In a single-institution phase I dose-expansion trial reported in The Lancet Oncology, Aggarwal et al found that a single dose of lutetium-177–PSMA-617 (LuPSMA) followed by pembrolizumab maintenance was associated with activity in patients with metastatic castration-resistant prostate cancer.
Study Details
The study involved 44 patients with disease progression on one or more androgen signaling inhibitors and at least three PSMA-avid lesions on gallium Ga-68–PSMA-11 positron-emission tomography. Patients were enrolled between August 2019 and May 2022 at the University of California, San Francisco. In part A of the study, 18 patients received one of three schedules consisting of LuPSMA given 28 days before, concomitant with, or 21 days after the start of maintenance pembrolizumab at 200 mg every 3 weeks; maintenance pembrolizumab was given until disease progression or unacceptable toxicity.
Key Findings
The recommended phase II schedule for part B of the study was LuPSMA given 28 days before the start of pembrolizumab maintenance, selected on the basis of safety and feasibility observed in part A. No dose-limiting toxicities were observed in part A.
In part B, 25 patients received the recommended phase II schedule. Objective response was observed in 14 patients (56%, 95% confidence interval [CI] = 35%–76%). Prostate-specific antigen reduction of ≥ 50% was observed in 14 patients (56%, 95% CI = 35%–76%), and reduction of ≥ 90% was observed in 4 (16%, 95% CI = 5%–36%). All patients with objective response had tumors that were microsatellite-stable and had low mutational burden on targeted somatic genomic sequencing.
Among 43 patients in the safety population, the most common treatment-related adverse events of any grade were fatigue (60%), nausea (40%), and joint pain (33%). Two patients (5%) had treatment-related grade ≥ 3 adverse events, consisting of grade 3 arthritis and grade 3 pneumonitis in part A schedules not selected for phase II. Death due to aspiration pneumonia was observed in one patient; no treatment-related deaths were reported.
The investigators concluded, “A single priming dose of [LuPSMA] followed by pembrolizumab maintenance was safe and had encouraging preliminary activity in patients with metastatic castration-resistant prostate cancer.”
Rahul Aggarwal, MD, of UCSF Helen Diller Family Comprehensive Cancer Center, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by the Prostate Cancer Foundation, National Cancer Institute, Novartis Pharmaceuticals, and Merck. For full disclosures of the study authors, visit thelancet.com.
