FDA Approves Olaparib for HRR-Mutant mCRPC

The FDA has approved olaparib (Lynparza) for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene mutations and have progressed following prior treatment with a new hormonal agent.^1,2

“The approval of olaparib as targeted therapy for metastatic castration-resistant prostate cancer is a major landmark in the treatment of this disease. It clearly demonstrates the feasibility, efficacy, and the promise of precision medicine–based therapy in this disease, which has lagged behind other solid tumors with regard to targeted therapy and precision medicine, and clearly opens the doors for more clinical trials in a genomically-preselected patient population evaluating promising targeted agents and combinations,” investigator Maha H. Hussain, MD, the Genevieve Teuton Professor of Medicine, Division of Hematology/Oncology, and deputy director of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, told Targeted Oncology about the impact of the approval.

The approval was based on findings from the phase III PROfound trial, which demonstrated a 66% reduction in the risk of disease progression or death with olaparib compared with enzalutamide (Xtandi) or abiraterone acetate (Zytiga) in patients with BRCA1/2 or ATM mutations. The median radiographic progression-free survival (rPFS) in this population, which was the study’s primary end point, was 7.39 months with olaparib compared with 3.55 months with either enzalutamide or abiraterone acetate (HR, 0.34; 95% CI, 0.25-0.47; P <.0001). 

PROfound is an open-label, randomized phase III trial that explored the efficacy and safety of olaparib in comparison with investigator’s choice of enzalutamide or abiraterone acetate in men with mCRPC who have failed prior therapy with a new hormonal agent and have an HRR gene mutation (NCT02987543). 

The trial included 2 cohorts, one for patients with BRCA1/2 or ATM mutations—more established markers of HRR (n = 245; cohort A), and another consisting of patients with alterations in BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, PPP2R2A, RAD51B/C/D, or RAD54L—genes associated with HRR (n = 142; cohort B). In both cohorts, patients were randomized 2:1 to either olaparib or the control arm. In the investigational arm, olaparib was administered at 300 mg twice daily.³ 

Patients in the trial had histologically confirmed prostate cancer and evidence of mCRPC that progressed on a prior new hormonal treatment. Ongoing therapy with an LHRH analog or bilateral orchiectomy was allowed as well as progression while on androgen deprivation therapy after bilateral orchiectomy.

Those who had previously received a PARP inhibitor or DNA-damaging cytotoxic chemotherapy as well as those with another malignancy or known brain metastases were excluded from the trial.

Secondary outcome measures included objective response rate (ORR) by blinded independent central review, time to pain progression, overall survival (OS), rPFS in cohort B, and safety. 

Patient characteristics were balanced between the 2 arms in each cohort. In the olaparib arm of cohort A, the median age was 68 years (range, 47-86), and 23.5% of patients had metastatic disease at initial diagnosis. The median baseline prostate-specific antigen 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 taxane prior to trial entry.

In cohort A, the ORR was 33.3% with olaparib and 2.3% with abiraterone acetate or enzalutamide (odds ratio, 20.86; 95% CI, 4.18-379.18; P <.0001). The median time to pain progression was not yet reached in the olaparib arm compared with 9.92 months in the control arm (HR, 0.44; 95% CI, 0.22-0.91; P = .0192).

In a press release, AstraZeneca and Merck announced that olaparib showed a statistically significant and clinically meaningful improvement in OS over enzalutamide or abiraterone acetate in cohort A.⁴ 

In both cohorts, adverse events (AEs) of any grade were more commonly observed in the olaparib arm (95.3% vs 87.7%), potentially related to a significantly longer treatment duration (7.4 vs 3.9 months). Grade ≥3 AEs were reported in 50.8% of patients in the olaparib arm and in 37.7% of patients in the control arm. 

The most common AEs reported with olaparib were anemia (46.1%), nausea (41.4%), decreased appetite (30.1%), and fatigue (26.2%). A total of 16.4% of patients discontinued treatment with olaparib due to an AE.

Olaparib is also approved for the maintenance treatment of patients with BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy; for the treatment of patients with germline BRCA-mutated, HER2-negative, metastatic breast cancer who were previously treated with chemotherapy; and for the treatment of patients with germline BRCA-mutated metastatic pancreatic cancer.

_References

_{1. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. FDA. Posted May 20, 2020. Accessed May 20, 2020. https://bit.ly/3cQc4ho}

_{2. LYNPARZA® (Olaparib) Approved in the US for HRR Gene-Mutated Metastatic Castration-Resistant Prostate Cancer. Wilmington, DE: AstraZeneca and Merck & Co, Inc; May 20, 2020. Accessed May 20, 2020. https://bwnews.pr/2z6SH5r}

_{3. 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.}

_{4. Lynparza demonstrated overall survival benefit in Phase III PROfound trial for BRCA1/2 or ATM-mutated metastatic castration-resistant prostate cancer [news release]. Kenilworth, NJ: Merck & Co., Inc.; April 24, 2020. https://bit.ly/2WCIVAR.}