ASCO GU 2022: Phase I/II Trial of Pembrolizumab and AR Signaling Inhibitor +/- 225Ac-J591 for Chemo-Naive Metastatic Castration-Resistant Prostate Cancer

( The most clinically developed PSMA-targeting radiopharmaceutical is 177Lu-PSMA-617, a beta-emitting isotope that targets cells expressing PSMA, including prostate cancer cells. This agent has recently been shown to improve patient outcomes in two randomized clinical trials published recently1,2. The alpha-emitting isotope radium-223 is also approved for advanced prostate cancer. Alpha particles are larger, emit higher energy, but have less depth of penetration relative to beta particles, which are smaller and lower energy but penetrate deeper into the target tissue.

Some data suggests that alpha-emitting particles, such as 225-actinium conjugated to the PSMA antibody J591, may have clinical efficacy after 177-lutetium-PSMA treatment. As these targeted radiopharmaceuticals may increase the immunogenicity of advanced prostate cancers, there is interest in combining alpha-emitting therapeutics with immune checkpoint blockade, a therapy so far limited to a relatively rare patient population having mismatch-repair deficient or microsatellite unstable prostate cancers.

In this study, chemotherapy-naïve patients who have progressive metastatic castration resistant prostate cancer (PCWG3 criteria) after receiving at least one androgen pathway inhibitor will be first enrolled in a phase I dose-finding study finding the optimal dose of 225Ac-J591 in combination with pembrolizumab and an androgen pathway inhibitor. In the subsequent phase II portion, patients will be randomized to androgen pathway inhibition plus pembrolizumab (for up to 2 years) without or without 225Ac-J591. The randomized phase 2 study is planned to open this year under clinical trial NCT04946370. The primary endpoints of the study are that the 225Ac-J591 treatment arm will increase measurable disease responses, PSA responses and CTC counts. Secondary endpoints include 1-year progression free survival, duration of response and overall survival. Exploratory objectives include assessment of immunogenic cell death, immune serologic and host microbiome changes, plasma circulating tumor DNA, serial PSMA-PET, and patient reported outcomes. These latter exploratory objectives will be critical to patient stratification if this treatment combination ultimately is advanced given recent demonstrated lack of overall survival benefit with the addition of the anti-PDL1 antibody atezolizumab to the androgen-pathway inhibitor enzalutamide.4


Presented By: Scott Tagawa, MD, medical oncologist at Weill Cornell Medicine, New York, NY

Written By: Alok K. Tewari, MD, PhD, medical oncologist at Dana-Farber Cancer Institute, @aloktewar on Twitter during the 2022 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, Thursday Feb 17 – Saturday Feb 19, 2022

  1. Sartor O, de Bono J, Chi KN et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021 Sep 16;385(12):1091-1103.
  2. Hofman M, Emmett L, Sandhu S, et al., [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. The Lancet 2021
  3. Feuerecker B., Tauber R., Knorr K., Activity and Adverse Events of Actinium-225-PSMA-617 in Advanced Metastatic Castration-resistant Prostate Cancer After Failure of Lutetium-177-PSMA. Eur Urol. 2021 Mar;79(3):343-350
  4. Powles T., Yuen K., Gillessen S., Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial. Nature Medicine. 2022 (28):144–153