Immune checkpoint inhibitors have demonstrated limited efficacy in treating prostate cancer. Efforts to improve outcomes with combination therapies have mostly failed to demonstrate improvements compared to other types of cancer. By contrast, radioligand therapy - a type of precision radiation treatment that uses a targeting compound to damage or destroy prostate cancer cells – has been shown to improve survival rates in metastatic castration resistant prostate cancer (mCRPC).

In a study published October 31, 2023 in The Lancet Oncology, UC San Francisco researchers conducted a phase 1 clinical trial to determine whether a single priming dose of radioligand therapy ¹⁷⁷Lu-PSMA-617 with pembrolizumab immunotherapy would have a beneficial effect in treating patients with mCPRC. Results from the trial demonstrated measurable anti-tumor activity with minimal toxicity in patients with mCRPC.

“This phase 1 trial represents the first clinical study to our knowledge to evaluate a single priming dose of targeted radioligand therapy coupled with immune checkpoint inhibition in patients with metastatic prostate cancer,” said study first author Rahul Aggarwal, MD, a genitourinary medical oncologist and UCSF professor of Medicine. “We observed lasting responses in a subset of patients, in whom there was an increase in circulating T cells and decreased activity of immunosuppressive cells following the priming dose of ¹⁷⁷Lu-PSMA-617.” 

The study included patients with mCRPC and prior treatment with one or more androgen signaling inhibitors – medications that work by reducing androgen production. A total of 43 male patients were enrolled between August 2019 and July 2022, with a median follow up of 16.5 months. Patients received a priming dose of ¹⁷⁷Lu-PSMA-617 followed by maintenance pembrolizumab (a sustained dose) administered intravenously every 3 weeks.

Targeted therapy enhances effectiveness 

The researchers found significant anti-tumor activity with 56% of participants having a positive response, and a subset of those with durable responses. The combination therapy also had favorable toxicity profile with minimal hematologic impact and a manageable rate of immune-related adverse events. Within the study cohort, 5% of patients had a complete response to the therapy, 47% had a confirmed partial response, 28% of patients had stable disease, and 21% of patients had progressive disease.

“Radiation therapy is an established treatment, but we are still learning how best to combine immunotherapy and radiation therapy,” said co-senior author, Lawrence Fong, MD, leader of UCSF’s Cancer Immunotherapy Program and the Efim Guzik Distinguished Professor in Cancer Biology. “Our study shows using just a single dose of radioligand therapy, rather than the usual 6 planned doses, can be combined with immunotherapy and have durable responses.”

“Targeted radioligand therapy can enhance the effectiveness of immune checkpoint inhibition by improving priming of an immune response or by resetting the immunosuppressive tumor microenvironment to enhance anti-tumor response,” said co-senior author Thomas Hope, MD, Vice Chair of the UCSF department of Radiology. “We thought that if ¹⁷⁷Lu-PSMA-617 induced anti-tumor immunity, the immune effector cells recruited to the sites of metastasis would increase with repeated doses given on a fixed schedule.”

The researchers acknowledge the limitation of the trial’s non-randomized design which does not evaluate the individual contribution of pembrolizumab and ¹⁷⁷Lu-PSMA-617. The research team is planning a phase 2 study combining maintenance pembrolizumab with repeated doses of ¹⁷⁷Lu-PSMA-617 delivered at variable intervals dependent on the anti-tumor response.

 

^{Authors: Additional UCSF authors include: Stephanie Starzinski, BS; Ivan de Kouchkovsky, MD; Vadim Koshkin, MD; Rohit Bose, MD, PhD; Jonathan Chou, MD, PhD; Arpita Desai, MD; Daniel Kwon, MD; Samuel Kaushal, BS; Lauren Trihy, BS; Medini Rastogi, BS; Robin Ippisch, PhD, Maya Aslam, BA; Terence Friedlander, MD; Felix Feng, MD; David Oh, MD, PhD; Alexander Cheung, BS; Eric Small, MD, Michael Evans, PhD; and Lawrence Fong, MD}

^{Funding: Funding for the study was in part supported by the National Cancer Institute (R01CA229354), the Prostate Cancer Foundation (20CHAL05) and philanthropic support from Gene and Ethel Daly.  Merck and Novartis supplied the investigational agents pembrolizumab and 177Lu-PSMA-617, respectively.}

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