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Olaparib Granted FDA Priority Review for HRR-Mutant mCRPC

Published Online:10:00 PM, Mon January 20, 2020
The FDA has granted a Priority Review to the New Drug Application for olaparib (Lynparza) as treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) and deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene mutations, who have progressed following prior treatment with a new hormonal agent, AstraZeneca reported in a press release.1 

The Priority Review was granted based on positive data from the phase III PROfound trial of olaparib (150 mg, twice daily) versus physician’s choice of abiraterone (1000 mg, once daily) or enzalutamide (160 mg, once daily) in 2 cohorts of patients with mCRPC, which were presented during the 2019 European Society of Medical Oncology (ESMO) Congress.

The PROfound study showed that olaparib reduced the risk of disease progression or death by 66% compared with pcNHA (HR, 0.34; P <.0001) versus abiraterone or enzalutamide. In the study, olaparib demonstrated a statistically significant and clinically meaningful improvement in radiographic progression-free survival (rPFS), meeting the primary end point of the trial. The rPFs in the cohort of patients with BRCA1/2 or ATM-mutated mCRPC was  7.4 months in the olaparib arm versus the arm that received the physician’s choice of enzalutamide or abiraterone (pcNHA), which was 3.6 months (HR, 0.34; 95% CI, 0.25-0.47;  <.0001). Of patients who received olaparib, 59.8% remained progression-free at 6 months, compared with 22.6% of the patients who received pcNHA. At 12 months, respectively, 28.1% and 9.4% were still progression-free.2 

Olaparib also showed a higher confirmed ORR, which was 33.3% compared with the 2.3% observed in patients who were given pcNHA (HR, 20.86; 95% CI, 4.18-379.18; P <.00010). The time to pain progression in these patients was not reached in the olaparib group, and 9.92 months in the pcNHA group (HR, 0.44; 95% CI, 0.22-0.91; P =.0192). Interim overall survival (OS), data were also reported in the phase III study which showed a longer OS of 18.5 months in patients who received olaparib, compared with the 15.1 months in those received pcNHA (HR, 0.64; 95% CI, 0.43-0.97; P =.0173).

In the overall population of patients with mCRPC and mutations in the HRR pathway, the rPFS was 5.8% in the olaparib group, and 3.5% in the pcNHA group (HR, 0.49; 95% CI, 0.38-0.63; <.0001). Patients also remained progression-free at 6 months in 49.7 of those in the olaparib group and 23.7of those in the pcNHA group. A percentage of patients who received olaparib (22.1%) also remained progression-free at 12 months compared with 13.5% of the patients who received pcNHA (HR, 0.49; 95% CI, 0.38-0.63; P <.0001).The proportion of individuals with a confirmed ORR in the overall population of patients with mCRPC and mutations in the HRR pathway was 21.7% in the olaparib group versus 4.5% in the pcNHA group (HR, 5.93; 95% CI, 2.01-25.40; P =.0006). Finally, the interim OS observed in this cohort of patients was 17.5% versus 14.3, respectively (HR, 0.67; 95% CI, 0.49-0.93; P =.0063).

The most common adverse events (AEs) occurred in ≥20% of patients. These AEs included anemia (47%), nausea (41%), fatigue/asthenia (41%), decreased appetite (30%) and diarrhea (21%). The AEs that were grade 3 or higher included anemia (22%), pulmonary embolism (4%), fatigue/asthenia (3%), vomiting (2%), dyspnea (2%), urinary tract infection (2%), decreased appetite (1%), diarrhea (1%) and back pain (1%). A total of 16% of patients on who were treated with olaparib discontinued treatment due to AEs.

PROfound was an open-label, randomized study to assess the efficacy and safety of olaparib as compared with pcNHA in men with mCRPC who have failed prior treatment with a new hormonal agent and have homologous recombination repair. The secondary end points of the study included confirmed ORR, time to pain progression, OS, rPFs in participants with HRR qualifying mutation, and AEs/serious AEs.

The study included patients with a histologically confirmed diagnosis of prostate cancer and documented evidence of mCRPC who have previously progressed on a new hormonal agent. Participants were also required to have ongoing therapy with luteinizing hormone-releasing hormone analog or bilateral orchiectomy. Finally, patients were required to have radiographic progress at study entry while on androgen deprivation therapy and a qualifying HRR mutation in their tumor tissue.

Individuals were excluded if they had previous treatment with olaparib or another PARP inhibitor or with DNA-damaging cytotoxic chemotherapy, with the exception of non-prostate cancer indication and a last dose > 5 years prior to randomization. Patients who have had another malignancy within the last 5 years except adequately treated non-melanoma skin cancer or other solid tumors curatively treated with no evidence of disease for ≥5 years and those with brain metastases were also excluded.

The Prescription Drug User Fee Act (PDUFA) date for olaparib is set for the second quarter of 2020.1
  1. Lynparza regulatory submission granted Priority Review in the US for HRR-mutated metastatic castration-resistant prostate cancer [news release]. Kenilworth, New Jersey: AstraZeneca and MSD Inc; January 20, 2020. https://bit.ly/36cIEpM. Accessed January 20, 2020.
  2. Lynparza more than doubled the time without radiographic disease progression in patients with BRCA1/2- or ATM-mutated metastatic castration-resistant prostate cancer [news release].
    Kenilworth, New Jersey: AstraZeneca and MSD Inc; September 30, 2019. https://bit.ly/2RChrrc. Accessed January 20, 2020.

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