Olaparib Significantly Improves OS in mCRPC Subgroup

Olaparib (Lynparza) significantly prolonged overall survival (OS), compared with enzalutamide (Xtandi) or abiraterone (Zytiga) plus prednisone, in men with metastatic castration-resistant prostate cancer who had tumors with at least 1 alteration in BRCA1, BRCA2, or ATM and whose disease had progressed during previous treatment with a next-generation hormonal agent.

In particular, the risk of death was 31% lower with olaparib than with control therapy, despite substantial crossover from control therapy to olaparib.

Updated fndings from the randomized, open-label phase 3 PROfound trial (NCT02987543) were presented at the 2020 ESMO Virtual Congress and were simultaneously published in the New England Journal of Medicine.1,2

“Exploratory analysis suggests that patients with BRCA mutations achieve the most benefit and additional studies may be required to further delineate genomic indicators of PARP response, particularly for those with less common gene alterations,” Joaquin Mateo, MD, Vall d'Hebron Institute of Oncology and Vall d'Hebron University Hospital, Barcelona, Spain, said during a presentation of the updated OS findings at the Congress.

“PROfound is the first randomized trial to prospectively demonstrate overall survival improvement in a molecularly-defined subset of prostate cancer, supporting implementation of genomic testing in daily clinical practice,” he added.

Median OS was superior with olaparib, compared with control therapy in cohort A (19.1 months vs 14.7 months; HR, 0.69; 95% CI, 0.50-0.97; P = .02) and cohort B (14.1 months vs 11.5 months; HR, 0.96; 95% CI, 0.63-1.49).

The crossover-adjusted analysis included 86 of 131 patients (66%) in the control group who had crossed over to receive olaparib, including 56 (67%) in cohort A. Patients were eligible for crossover if they had radiographic disease progression, no other subsequent anticancer therapy, any toxicities from prior therapy grade £ 1, and agreed to continue with the study visit schedule.

A sensitivity analysis that adjusted for crossover to olaparib showed a hazard ratio for death of 0.42 (95% CI, 0.19-0.91) in cohort A, and 0.83 (95% CI, 0.11-5.98) in cohort B. Moreover, the analysis showed a hazard ratio of 0.55 (95% CI, 0.29-1.06) in the overall population in the study.

Median duration of treatment with olaparib in patients who crossed over was 4.8 months, and median duration of treatment with control therapy was 3.9 months. The researchers noted that this was an investigator-assessed end point, which could mean the results are potentially subject to reporting bias. “Patients who crossed over from control therapy to receive olaparib had a shorter median duration of olaparib exposure (4.8 months) than those who were randomly assigned to receive olaparib (7.6 months). Thus, earlier treatment with olaparib may have an advantage over its use later in the disease course,” they wrote.2

The safety profile of olaparib appeared consistent with that found in the primary analysis. No cumulative toxic effects were observed during the extended exposure period.

The most common adverse events among the patients in the olaparib group and those who crossed over to receive olaparib were anemia (39%), nausea (36%), and fatigue or asthenia (32%). Treatment with olaparib was discontinued because of anemia in 7% of patients and because of neutropenia, thrombocytopenia, nausea, vomiting, or fatigue or asthenia in 1% of the patients for each.

The PROfound trial enrolled patients with metastatic castration-resistant prostate cancer who had alterations in at least 1 of 15 prespecified genes with a direct or indirect role in homologous recombination repair (HRR) and whose disease had progressed during previous treatment with a next- generation hormonal agents.

Cohort A (n = 245) consisted of patients with at least 1 alteration in BRCA1, BRCA2, or ATM, while cohort B (n = 142) comprised patients with at least one alteration in any of the other 12 prespecified genes.

Patients were randomly assigned 2:1 to receive either olaparib or the physician’s choice of enzalutamide or abiraterone. In cohort A, 162 patients received 300 mg olaparib twice daily and 83 patients were assigned to control therapy. In cohort B, 94 patients received the same olarparib regimen while 48 patients were in the control arm.

The primary end point was imaging-based progression-free survival (PFS) in cohort A, according to blinded independent central review.3

In cohort A, imaging-based PFS was significantly longer in the olaparib arm, compared with the control arm (median, 7.4 months vs. 3.6 months; HR, 0.34; 95% CI, 0.25-0.47; P < .001). In the initial analysis, a significant benefit was also observed with confirmed objective response rate and the time to pain progression.

“PROfound is the first positive phase 3 PARP inhibitor trial in metastatic castration-resistant prostate cancer, meeting its primary end point of prolonged radiographic progression-free survival for metastatic castration-resistant prostate cancer with alterations in BRCA1, BRCA2, or ATM progressing on prior next-generation hormonal agents and treated with olaparib versus with enzalutamide or abiraterone,” Mateo said, adding that these data supported the FDA’s approval of olaparib in this setting.

References:

1. J.S. de Bono, J. Mateo, K. Fizazi, et al. Final overall survival (OS) analysis of PROfound: Olaparib vs physician’s choice of enzalutamide or abiraterone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 610O.

2. M. Hussain, J. Mateo, K. Fizazi, et al. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. doi:10.1056/NEJMoa2022485

3. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020; 382:2091-102.