FDA Delays PDUFA Hearing for Olaparib/Abiraterone Combo in mCRPC

Article

The FDA has told AstraZeneca and MSD that the agency will extend the Prescription Drug User Fee Act date by 3 months to provide further time for a full review of the supplementary new drug application for olaparib plus abiraterone and prednisone or prednisolone for patients with mCRPC.

The FDA has told AstraZeneca and MSD that the agency will extend the Prescription Drug User Fee Act (PDUFA) date by 3 months to provide further time for a full review of the supplementary new drug application (sNDA) for olaparib (Lynparza) plus abiraterone acetate (Zytiga) and prednisone or prednisolone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).1

The FDA granted a priority review for the sNDA in August 2022 based on results from the phase 3 PROpel trial (NCT03732820). Olaparib plus abiraterone and prednisone or prednisolone (n = 399) significantly prolonged imaging-based progression-free survival (ibPFS) vs placebo plus abiraterone and prednisone or prednisolone (n = 397), at 24.8 months vs 16.6 months, respectively (HR, 0.66; 95% CI, 0.54-0.81; P < .001).2 These data proved to be consistent with what was observed with blinded independent central review (HR, 0.61; 95% CI, 0.49-0.74).3

Updated PROpel results presented during the 2022 ESMO Congress showed that the olaparib combination produced a radiologic progression-free survival (rPFS) benefit that was 8.6 months longer than abiraterone alone at the March 14, 2022, data cutoff. The median rPFS in the investigative arm was 25.0 months vs 16.4 months in the control arm (HR, 0.67; 95% CI, 0.56-0.81; P < .0001).4

Investigators noted that time to first subsequent therapy or death (TFST) and time to second progression or death (PFS2) findings suggested a trend toward longer-term benefit with the olaparib combination vs abiraterone alone, at 25.4 months vs 19.5 months, respectively (HR, 0.76; 95% CI, 0.63-0.90; P = .0032). PFS2 had not yet been reached in either arm (HR, 0.71; 95% CI, 0.54-0.94; P = .019).

Additionally, investigators observed a continued trend toward overall survival (OS) improvement with the investigative regimen vs the control. After about 22 months before extensive censoring, Kaplan-Meier curves showed a clear separation between the treatment arms. At 40.1% maturity, the median OS in the intention-to-treat population was not yet reached in either arm (HR, 0.83; 95% CI, 0.66-1.03; P = .11).

In November 2022, the European Medicines Agency’s Committee for Medicinal Products for Human Use recommended the combination for adults with mCRPC based on the PROpel results.5

The FDA originally expected to rule on the sNDA in the fourth quarter of 2022. AstraZeneca and MSD have said they are going to continue working with the regulatory agency to facilitate the completion of the agency’s review.1

The double-blind, global, randomized phase 3 trial enrolled patients with mCRPC who had an ECOG performance status of 0 or 1. Although neoadjuvant or adjuvant treatment with docetaxel for localized disease and metastatic hormone-sensitive disease was permitted, prior receipt of abiraterone was not. Patients were able to have previously received next-generation hormonal agents if they stopped at least 1 year before enrollment to the trial.

Patients were randomly assigned to 300 mg twice-daily olaparib or placebo in combination with 1000 mg daily abiraterone. Randomization was stratified based on site of distant metastases (bone only vs visceral vs other) and previous taxane for metastatic hormone-sensitive prostate cancer (yes vs no).

The primary end point of the trial was investigator-assessed rPFS, and a key secondary end point was overall survival (OS). Investigators also evaluated TFST, PFS2, objective response rate, homologous recombination repair (HRR) gene mutational status testing, safety, and tolerability.

References

  1. Update on US regulatory priority review of Lynparza in combination with abiraterone in metastatic castration-resistant prostate cancer. News release. AstraZeneca. December 15, 2022. Accessed December 15, 2022. https://bit.ly/3hrYecK
  2. Lynparza (olaparib) in combination with abiraterone and prednisone or prednisolone receives positive opinion from CHMP as treatment for certain patients with metastatic castration-resistant prostate cancer. News release. Merck. November 14, 2022. Accessed December 15, 2022. http://bit.ly/3ExIXja
  3. Saad F, Armstrong AJ, Thiery-Vuillemin A, et al. PROpel: Phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2022;40(suppl 6):11. doi:10.1200/JCO.2022.40.6_suppl.011
  4. Oya M, Armstrong AJ, Thiery-Vuillemin A, et al. Biomarker analysis and updated results from the phase III PROpel trial of abiraterone and olaparib vs abi and placebo as first-line therapy for patients with metastatic castration-resistant prostate cancer. Ann Oncol. 2022;33(suppl 9):S1495. doi:10.1016/j.annonc.2022.10.194
  5. Lynparza in combination with abiraterone granted priority review in the US for patients with metastatic castration-resistant prostate cancer. News release. AstraZeneca. August 16, 2022. Accessed December 15, 2022. https://bit.ly/3Pw4Lhs
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