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Novel Radiation Therapy Induces Responses in Prostate Cancer

Fuerst, Mark L.

doi: 10.1097/01.COT.0000557608.70571.b2
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SAN FRANCISCO—A novel, radiolabeled targeted treatment induces high response rates in men with metastatic, castration-resistant prostate cancer. The majority of men with prostate-specific membrane antigen (PSMA)-positive metastatic, castration-resistant prostate cancer that progressed despite standard therapies were responsive to treatment with a novel, targeted radiation therapy called Lutetium-177 PSMA-617 (LuPSMA). This is the first prospective study of LuPSMA, part of a potential new class of treatments for men with metastatic prostate cancer.

“For men with localized prostate cancer, brachytherapy, or radioactive seeds implanted by needle directly into the tumor, as well as external beam radiotherapy, have been effective forms of treatment,” said lead author Michael Hofman, MBBS, Professor of Nuclear Medicine at the Peter MacCallum Cancer Centre, 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.”

Hofman presented the results of the study at a presscast before the 2019 Genitourinary Cancers Symposium (Abstract 228).

The new therapy is composed of a small-molecule targeting ligand that selectively targets PSMA, a receptor common on prostate cancer cells, attached to Lutetium-177, a radioactive payload. It delivers high doses of beta 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. 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.

Previously, the researchers had reported favorable activity and toxicity with LuPSMA in a study of 30 patients with metastatic castration-resistant prostate cancer.

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About the Study

In a phase II trial, 50 patients with PSMA-avid metastatic castration-resistant prostate cancer who had progressed after standard therapies received up to 4 cycles of LuPSMA every 6 weeks. All patients enrolled in the trial were diagnosed with a form of 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, median age 71 years, saw their prostate-specific antigen (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). About half of them (48%) had also received second-line cabazitaxel chemotherapy.

The researchers tracked PSA levels and imaging using CT, bone, or PET scans. For some patients who responded but subsequently progressed, further cycles of LuPSMA were administered.

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Key Findings

A PSA decline of 50 percent or more was seen in 32 of the 50 men, including 22 men with a PSA decline of 80 percent or more. One-quarter of patients had measurable soft tissue at baseline and more than half (56%) of these patients had a partial or complete response.

Men receiving the treatment lived a median of 13.3 months after treatment, longer than the average 9-month survival time for men with this stage of disease, Hofman noted.

Among responders, PSA values did not increase for a median of 6.9 months, indicating that the disease was not progressing. Cancer progressed in 14 men, and they received a median of 2 more cycles of LuPSMA. In nine of these men, PSA subsequently declined 50 percent or more, and their survival was 33 months.

The most common side effects were nausea (48%), fatigue (36%), and dry mouth (68%) as PSMA is also present on cells in salivary and tear glands. Grade 3-4 toxicities attributed to LuPSMA were infrequent, including thrombocytopenia (10%) and anemia (10%).

“In this trial, we treated men who would have otherwise been directed to palliative care. 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,” said Hofman.

“These results in 50 men provide further confidence to our previously published 30 patient cohort, demonstrating high response rates and low toxicity in men with metastatic castration-resistant prostate cancer who progressed after multiple conventional therapies. Despite multiple lines of prior therapies failing, the high response rates observed in these patients support a novel mechanism of action of LuPSMA compared to existing therapies.

“I have a strong impression that this is life-altering therapy,” he stated. “Many of these patients have no further treatment options. With personalized treatment, they may be likely to respond to therapy.”

Hofman noted that 76 patients were initially screened for eligibility into the trial, and 16 patients were excluded because of insufficient PSMA uptake on PSMA/FDG PET. “The majority of these patients are suitable for therapy.”

In comparison, brachytherapy is a mechanical approach that is effective in early-stage disease confined to the prostate gland. “Advanced prostate cancer is spread widely and therefore it is not possible to insert brachytherapy seeds. This radioactive compound finds its way to prostate cancer cells wherever they are in the body, homes in, and attacks tumors,” said Hofman.

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Next Steps

Based on positive early-stage results, two randomized, controlled trials have been launched to further evaluate LuPSMA. The ANZUP/Prostate Cancer Foundation of Australia TheraP trial compares LuPSMA to cabazitaxel chemotherapy and the Endocyte VISION trial compares LuPSMA to best standard of care.

ASCO Expert Robert Dreicer, MD, MS, Deputy Director of the UVA Cancer Center and moderator of the presscast, commented: “Survival rates are low for patients with prostate cancer that has spread to distant parts of the body, and providing effective treatments for this type of cancer has been an ongoing challenge for physicians. 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.”

Mark L. Fuerst is a contributing writer.

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
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