Phase 3 trial pits PARP/PD-1 inhibitor combo against ARPIs in prostate cancer

The ongoing phase 3 KEYLYNK-010 trial is evaluating the combination of the PD-1 inhibitor pembrolizumab (Keytruda) plus the PARP inhibitor olaparib (Lynparza) against monotherapy with either enzalutamide (Xtandi) or abiraterone acetate (Zytiga) in heavily pretreated patients with metastatic castration-resistant prostate cancer (mCRPC).¹

The trial follows the phase 1b/2 KEYNOTE-365 trial, in which the olaparib/pembrolizumab combination showed early promise in this molecularly unselected population of patients with limited treatment options.² In KEYNOTE-365, the combination had an overall response rate (ORR) of 8.3%, with a median radiographic progression-free survival (rPFS) of 4.3 months and a median overall survival (OS) of 14.4 months.

The open-label KEYLYNK-010 trial (NCT03834519) is specifically enrolling patients with mCRPC and treatment failure on an androgen receptor pathway inhibitor (ARPI; either abiraterone or enzalutamide, but not both), as well as docetaxel. Patients must have an ECOG performance status of 0 or 1. The patient population is unselected for homologous recombination repair defects.

Patients are not eligible to enroll if they have CNS metastases or if they had prior treatment with an anticancer monoclonal antibody, a PARP inhibitor, apalutamide (Erleada), darolutamide (Nubeqa), an immune checkpoint inhibitor, or a radiopharmaceutical for prostate cancer.

Patients randomized to the experimental arm will receive continuous oral olaparib at 600 mg daily plus 200 mg of IV pembrolizumab on day 1 of each 21-day cycle until disease progression or a maximum of 35 cycles (about 2 years). In the control arm, patients with prior enzalutamide will receive abiraterone acetate at 1000 mg daily plus 10 mg of prednisone daily until progression, and patients with prior abiraterone will receive enzalutamide at 160 mg daily until progression.

The dual primary end points of the trial are OS and rPFS. Secondary end points include ORR, time to first subsequent anticancer therapy, duration of response, time to PSA progression, time to first symptomatic skeletal-related event, time to radiographic soft tissue progression, and safety.

The international trial has a target enrollment of 780 patients and is accruing patients in the United States and several other countries, including Argentina, Australia, Austria, Brazil, Canada, Chile, France, Germany, Ireland, Israel, Japan, Korea, the Netherlands, New Zealand, Russia Spain, and the United Kingdom. The estimated primary completion date is October 12, 2021.

KEYNOTE-365

The latest findings from the KEYNOTE-365 trial were presented during the 2020 European Association of Urology Virtual Congress. The phase 1b/2 trial evaluated several combinations of pembrolizumab and other agents in patients with mCRPC. Cohort A of the trial assessed the combination of pembrolizumab and olaparib. The cohort included molecularly unselected patients who previously received docetaxel. Patients were allowed to have received a maximum of 1 prior ARPI.

Among the 24 patients on the trial with RECIST-measurable disease, there were 2 partial responses and 3 cases of stable disease lasting for at least 6 months, for a disease control rate of 20.8%. Another 6 patients had stable disease lasting <6 months, with the remaining 13 patients having disease progression.

Safety for the combination was evaluated in all 84 patients who received treatment in the cohort. The study investigators reported that the safety profile for the combination was consistent with the individual safety profiles for pembrolizumab and olaparib reported in previous studies. Overall, 83.3% of patients experienced a treatment-related adverse event (TRAE) of any grade and 34.6% had a grade 3 to 5 TRAE.

Grade 3 to 5 TRAEs included anemia (17.9%), neutropenia (4.8%), asthenia (3.6%), fatigue (3.6%), thrombocytopenia (2.4%), vomiting (1.2%), and nausea (1.2%). There were 3 patient deaths due to AEs, 2 of which the investigators concluded were related to treatment (myocardial infarction and unknown cause).

Olaparib has an FDA-approved indication for patients with homologous recombination repair gene–mutated mCRPC. Pembrolizumab has 2 tumor-agnostic FDA approvals, one for tumor mutational burden-high cancer, and one for microsatellite instability-high or mismatch repair deficient cancer.

References

1. Study of Pembrolizumab (MK-3475) Plus Olaparib Versus Abiraterone Acetate or Enzalutamide in Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-7339-010/KEYLYNK-010) (KEYLYNK-010). NIH US National Library of Medicine: ClinicalTrials.gov. Last updated August 7, 2020. https://clinicaltrials.gov/ct2/show/NCT03834519. Accessed August 10, 2020.

2. Piulats JM, Yu E, Gravis G, et al. Pembrolizumab (pembro) plus olaparib in docetaxel-pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-365 cohort A updated results. 2020 European Association of Urology Virtual Congress. July 17-26, 2020. Abstract 561.