Olaparib Doubles rPFS in Heavily Pretreated HRR+ mCRPC

Maha H. Hussain, MB ChB

Treatment with the PARP inhibitor olaparib (Lynparza) improved radiographic progression-free survival (rPFS) compared with physician's choice of abiraterone acetate (Zytiga) or enzalutamide (Xtandi) in men with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations, according to findings from the phase III PROfound trial presented at the ESMO Congress 2019.

The median rPFS by blinded independent review for patients with BRCA1/2 or ATM alterations (cohort A) was 7.39 months for patients treated with olaparib compared with 3.55 months for patients treated with abiraterone or enzalutamide (HR, 0.34; 95% CI, 0.25-0.47; P <.0001). The 12-month rPFS rate was 40% with olaparib and 11% for physician’s choice of therapy. Additionally, other improvements were seen in objective response rate (ORR), pain progression, and overall survival (OS), although the latter endpoint did not reach statistical significance due to high rates of crossover (80.6% of patients).

“PROfound is the first positive biomarker-selected phase Ill study evaluating a molecularly-targeted therapy in men with mCRPC and highlights the importance of genomic testing in this population," said lead investigator Maha Hussain, MBChB, from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, an OncLive Giant of Cancer Care. "Prostate cancer has lagged behind all other common solid tumors in the use of molecularly targeted treatment, so it is very exciting that now we can personalize an individual’s treatment based on specific genomic alterations in their cancer cells.”

The phase III study contained 2 cohorts. In cohort A, patients had alterations in BRCA1/2 or ATM (n = 245), which are more established markers of HRR. In cohort B (n = 142), patients had an alteration in BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, PPP2R2A, RAD51B/C/D, or RAD54L, which are all associated with HRR but not as established as those in cohort A. Within each cohort, patients were randomized in a 2:1 ratio to olaparib or physician's choice of abiraterone acetate plus prednisone or enzalutamide.

In cohort A, 162 patients received olaparib and 83 got abiraterone acetate plus prednisone or enzalutamide. In cohort B, 94 patients received olaparib and 48 got physician's choice of abiraterone acetate plus prednisone or enzalutamide. In addition to each cohort, a combined assessment of patients was also analyzed (N = 387). Across cohorts, olaparib was given at 300 mg twice daily, abiraterone at 1000 mg per day with prednisone at 5 mg twice daily, and enzalutamide at 160 mg per day.

Patients characteristics were well-balanced between arms in each group. In cohort A for the olaparib arm, the median age of patients was 68 years (range, 47-86), and 23.5% of patients had metastatic disease as an initial diagnosis. The median baseline PSA level was 62.2 ug/L. In both arms, between 42% and 48.2% of patients had received prior enzalutamide and between 38.3% and 34.9% had received prior abiraterone. Both treatments were received by 16.9% to 19.8% of patients. Two-thirds of patients had also received a prior taxane prior to trial entry.

"Why did they give abiraterone after enzalutamide or enzalutamide after abiraterone? Because it is done [in practice]. And, maybe this will be the last day it is done. We know it is done because of ease of use," said invited ESMO discussant Eleni Efstathiou, MD, PhD, from the University of Texas MD Anderson Cancer Center. "The investigators made sure to allow crossover to olaparib on progression. This is a heavily pretreated population, there are no real alternatives. The primary endpoint was met, there was a doubling of rPFS in the BRCA1/2, ATM group. And, you can suddenly see how using abiraterone after enzalutamide or enzalutamide after abiraterone quickly becomes a placebo.”

In the combined cohorts, the median age in both arms was 69 years and approximately a quarter of patients had de novo metastatic disease. The median PSA was 68.2 ug/L in the olaparib group and 106.5 ug/L for physician's choice. Patients in the olaparib and physician's choice arms, respectively, received prior enzalutamide (41% and 41.2%), abiraterone (39.1% and 41.2%), both agents (19.9% and 17.6%), and a taxane (66.4% and 64.1%).

In cohort A, the ORR was 33.3% with olaparib compared with 2.3% with the hormonal therapies (odds ratio, 20.86; 95% CI, 4.18-379.18; P <.0001). The median time to pain progression was not yet reached with olaparib compared with 9.92 months for the hormonal agents, representing a 56% reduction in the risk of pain progression (HR, 0.44; 95% CI, 0.22-0.91; P = .0192). The median OS was 18.50 months for olaparib compared with 15.11 months for abiraterone or enzalutamide (HR, 0.64; 95% CI, 0.43-0.97; P = .0173).

Although a slight trend was noted for benefit in cohort B, it was not statistically significant for rPFS nor was the magnitude as pronounced. For rPFS by blinded review, the hazard ratio in cohort B was 0.88 (95% CI, 0.58-1.36). In this cohort, the ORR was lower in the olaparib arm versus the control group (3.7% vs 8.3%). The hazard ratio for OS was 0.73 (95% CI, 0.45-1.23).

Since the biomarkers selected were still experimental in prostate cancer, an exploratory analysis of rPFS per mutation was conducted to discovery if one particular population was driving the majority of responses. Overall, those with BRCA2 mutations had the greatest benefit in cohort A. In cohort B, those with RAD51B, RAD54L, and CDK12 had the greatest overall rPFS, although the numbers were small and preliminary.

Across both cohorts A and B, adverse events (AEs) of any grade were more commonly observed in the olaparib arm (95.3% of patients versus 87.7%), potentially related to a significantly longer treatment duration (7.4 versus 3.9 months). Grade ≥3 AEs were experienced by 50.8% of patients in the olaparib arm and for 37.7% of patients in the hormonal therapy arm. "Olaparib was well tolerated, with a safety profile generally consistent with that seen in other cancers," said Hussain.

Hussain M, Mateo J, Fizazi K, et al. PROfound: Phase III study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations. Presented at ESMO Congress 2019; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA12_PR.

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