PSMA-targeted therapy well tolerated in men with mCRPC

A radiolabeled small molecule that binds to prostate-specific membrane antigen (PSMA) is continuing to show promise for treating progressive metastatic castrate-resistant prostate cancer (mCRPC), according to researchers at the University of California, Los Angeles.

UCLA researchers have been investigating lutetium-177 (177Lu)-PSMA-617, which binds with high affinity to PSMA, allowing beta particle targeted molecular radiotherapy for men with mCRPC. An analysis of 64 men treated with this agent showed that it was well tolerated, and PSA declined by 50% or greater in 38% of patients.

The findings from the RESIST-PC phase II trial, which were presented at the 2019 AUA annual meeting in Chicago, showed that best PSA response rate occurred after three cycles of treatment. Currently, Lu-PSMA-617 is being developed as targeted molecular radiotherapy for mCRPC by Endocyte with an international multicenter randomized phase III trial (VISION).

“The response rate of the patients who responded by a PSA decline of more than 50% at any time was 38%, so we were pretty close to the 40% we expected. We were not surprised by our findings,” said study investigator Jeremie Calais, MD, MSc, assistant professor of nuclear medicine at the David A. Geffen School of Medicine at UCLA.

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He said these findings are good news because in this patient population with advanced disease, the survival and response rates to third-line therapy are very low. In this population, having a PSA decline of more than 50% in 38% of patients is very satisfying, according to Dr. Calais.

He collaborated with investigators in Germany and Houston and conducted an open-label prospective, bi-centric, single-arm phase II clinical trial (NCT03042312) in men who had progressive mCRPC (biochemical, radiographic, or clinical) after one or more novel androgen axis drugs. All the men had sufficient bone marrow reserve and normal kidney function and were screened with PSMA PET/CT to confirm target expression. The 64 men received either of 6.0 or 7.4 GBq of 177Lu-PSMA-617 every 8 +/–1 weeks, and the authors performed kidney dosimetry for the first cycle.

For this investigation, the authors defined efficacy as serum PSA decline of 50% or greater from baseline at 12 weeks, which was the study’s primary endpoint. In this cohort, the median PSA level was 75 ng/mL (range, 0.5-2,425) and 20% of the men were chemotherapy naive and 80% were post-chemotherapy (1.9 chemotherapy regimens on average; range, 1-4). Only 45% of the men completed four cycles of 177Lu-PSMA-617. Androgen deprivation therapy (ADT) was given concomitantly to 83% of the men, 23% received a novel androgen axis drug, and 6% received immunotherapy.

Dr. Calais said the median time to best PSA response was 22 weeks; however, there was a wide range from 6 to 49 weeks.

“I think we are under-dosing patients. The safety profile was very favorable. We could maybe get better radiation dose delivery to the tumor targets and enhance efficacy by increasing the amount of injected drug or by reducing the time interval between each cycle. The primary endpoint hypothesis of 40% responders after two cycles was a little bit too ambitious. Maybe after three cycles or at any time (best response) would have been more appropriate,” Dr. Calais told Urology Times.

He said the study was powered for a sample size of 200 patients, and the enrollment of this phase II trial was closed by industry (Endocyte) before reaching the target. Some men did quite well on this agent and 10% to 15% had a deep and durable response with a PSA decline of 90% or greater.

Next: Adverse events mild, transientAdverse events mild, transient

The authors were pleased to find that adverse events were mild and transient. They included xerostomia (72%), nausea/vomiting (69%), and bowel movement disorders (45%). Grade 3 toxicity included nausea/vomiting (6%), anemia (8%), leukopenia (5%), kidney failure (3%), thrombocytopenia (3%), and neutropenia (3%).

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“The side effects were very well tolerated, especially for a third-line therapy,” said Dr. Calais. The authors found no difference between the efficacy and toxicity for the two doses, and no kidney abnormalities were detected.

Dr. Calais said many improvements could be made, such as finding tools to better identify responders versus non-responders prior to treatment, optimization of the radiation dose delivery to the tumor targets, and moving the treatment indication at an earlier stage of the disease instead of third-line therapy.