Randomized Trial of Olaparib With or Without Cediranib for Metastatic Castration-Resistant Prostate Cancer: The Results From National Cancer Institute 9984

Abstract

Purpose: Cediranib, a pan-vascular endothelial growth factor receptor inhibitor, suppresses expression of homologous recombination repair (HRR) genes and increases sensitivity to poly-(ADP-ribose) polymerase inhibition in preclinical models. We investigated whether cediranib combined with olaparib improves the clinical outcomes of patients with prostate cancer.

Methods: Patients with progressive metastatic castration-resistant prostate cancer (mCRPC) were randomly assigned 1:1 to arm A: cediranib 30 mg once daily plus olaparib 200 mg twice daily or arm B: olaparib 300 mg twice daily alone. The primary end point was radiographic progression-free survival (rPFS) in the intention-to-treat patients. The secondary end points were rPFS in patients with HRR-deficient and HRR-proficient mCRPC.

Results: In the intention-to-treat set of 90 patients, median rPFS was 8.5 (95% CI, 5.4 to 12.0) and 4.0 (95% CI, 3.2 to 8.5) months in arms A and B, respectively. Cediranib/olaparib significantly improved rPFS versus olaparib alone (hazard ratio [HR], 0.617; 95% CI, 0.392 to 0.969; P = .0359). Descriptive analyses showed a median rPFS of 10.6 (95% CI, 5.9 to not assessed [NA]) and 3.8 (95% CI, 2.33 to NA) months (HR, 0.64; 95% CI, 0.272 to 1.504) among patients with HRR-deficient mCRPC, and 13.8 (95% CI, 3.3 to NA) and 11.3 (95% CI, 3.8 to NA) months (HR, 0.98; 95% CI, 0.321 to 2.988) among patients with BRCA2-mutated mCRPC in arms A and B, respectively. The incidence of grades 3-4 adverse events was 61% and 18% in arms A and B, respectively.

Conclusion: Cediranib combined with olaparib improved rPFS compared with olaparib alone in men with mCRPC. This combination was associated with an increased incidence of grades 3-4 adverse events. BRCA2-mutated subgroups treated with olaparib with or without cediranib were associated with a numerically longer median rPFS.

Trial registration: ClinicalTrials.gov NCT02893917.

Conflict of interest statement

Daniel P. Petrylak

Stock and Other Ownership Interests: Bellicum Pharmaceuticals, TYME

Consulting or Advisory Role: Bayer, Exelixis, Pfizer, Roche, Astellas Pharma, AstraZeneca, Lilly, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Incyte, Janssen, Pharmacyclics, Seattle Genetics, Urogen Pharma, Advanced Accelerator Applications, Ipsen, Bicycle Therapeutics, Mirati Therapeutics, Monopteros Therapeutics, Regeneron, Gilead Sciences

Research Funding: Progenics (Inst), Sanofi (Inst), Endocyte (Inst), Genentech (Inst), Merck (Inst), Astellas Medivation (Inst), Novartis (Inst), AstraZeneca (Inst), Bayer (Inst), Lilly (Inst), Innocrin Pharma (Inst), MedImmune (Inst), Pfizer (Inst), Roche (Inst), Seattle Genetics (Inst), Clovis Oncology (Inst), Bristol Myers Squibb (Inst), Advanced Accelerator Applications (Inst), Agensys (Inst), BioXCel therapeutics (Inst), Eisai (Inst), Mirati Therapeutics (Inst), Replimune (Inst), Medivation (Inst), Gilead Sciences (Inst)

Expert Testimony: Celgene, Sanofi

No other potential conflicts of interest were reported.

Figures

FIG 1.

CONSORT diagram. ITT, intention-to-treat; PD, progression of disease.

FIG 2.

Kaplan-Meier curves in the ITT analysis set and biomarker subgroups: (A) rPFS in the ITT, (B) OS in the ITT, (C) rPFS in the homologous recombination repair-deficient subgroup, and (D) rPFS in the homologous recombination repair-proficient subgroup. (E) An exploratory analysis of rPFS in BRCA2 mutation subgroup. Data cutoff date, October 1, 2020. The number in parentheses refers to the cumulative number censored associated with number at risk. C + O, cediranib plus olaparib; HR, hazard ratio; ITT, intention-to-treat; NA, not assessed; O, olaparib; OS, overall survival; rPFS, radiographic progression free-survival; Total, total analytic unit.

FIG 3.

Swimmer plot of duration of treatment in patients with homologous recombination repair-deficient metastatic castration-resistant prostate cancer subgroup. Each bar represents an individual patient with the length corresponding to length of time on study drug. The panel to the left of the plot shows the homologous recombination deficiency subgroup of each patient and homologous recombination gene mutation type identified in tumor or blood samples. Mutations are somatic in origin unless specified as germline. AE, adverse event; C + O, cediranib plus olaparib; O, olaparib; POD, disease progression; PR, partial response; SD, stable disease.

FIG 4.

Waterfall plots of (A) best tumor burden changes and (B) best PSA change. (A) Each bar represents an individual patient with the length corresponding to the maximal percentage change from baseline in sum of the target lesions according to RECIST v1.1. (B) Each bar represents an individual with the length corresponding to the best percentage change of PSA from the baseline value. Each bar is color-coded by the HRR gene mutation status. C + O, cediranib plus olaparib; HRP, homologous recombination repair-proficient; HRR, homologous recombination repair; O, olaparib; PSA, prostate-specific antigen.