Olaparib combined with cediranib improves radiographic progression-free survival (rPFS) compared with olaparib alone in men with metastatic castration-resistant prostate cancer (mCRPC), results from a recent randomized phase 2 clinical trial suggest.
In an analysis of an intention-to-treat set of 90 patients with progressive mCRPC, median rPFS was 8.5 months for patients who received olaparib plus cediranib compared with 4.0 months among those treated with olaparib alone, Joseph W. Kim, MD, of the Yale School of Medicine and Yale Cancer Center in New Haven, Connecticut, and colleagues reported in the Journal of Clinical Oncology. The combination treatment was significantly associated with a 38.3% decreased risk for radiographic progression compared with olaparib alone. The combination arm had a higher incidence of grade 3-4 adverse events than the monotherapy arm (61% vs 18%).
Cediranib is a pan-vascular endothelial growth factor receptor (VEGFR) inhibitor that suppresses expression of homologous recombination repair (HRR) genes. Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor. Patients in the combination arm received olaparib 200 mg twice daily plus cediranib 30 mg once daily; patients in the olaparib-only arm received the drug at a dosage of 300 mg twice daily. The investigators examined treatment effects according to gene biomarker subgroups.
The investigators defined radiographic progression as bone scans showing new lesions compared with baseline, soft tissue progression defined by modified RECIST version 1.1 criteria, and death from any cause.
Descriptive analyses revealed that rPFS was longer in olaparib/cediranib recipients than the olaparib-only arm among men with HRR-deficient mCRPC and those with BRCA2-mutated mCRPC, although the differences did not reach statistical significance, according to the investigators.
Dr Kim’s team noted that, to their knowledge, their study is the first randomized trial to demonstrate the potential clinical efficacy of adding a VEGFR inhibitor to a PARP inhibitor. “Unfortunately, the combination of cediranib and olaparib is associated with increased toxicity rates,” they wrote. “Although they were manageable with supportive care, treatment interruptions were frequent. Descriptive analyses of rPFS in biomarker subgroups indicated that a deleterious BRCA2 mutation is the best predictor of olaparib efficacy. Whether cediranib adds any benefit to olaparib in BRCA2-mutated mCRPC remains unclear.”
The authors acknowledged that a key limitation of their study was that it was not powered for subgroup analyses by biomarkers. “The small sample sizes in each biomarker subgroup and wide [confidence intervals] limited our ability to evaluate the observed clinical activity using the biomarkers with statistical confidence. Thus, our biomarker analyses are descriptive, and should only be interpreted as hypothesis-generating.”
Kim JW, McKay RR, Radke MR, et al. Randomized trial of olaparib with or without cediranib for metastatic castration-resistant prostate cancer: The results from National Cancer Institute 9984. J Clin Oncol. Published online October 18, 2022. doi:10.1200/JCO.21.02947