCA mutations was not as strong, and that the FDA approval of olaparib may have been too broad.

Despite the practice-changing results of the PROfound trial, Hussain concluded by noting that questions and answers still remained.

“Certainly, there is plenty of work to be done,” Hussain said. “Clearly we have to optimize the timing of therapy in relationship to other life prolonging treatments for castration-resistant disease, develop PARP inhibitor-based combination treatments, evaluate the role of PARP inhibitors in an earlier disease setting, and continue to invest in research to conquer prostate cancer.”

_References:

_{1. Hussain M. New Second Line Therapy for mCRPS:PARPi: Results from PROfound. Presented at 2020 SUO Annual Meeting; December 2-5.}

_{2. Hussain M, Mateo J, Fizazi K, et al. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer [published online ahead of print, 2020 Sep 20]. N Engl J Med. 2020;10.1056/NEJMoa2022485. doi:10.1056/NEJMoa2022485}