Dr. Bander on Preliminary Data on 225Ac-J591 Plus Pembrolizumab in mCRPC

Neil H. Bander, MD, professor of Urology, Josephine and Bernard Chaus Professor of Urologic Oncology, director, Urological Oncology Research, Weill Cornell Medicine, discusses preliminary results from a phase 1/2 trial (NCT04946370) of the alpha–prostate-specific membrane antigen (PSMA)–targeted radionuclide therapy (alpha-PSMA-TCT ) ²²⁵Ac-J591 in combination with pembrolizumab (Keytruda) and an androgen receptor signaling inhibitor (ARSI) in metastatic castration-resistant prostate cancer (mCRPC).

The study was designed to evaluate whether the addition of ²²⁵Ac-J591 to pembrolizumab plus an ARSI could upregulate PSMA expression and increase PD-L1 expression to lead to improved responses in patients with progressive mCRPC, Bander begins. In phase 1, patients received physician's choice of ARSI and pembrolizumab plus a single infusion of ²²⁵Ac-J591 at 65 or 80 KBq/kg. Both dose levels were below the previously determined maximum-tolerated dosage, Bander adds. The primary end point for phase 1 was the determination of the recommended phase 2 dose of ²²⁵Ac-J591 dose.

Preliminary phase 1 results showed that PSA levels decreased in all 12 patients receiving the regimen, with 6 patients in the higher-dose cohort experiencing a decline greater than 50%. Responses were highly durable, with 3 patients in the higher-dose cohort remaining progression-free and enrolled on treatment after more than 9 months of follow-up, he continues. Of these 3 patients, the longest response duration was 13 months post-treatment. The other two patients were at 10 and 11 months post-treatment, respectively.

Patients were able to continue treatment every 6 weeks for up to 2 years. As PSA progression often precedes radiographic progression by several months, these results were particularly impressive and exceeded expectations, Bander emphasizes.

Safety data revealed an unexpected incidence a transient syndrome between 7 and 14 days post-treatment in 7 patients, Bander says. The event was characterized by a fever above 101 degrees Fahrenheit, low platelet and leukocyte counts, and morbilliform rash, the latter of which is commonly associated with immune checkpoint inhibitors, Bander explains. Although these adverse effects (AEs) occurred at high grades, they improved within 1 week of pausing ARSI administration and the AEs did not recur in subsequent cycles or ARSI rechallenge. This key safety signal has not been previously seen with the use of ²²⁵Ac-J591, and it should be closely monitored going forward, Bander concludes.

Editor's Note: Dr Bander reports serving as a consultant or in an advisory and leadership role for Convergent Therapeutics, XenImmune Therapeutics; he reports stock and ownership interests from Convergent Therapeutics, Telix Pharmaceuticals and XenImmune Therapeutics; he received royalties from Cook Urological.