(UroToday.com) Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease despite the increased number of treatment options that have been Federal Drug Administration (FDA) approved in the past decade. Most recently, the PARP inhibitors olaparib and rucaparib were approved for men with mCRPC harboring certain gene alterations associated with homologous recombination deficiency. In this study, Dr. Rana McKay presented a phase 2 study of olaparib versus olaparib in combination with the cediranib, an oral antagonist of VEGF receptors 1-3. The rationale from this study comes from preclinical and clinical studies showing that anti-angiogenic agents can result in a hypoxic tumor environment that downregulates the expression of homologous recombination genes, as well as studies in other cancers showing antitumor activity of cediranib and olaparib in combination.
The primary outcome of this trial was an improvement in radiographic progression free survival independent of homologous recombination repair gene status. The study schema is shown below. Patient with mCRPC who had received at least 1 prior line of therapy were randomized 1:1 to either olaparib monotherapy at the standard dose (300 mg BID) or cediranib plus a reduced dose of olaparib based on the recommended phase 2 dose from an earlier study of 200 mg BID (slide has a typo). A baseline tumor biopsy was obtained. Crossover was allowed from Arm B to Arm A at the time of progression.
The null hypothesis was a rPFS interval of 4.8 months, and the alternative hypothesis was that combination therapy would result in an rPFS interval of 8.8 months. 84 evaluable patients were required. The BROCA-HR assay was used to assess homologous recombination deficiency, defined as bi-allelic loss of ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, NBN, PALB2, RAD51C, or RAD51D.
In total, 90 patients were enrolled. 12 patients in the combination arm were found to be HR deficient, 14 patients in the monotherapy arm were HR deficient. Baseline characteristics between the group were comparable, as shown below. In contrast to PROfound, patients were heavily pre-treated, with ~70% of patients having received prior docetaxel and ~80% of patients having received abiraterone. The most common HR gene alterations were in BRCA2, followed by CKD12 and ATM.
At a median follow-up of 10.98 months, the study met its primary endpoint of rPFS benefit with combination cediranib and olaparib. 13 out of 45 patients crossed over from Arm B to Arm A.
When stratifying by HR status, there was a non-statistically significant trend towards benefit from combination therapy in HR deficient patients, but not HR proficient patients.
The study was not adequately powered for overall survival analysis, however, the available data on this outcome is shown below. A total of 13 out of 45.
Rates of PSA50 decline were higher in combination Arm A (29% versus 18%), and this held in both HR proficient and HR deficient patients. ORR in the combination arm was 19%, and 11% in the monotherapy arm. More patients in the combination arm experienced any grade 3 or higher adverse event (77% vs 55%).
Dr. McKay concluded that the trial met its primary endpoint, demonstrating an improved radiographic progression-free survival with combination cediranib and Olaparib in pre-treated mCRPC. This benefit seemed strongest in patients with tumors deficient in homologous recombination. The combination regimen was associated with her toxicity than monotherapy with olaparib. Further study of this combination in HR deficient tumors is under consideration.
Presented by: Rana R. McKay, MD, Medical Oncologist, Assistant Professor of Medicine, UC San Diego Health
Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, during the 2021 ASCO Genitourinary Cancers Symposium (ASCO GU), February 11th to 13th, 2021