Combination of pembrolizumab plus olaparib efficacious in mCRPC

In a study presented at the 2021 European Society for Medical Oncology (ESMO) Annual Meeting¹, investigators found that combined therapy of pembrolizumab (Keytruda) plus olaparib (Lynparza) produced promising antitumor activity in men with molecularly unselected docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC).1

At a minimum of 11.4 months follow-up, 15 out of 102 patients (14.7%) from cohort A of the phase 1b/2 KEYNOTE-365 trial (NCT02861573) exhibited a confirmed prostate-specific antigen (PSA) response, with an overall response rate of 6.9% and a disease control rate of 26.5%.

A total of 102 patients received treatment. Those who were treated received pembrolizumab on the first day of every 3-week dosing cycle for up to 35 weeks (approximately 2 years) and olaparib, 400-mg (first 41 patients enrolled) capsules or 300-mg tablets orally twice a day continuously. Treatment was discontinued when there was confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients who discontinued 1 drug were permitted to continue the other until discontinuation from the previously stated criteria.

Over the course of the study, 52 patients discontinued treatment due to progressive disease, 19 discontinued due to clinical progression, 17 discontinued due to adverse events (AEs), 3 discontinued due to withdrawal of consent, and 1 discontinued due to the physician’s decision.

Median age of enrolled patients was 69.5 years (range, 47-84 years), median initial PSA value was 109.4 ng/mL (range, 1.2-5000.0 ng/mL), 58 patients (56.9%) had measurable disease, and 40 patients (39.2%) had previously been treated with cabazitaxel (Jevtana). Additionally, 24 patients (23.5%) had previously been treated with abiraterone (Zytiga) only, 24 (23.5%) had previously been treated with enzalutamide (Xtandi) only, and 46 patients (45.1%) had previously been treated with both.

Confirmed response rate was 19.0% (11/58) in patients with measurable disease and 9.1% (4/44) in patients with nonmeasurable disease. In patients with both measurable and nonmeasurable disease, PSA reduction from baseline was 50.0% (51/102) and the median time to PSA progression was 4.0 months (range, 3.0-4.9 months).

Other outcomes include target lesion change from baseline for patients with both measurable and nonmeasurable disease, which was 58.6% (34/58), as well as Kaplan Meier estimates of median radiographic progression-free survival (rPFS) and overall survival (OS), which was 5.2 months (range, 4.1-6.5 months) and 14.4 months (range, 10.4-17.9 months), respectively.

Overall, 93 patients (91.2%) experienced treatment-related AEs (TRAEs) of any grade and 49 patients (48.0%) experienced grades 3 to 5 TRAEs. The most-experienced TRAEs were anemia (41.2% any grade, 27.5% grade 3-5), nausea (41.2% any grade, 2.0% grade 3-5), decreased appetite (30.4%any grade, 0.0% grade 3-5), and fatigue (30.4% any grade, 5.9% grade 3-5). Six patients died of AEs, 2 of which were considered treatment-related and the remaining 4 not treatment-related. Immune-mediated AEs were also experienced among patients, with 12 (11.8%) patients experiencing any grade of any immune-mediated AE and 4 (3.9%) experiencing grades 3 to 5 immune-mediated AEs.

“The safety and tolerability profile of pembrolizumab plus Olaparib therapy is consistent with the individual profiles of each agent…The promising rPFS and overall survival data support further evaluation of pembrolizumab plus olaparib in molecularly unselected patients with mCRPC who received prior docetaxel treatment,” the authors concluded.

The phase 3 KEYLYNK-010 trial (NCT03834519) is currently investigating the combination of pembrolizumab plus olaparib vs abiraterone or enzalutamide in patients with mCRPC who have previously been treated with abirtaterone or enzalutamide. It is a randomized, global, parallel-group, double-blind study.

Reference

1. Yu E, Piulats JM, Gravis G, et al. Pembrolizumab (pembro) plus olaparib in patients with docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC): update of KEYNOTE-365 Cohort A with a minimum of 11 months of follow-up for all patients. Paper presented at 2021 European Society for Medical Oncology Annual Meeting; September 16-21, 2021; virtual. Abstract 612P