Update offers clues to optimal olaparib use in prostate cancer

Findings from the pivotal phase 3 PROfound trial presented during the 2021 AUA Annual Meeting provided fresh insight into the optimal use of olaparib (Lynparza) in patients with metastatic castration-resistant prostate cancer (mCRPC).1

Specifically, the investigators showed that the PARP inhibitor still produced a greater clinical benefit than enzalutamide (Erleada) or abiraterone acetate (Zytiga) in patients with mCRPC when the 2 novel hormonal agents (NHAs) were examined separately rather than combined.

The median radiographic progression-free survival (rPFS) with olaparib was 7.4 months vs 3.5 months (hazard ratio [HR], 0.35; 95% CI, 0.24-0.51) with abiraterone and 3.6 months (HR, 0.33; 95% CI, 0.21-0.52) with enzalutamide. Additionally, olaparib resulted in a median OS of 19.1 months vs 14.5 months (HR, 0.72; 95% CI, 0.48-1.11) with abiraterone and 14.9 months (HR, 0.65; 95% CI, 0.43-1.03) with enzalutamide.

Additionally, results from the trial indicated that there is limited benefit to sequential use of NHA and olaparib, suggesting that giving olaparib earlier in the treatment sequence may be beneficial.

“There is little, if any, benefit for sequential use of NHAs on rPFS, and this practice may actually be harmful by delaying the use of more effective therapies,” according to Fred Saad, MD, FRCS, professor and chairman of urology, as well as director of genitourinary oncology at the University of Montreal Hospital Center. “The practice of prescribing a second-line NHA needs revisiting, given available treatment options that are potentially superior when used in the appropriate patient population.”

PROfound (NCT02987543) was the first positive phase 3 trial with a PARP inhibitor conducted in patients with mCRPC; it was also the first phase 3 trial that was done in the post-NHA treatment setting. The trial enrolled patients with confirmed mCRPC who experienced disease progression on prior NHA treatment. Patients had to have alterations in at least 1 qualifying gene with a direct or indirect role in homologous recombination repair (HRR). Patients were stratified by previous taxane treatment received and measurable disease.

Cohort A of the study enrolled 245 patients with BRCA1BRCA2, or ATM mutations who were randomized 2:1 to receive either olaparib at 300 mg twice daily (n = 162) or enzalutamide or abiraterone (n = 83). Cohort B enrolled 142 patients with other alterations and randomized them 2:1 to olaparib at the same dose/schedule (n = 94) or enzalutamide or abiraterone (n = 48).

The primary end point for cohort A was rPFS per RECIST v1.1 criteria, Prostate Cancer Working Group 3 criteria, and blinded independent central review. Secondary end points included confirmed radiographic overall response rate in cohort A, rPFS in cohorts A and B, time to prostate-specific antigen (PSA) progression in cohort A, and OS in cohort A.

Across the 2 arms, 64.1% of patients had previous taxane use, 23.2% had metastatic disease at initial diagnosis, and 57% had measurable disease at baseline. Moreover, 31.5% had bone-only metastases, 33.5% had visceral metastases, and 29.0% had other metastases. The median baseline PSA was 87.55 μg/L, and 94.8% of patients had an ECOG performance status of 0 to 1.

Olaparib significantly prolonged rPFS and OS compared with physicians’ choice of enzalutamide or abiraterone in patients with alterations in BRCA1BRCA2, and ATM whose disease had progressed on a prior NHA.

Earlier data from the trial showed that the median rPFS with olaparib was 7.4 months vs 3.6 months in the control arm, which had combined data with enzalutamide and abiraterone (HR, 0.34; 95% CI, 0.25-0.47; P < .001). The median OS in the investigative and control arms was 19.1 months vs 14.7 months, respectively (HR, 0.69; 95% CI, 0.50-0.97; P = .02). Additionally, 43.1% of patients in the olaparib arm had a PSA response vs 7.8% of those in the control arm.

Olaparib was also found to have improved multiple clinical and patient-reported outcomes, and was thus, the PARP inhibitor was FDA approved for use in patients with mCRPC and qualifying alterations in HRR genes following treatment with enzalutamide or abiraterone.

Additional results were presented during the 2021 AUA Annual Meeting. Specifically, a multivariate analysis adjusted for key baseline characteristics such as prior taxane use, metastatic disease at initial diagnosis, site of disease, measurable disease, median PSA, and ECOG performance status, did not have an impact on the efficacy of olaparib with respect to rPFS and OS.

The adjusted analysis showed that the HR for rPFS was 0.33 (95% CI, 0.23-0.47); it was 0.34 (95% CI, 0.25-0.47) in the primary analysis. The adjusted analysis demonstrated that the HR for OS was 0.68 (95% CI, 0.45-1.04); it was 0.64 (95% CI, 0.43-0.97) in the primary analysis.

The best percentage change from baseline in PSA in cohort A with olaparib was 43.1% vs 7.8% with the control. These data suggest that best percentage change from baseline in PSA was not influenced by sequence of NHA.

“Twenty to twenty-five percent of patients with mCRPC are known to harbor deleterious alterations in genes with a role in HRR,” Saad said. “Therefore, routinely testing patients for alterations in HRR genes will enable patient-specific treatments to be considered that can make a real difference to patient outcomes.”

Combination therapies may build upon the efficacy achieved in PROfound and results from the phase 3 PROpel trial (NCT03732820) are highly anticipated, according to Saad.

Reference

1. Saad F, Shore N, Feyerabend S, et al. Efficacy of physician's choice of enzalutamide or abiraterone in the control arm of PROfound. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. PD34-09.