Pembrolizumab plus Enzalutamide Shows Activity in Metastatic Castration-Resistant Prostate Cancer

Treatment with a combination of pembrolizumab (Keytruda) and enzalutamide (Xtandi) continues to show substantial activity in patients with metastatic castration-resistant prostate cancer (CRPC) who have already been treated with abiraterone (Zytiga), according to results of a recent clinical trial, which were presented during the virtual 2020 American Urological Association Annual Meeting.

“The promising results from KEYNOTE-365 support further evaluation of pembrolizumab plus enzalutamide in patients with metastatic CRPC previously treated with abiraterone,” said Evan Yu, MD, Professor, Department of Medicine, University of Washington, Seattle.

Researchers in the phase 2 single-institution study of patients with prostate cancer who were progressing while being treated with enzalutamide explored the addition of pembrolizumab to enzalutamide and found that 18% of patients had a ≥50% reduction in the level of prostate-specific antigen (PSA) from baseline and an overall survival of 22.2 months.

The results were compelling enough to pursue the strategy further, said Dr Yu. Therefore, cohort C of the KEYNOTE-365 phase 1b/2 study assessed the combination of pembrolizumab and enzalutamide in patients with metastatic CRPC who had previously received abiraterone. Initial data showed the combination to be safe and well-tolerated with promising activity. Updated data from this cohort were presented here after additional enrollment, extended follow-up, and radiologic data by a blinded independent review committee.

Cohort C of KEYNOTE-365 enrolled patients with metastatic CRPC who had progressive disease ≤6 months before screening, and who either did not respond to or became intolerant to ≥4 weeks of treatment with abiraterone in the prechemotherapy state. Patients were treated with intravenous pembrolizumab 200 mg every 3 weeks, and oral enzalutamide 160 mg/day.

A total of 102 patients had been treated at the data cutoff for the analysis. The median time from enrollment to data cutoff was 19.1 months for all patients and 21.4 months for those with at least 27 weeks of follow-up (N = 69). Of the 102 patients, treatment is ongoing in 29 patients, whereas 73 patients discontinued treatment. Reasons for discontinuation included radiographic disease progression (n = 50), clinical progression (n = 11), adverse events (n = 7), and withdrawn consent (n = 5).

Median age at baseline was 70 years. Thirty patients (29.4%) had PD-L1–positive disease. Median PSA value was 24.5 ng/mL, 16.7% had visceral disease, and 39.2% had measurable disease.

The confirmed PSA response rate (the primary end point of the study) was 21.8% in the overall population, and was similar among those with measurable disease (22.5%) versus nonmeasurable disease (21.3%). The confirmed decline in PSA level from baseline in the total study population was 71.3%, and 29.7% of patients had a decrease in PSA level ≥50%.

The median time to PSA progression among patients who had a PSA level measured at baseline was 3.5 months.

At ≥27 weeks of follow-up, the confirmed objective response rate among patients with measurable disease was 12% (2 complete responses and 1 partial response) and the disease control rate was 32%. Among all patients with measurable disease, 56.5% experienced a reduction in the size of target lesions, with 24.0% having a reduction ≥30%.

Median radiographic progression-free survival was 6.1 months, “and at 6 months, 55.1% of patients had not yet progressed,” said Dr Yu. “Median overall survival was 20.4 months, and 88.2% of patients were still alive after 6 months on treatment.”

The rate of treatment-related adverse events (AEs) was 90.2%; these included fatigue (38.2%), nausea (21.6%), and rash (19.6%). Grade 3-5 treatment-related AEs occurred in 39.2% of patients and included 7.8% with grade 3 rash. Some 37.3% had immune-mediated AEs, the most common being severe skin reactions (17.6%) and hypothyroidism (14.7%).

“These AEs resolved with standard of care treatment, and 9 patients required steroids, with only 1 requiring [intravenous] steroids,” Dr Yu said.

A randomized phase 3 study of enzalutamide with or without pembrolizumab (KEYNOTE-641) is open to enrollment for patients who are intolerant to or who have progressed on or after abiraterone therapy for metastatic CRPC without having received chemotherapy for metastatic CRPC.

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