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

(UroToday.com) On the first day of the American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2022, Trials in Progress Poster Session A focussed on ongoing trials that will contribute to the care of patients with prostate cancer moving forward. Dr. Tagawa described the rationale and design of a phase I/II trial of pembrolizumab and an AR signaling inhibitor with or without 225Ac-J591 among patients with chemo-naive metastatic castration-resistant prostate cancer (mCRPC).

By way of background, the role of immune checkpoint inhibition (ICI) in prostate cancer is poorly defined, outside the relatively small subset of men with mismatch repair defects. However, several studies have suggested that the combination of immune checkpoint inhibition with androgen receptor signaling inhibitors (ARSI) or kinase inhibitors may result in improved responses in men with mCRPC. Further, preliminary data suggest that the addition of external beam radiotherapy may potentiate the effect of immune checkpoint inhibition. Radiotherapy may be alternatively administered with radioligand therapy. PSMA targeted radioligand therapy with 177Lu-PSMA-617 has been shown to improve survival in men with mCRPC in phase II and III trials. Early clinical studies have demonstrated a potential role for combination therapy with immune checkpoint inhibitors with radioligand therapy. In particular, PSMA-targeted alpha-emitters (such as radiolabeled mAb J591) have a very high potency and the potential to generate immune response.

Thus, the authors hypothesized that the addition of an alpha-emitting radionuclide (225Ac) targeting prostate cancer (i.e PSMA+ tumors targeted with J591) will lead to double-stranded DNA breaks, cell death, and subsequent release of neoantigens, and thus will increase the response proportion to pembrolizumab plus ARSI resulting in more durable response based on the rationale that ARSI may increase PSMA expression, ARSI may radiosensitize tumors, ARSI resistance may lead to increased PD-L1 expression, and alpha emitters may generate an immune response.

The authors will accrue patients with progressive mCRPC by PCWG3 on at least 1 prior AR pathway inhibitor and no prior chemotherapy for mCRPC (NCT04946370). First, the authors will undertake a phase I dose-finding study to test the safety of the triplet combination of pembrolizumab, an ARSI of physician choice, and 2 different doses of 225Ac-J591 (one with minimal and one with moderate single-agent toxicity).

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Subsequently, following the determination of the optimal dose in phase I, a randomized phase II trial will treat subjects with a fixed dose of pembrolizumab 400 mg every 6 weeks (for up to 2 years) plus a standard ARSI (until progression or intolerance) with or without 225Ac-J591.

The primary endpoint of the study is a composite response defined based on measurable disease per PCWG3 modified RECIST v1.1, PSA decline of at least 50% from baseline, and CTC count conversion from baseline to week 12. A sample size of 64 randomized patients will provide a 90% power with a 0.10 one-sided alpha level to determine a difference in response rate between 50% in the experimental group and 20% in the control group.

Key secondary clinical 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 ctDNA, serial PSMA PET, and patient reported outcomes (FACT-P, BPI, EQ-5D-5L). The phase I portion of this DOD-funded study was activated in summer 2021 with the randomized phase II portion expected to open at PCCTC sites in 2022.


Presented by: Scott T. Tagawa, MD, Associate Professor of Clinical Medicine, Clinical Urology, Medical Director, Genitourinary Oncology Research Program, Weill Cornell Medicine, New York, NY