A single-arm, phase II trial in men with prostate-specific membrane antigen (PSMA)-positive, metastatic, castration-resistant prostate cancer that progressed despite standard therapies found that a majority of men treated with a novel, targeted radiation therapy called lutetium-177 PSMA-617 (LuPSMA) experienced disease response to treatment. This is the first prospective study of LuPSMA, part of a potential new class of treatments for men with metastatic prostate cancer. According to the researchers, men receiving the medication lived a median of 13.3 months after treatment, longer than the average 9-month survival time for men with this stage of disease. These findings will be presented by Hofman et al at the upcoming 2019 Genitourinary Cancers Symposium (Abstract 228).
“For men with localized prostate cancer, brachytherapy—radioactive seeds implanted by needle directly into the tumor—as well as external beam radiotherapy have been effective forms of treatment,” said lead study author Michael Hofman, MBBS, Professor of Nuclear Medicine at the Peter MacCallum Cancer Centre in Melbourne, Australia. “However, for men in our trial, with cancer cells spread throughout the body, LuPSMA provides a new approach to a form of the disease that has been difficult to treat.”
LuPSMA is composed of a small-molecule targeting ligand that selectively targets PSMA attached to lutetium-177, a radioactive payload. With this approach, LuPSMA delivers high doses of radiation precisely to the cancer metastases, while avoiding delivery of potentially hazardous radiation to normal cells.
The half-life of the radioactive payload is 7 days. Additionally, LuPSMA emits low levels of gamma rays, which can be visualized with nuclear medicine imaging, which allows clinicians to see if the cancer is regressing.
All patients enrolled in the trial were diagnosed with a form of metastatic, castration-resistant prostate cancer in which PSMA is present on the surface of the cancer cell when scanned with positron-emission tomography (PET). Prior to enrollment, the men—aged 50–87—saw their PSA levels rapidly double after a median of 2.6 months. Because of the aggressiveness of the disease, most had previously been treated with docetaxel chemotherapy or antiandrogen therapy (abiraterone and/or enzalutamide). Forty-eight percent had also received second-line cabazitaxel.
In this trial, clinicians administered up to four intravenous cycles of LuPSMA in an outpatient setting every 6 weeks and tracked prostate-specific antigen (PSA) levels and imaging using computed tomography (CT), bone, or PET scans. In some patients in whom the cancer responded but subsequently progressed, further cycles of LuPSMA were administered.
A PSA decline of 50% or more was seen in 32 of the 50 men in the study (64%; 95% confidence interval [CI] 50–77). In 22 (44%) of them, PSA declined 80% or more. Among men in which the cancer responded to LuPSMA therapy, PSA values did not increase for a median of 6.9 months, indicating that the disease was not progressing. Fourteen of the men in whom the cancer progressed received a median of two more cycles of LuPSMA. In nine of these men, PSA subsequently declined 50% or more; survival in this group of men was 33 months.
The most common side effects were nausea, fatigue, and dry mouth, as PSMA is also present on cells in salivary and tear glands. Some of the more serious side effects of the drug, seen in about 10% of the men, were anemia and thrombocytopenia.
“In this trial, we treated men who would have otherwise been directed to palliative care,” said Dr. Hofman. “It’s exciting to see that LuPSMA can potentially offer benefits for many men with these very aggressive cancers, with few side effects and significant improvements in quality of life. Importantly, we saw continued benefits with LuPSMA retreatment in some men whose cancer progressed.”
Based on positive early-stage results, two randomized trials have been launched to further evaluate LuPSMA. One trial compares LuPSMA with chemotherapy and the other with the standard of care, according to the study authors.
Disclosure: This study was sponsored by the Peter MacCallum Cancer Centre, Melbourne, Australia. PSMA-617 was supplied by Endocyte (Indiana, USA), and lutetium-177 by ANSTO (Sydney, Australia). The study authors' full disclosures can be found at coi.asco.org.
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