Introduction:

Most patients with PC do not respond to immunotherapy. One potential to increase response to immunotherapy is the addition of radiation with occasional abscopal responses. PSMA-targeted radionuclide therapy is a method of radiating multiple sites of disease simultaneously. Furthermore, ARSI can lead to radiosensitization, upregulate PSMA and possibly PDL1 expression. We hypothesize that the addition of a potent alpha-PSMA-TRT (225Ac-J591) will lead to double-stranded DNA breaks, cell death, and subsequent release of neoantigens, thereby increasing the response proportion and duration to pembrolizumab plus ARSI. Here, we present preliminary phase I results of a phase I/II study.

Methods:

Patients enrolled have progressive mCRPC by PCWG3 criteria (at least one AR pathway inhibitor, no chemotherapy in the mCRPC setting). In the phase I component, patients received ARSI of physician’s choice, pembrolizumab (400mg every 6 weeks), and single infusion of 225Ac-J591 in two different cohorts of 6 patients (at 65 or 80 KBq/kg). The primary endpoint of phase I is determination of 225Ac-J591 dose for the randomized phase II portion of the study (pembro and ARSI +/- 225Ac-J591).

Results:

Median age 66.5, median PSA 7.75, 6 (50%) CALGB intermediate risk, 4 (33%) low risk, 11 (92%) with bone metastases. All had at least 1 prior ARPI (6 abi, 5 enza, 1 both), 5 (42%) prior sip-T, 1 prior Ra-223, 2 (17%) prior PSMA-TRT. ARSI in the combo regimen was enzaluamide in 7 (58%), apalutamide in 3 (25%), and darolutamide in 2 (17%). 12 (100%) with PSA decline, 6 (50%) with >50% decline. Of 7 with at least 6 months follow up, 3 progression-free. An unexpected temporary reaction occurred in 9 (75%), characterized by rash, fever, and decreased blood counts at 1-2 weeks. All grade AEs include 9 (75%) thrombocytopenia (3 grade >2), 7 (58%) neutropenia (none grade >2), 5 (42%) nausea, 6 (50%) fatigue, 5 (42%) grade 1 xerostomia, 4 (33%) grade 1 AST. Most higher grade instances of myelosuppression were associated with the inflammatory reaction week 2.

Conclusion:

Combination therapy with alpha-PSMA-TRT, ARSI, and pembrolizumab demonstrates early signs of efficacy in the phase I run-in with majority of patients currently on active therapy. The early inflammatory reaction is under study and the plan is transitioning to the randomized phase II portion in August 2022.

Funding: Department of Defense, Merck