A novel targeted radionuclide therapy has shown promising clinical activity and low toxicity in a group of heavily pretreated men with metastatic castration-resistant prostate cancer (mCRPC).
The novel product is Lutetium-177 (177Lu)-PSMA-617 (under development by Endocyte) is a radiolabeled small molecule that binds with high affinity to prostate specific membrane antigen (PSMA), enabling tumor-targeted delivery of beta-radiation. PSMA is over-expressed 100-1000 times in prostate cancers, and expression is further increased in metastatic and castration-resistant carcinomas.
The new results come from an updated report on 50 patients with PSMA-positive mCRPC who had progressed on standard therapies and were treated with the new product. The results show a median overall survival of 13.3 months, which is longer than the average 9-month survival time for men with this stage of disease, noted lead author Michael Hofman, MBBS, a professor of nuclear medicine at the Peter MacCallum Cancer Centre, Melbourne, Australia.
While he believes that this may be a life-prolonging therapy, "this is not a claim that we can make yet, because there's no comparator arm," he said.
Hofman was speaking at a press briefing for this week's Genitourinary Cancers Symposium (GUCS) 2019 in San Francisco, California. The study was presented today at the conference.
"Metastatic castration-resistant prostate cancer is a fatal disease and there is an urgent need for new effective therapies," said Hofman, adding that based on the results of this trial, two randomized trials were now underway.
One is the TheraP trial, which compares LuPSMA with cabazitaxel (Jevtana, sanofi-aventis) and the other is the VISION trial, which is comparing LuPSMA to best standard of care; both trials are being conducted in men with PSMA-positive, progressive mCRPC.
"This is a very intriguing agent, and the VISION study is open in the US," commented briefing moderator Robert Dreicer, MD, of the University of Virginia in Charlottesville and an American Society of Clinical Oncology (ASCO)-designated expert.
"For this group of patients in dire need of new options, using an entirely new approach, this study provides hope that we can start to change their outcomes," he added.
Prolonged Survival, Decreased PSA
Hofman noted that in an earlier study his team found favorable activity and low toxicity in 30 patients with mCRPC. The current study is an updated report on the safety and efficacy, and with a larger cohort and a median follow-up of 23.5 months.
In this updated phase 2 study, the 50 patients received up to four cycles of 177Lu-PSMA-617 intravenously every 6 weeks. All patients had progressed on standard therapies, and 90% of the men had been treated with abiraterone (Zytiga, Janssen) or enzalutamide (Xtandi, Astellas) or both. The median PSA was 190 and the median PSA doubling time was 2.6 months.
Eight patients received fewer than 4 cycles owing to an exceptional response, Hofman said, while 10 patients did not complete all planned cycles owing to disease progression. The mean administered radioactivity was 7.5 GBq/cycle.
A prostate-specific antigen (PSA) decline of ≥50% was achieved in 32 (64%) of 50 patients, including 22 patients (44%) who achieved a PSA decline ≥80%.
The median overall survival was significantly longer among patients who achieved a greater drop in their PSA levels: 18 months for those with a PSA decline of ≥50% vs 8.7 months for those with a decline <50 em="" style="max-width: 100%;">P
In addition, 14 patients who progressed with PSMA-avid disease after the study was completed received additional treatment with Lu-PSMA. In this patient subset, 64% had a PSA decline ≥50% and the median overall survival was 33 months.
The most common toxicities associated with Lu-PSMA treatment were transient grade 1 to 2 dry mouth in 68%, grade 1 to 2 nausea in 48%, and grade 1 to 2 fatigue in 36%. Grade 3 to 4 toxicities were infrequent and included thrombocytopenia in 10% and anemia in 10% of patients.
The study was sponsored by the Peter MacCallum Cancer Centre, Melbourne, Australia. PSMA-617 was supplied by Endocyte and Lutetium-177 by ANSTO. Hofman disclosed relevant relationships with Endocyte, Ipsen, and Sanofi. Coauthors disclosed multiple relevant relationships with industry. Dreicer disclosed relationships with Astellas Pharma, AstraZeneca, Genentech/Roche, EMD Serono, Incyte, Pfizer, Seattle Genetics, Rainier Therapeutics, Janssen, and Merck.
Genitourinary Cancer Symposium: Abstract 228. Presented February 14, 2019.
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