Lutetium-177–PSMA-617 (LuPSMA)—an investigational radiolabeled small molecule—significantly improved radiographic progression-free survival and overall survival when added to the standard of care compared with the standard of care alone for men with metastatic castration-resistant prostate cancer who had experienced disease progression on other lines of treatment. These findings were from the phase III VISION trial presented during the 2021 ASCO Annual Meeting.¹

LuPSMA plus the standard of care achieved a median of 8.7 months of radiographic progression-free survival vs 3.4 months with the standard of care alone—more than doubled in this pretreated population with advanced disease. Overall survival was also extended to 15.3 months with LuPSMA plus the standard of care vs 11.3 months with the standard of care alone.

Michael J. Morris, MD

“In patients with metastatic castration-resistant prostate cancer whose cancer had progressed after chemotherapy and androgen receptor pathway inhibitors, LuPSMA prolonged life and delayed the time to progression of cancer on scans. It was well tolerated, with no new safety signals of concern. These findings warrant LuPSMA as a new treatment option for metastatic castration-resistant prostate cancer, pending FDA [U.S. Food and Drug Administration] review,” stated presenting author Michael J. Morris, MD, Head of the Prostate Section at Memorial Sloan Kettering Cancer Center, New York.

“This trial is clearly important. These men had disease progression even with very low levels of testosterone. LuPSMA is an alternative therapy delivered directly to the prostate cancer cells, and survival was significantly improved. The use of LuPSMA, if it gets regulatory approval, could become an important new treatment option for patients with metastatic castration-resistant prostate cancer,” said Immediate Past President of ASCO Lori J. Pierce, MD, FASTRO, FASCO, at a press conference where the findings were discussed.

Background

Prostate cancer is the most common cancer in men and the second leading cause of male cancer-related deaths in the United States. Although a number of treatment options are available for metastatic castration-resistant prostate cancer, most patients experience disease progression and need several lines of therapy; durable remissions are uncommon with each new line of therapy.

PSMA (prostate-specific membrane antigen) is highly expressed on prostate cells across the disease spectrum and disease sites and is an excellent target for treatment and imaging. PSMA positron-emission tomography (PET) scans are FDA approved to detect occult cancers in patients with high-risk localized disease and also biochemically relapsed disease. In VISION, PSMA PET imaging was used to establish PSMA expression in men with metastatic disease as a companion diagnostic to the therapeutic ­PSMA-directed treatment. Targeting PSMA with a radioligand such as LuPSMA is a novel treatment approach, and hopes were high in the prostate cancer community that it would be successful.

LuPSMA is an alternative therapy delivered directly to the prostate cancer cells, and survival was significantly improved.

— Lori J. Pierce, MD, FASTRO, FASCO

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“LuPSMA targets PSMA with high affinity. It releases its payload of beta radiation into the prostate cancer cell, which is exposed to lethal radiation and dies,” Dr. Morris explained.

Study Details

VISION enrolled patients with metastatic castration-resistant prostate cancer and a PSMA-positive PET scan who had experienced disease progression on previous treatment with an androgen receptor pathway inhibitor and one to two taxane chemotherapy regimens. Patients (n = 831) were randomly assigned 2:1 to receive the standard of care (determined by the treating physician) plus LuPSMA or the standard of care alone. The experimental radioligand pharmaceutical was given for four cycles every 6 weeks; responders with residual disease could have an extra two cycles.

“The standard of care excluded chemotherapy, immunotherapy, radium-223, and investigational drugs because the toxicity of these treatments in combination with LuPSMA was unknown,” Dr. Morris explained.

There were two primary endpoints: overall survival and radiographic progression-free survival. If either or both were positive, the trial would be considered a success.

Baseline characteristics were as expected for this population, and previous exposure to androgen receptor inhibitors and taxanes was evenly distributed in both arms of the study. The analysis of radiographic progression-free survival was performed on 531 patients; the overall survival analysis was based on 831 patients.

“Nine months after enrollment, a high dropout rate was observed in the standard-of-care arm [56%], but enhanced study site education and communication reduced the dropout rate in both arms,” Dr. Morris said. 

Key Results

Median follow-up was 20.9 months at the time of data cutoff. LuPSMA plus the standard of care significantly improved radiographic progression-free survival by 60% vs the standard of care alone: median radiographic progression-free survival was 8.7 months vs 3.4 months, respectively (P < .001). Overall survival was also significantly improved by 38% with LuPSMA plus the standard of care vs the standard of care alone: median overall survival was 15.3 months vs 11.3 months (P < .001). All key secondary endpoints were also statistically improved for the experimental arm vs the control arm.

“These benefits were maintained in the entire population of randomly assigned patients,” Dr. Morris said.

“Dramatic differences were observed between treatment arms favoring LuPSMA for prostate-specific antigen (PSA) reductions of more than 50% and more than 80%,” he added. PSA reductions of 50% or more were observed in 46% of the experimental arm and 7.1% of the standard-of-care-alone arm; PSA reductions of 80% or more were seen in 33% and 2%, respectively.

A slightly higher percentage of patients in the control arm received post-protocol chemotherapy and radiotherapy.

Dramatic differences were observed between treatment arms favoring LuPSMA for PSA reductions of more than 50% and more than 80%.

— Michael J. Morris, MD

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Toxicity

“Side effects of all grades and higher grades were more common with LuPSMA, but none were unexpected,” Dr. Morris said.

Fatigue, bone marrow suppression, dry mouth, and nausea/vomiting of all grades were the most commonly reported side effects (about 40% to 50% of patients in the experimental arm). More treatment-emergent adverse events were observed in the experimental arm: 52.7% vs 38% with the standard of care alone.

Among patients receiving LuPSMA, high-grade bone marrow suppression was observed in 23.4%; high-grade anemia, in 13%; low platelet count, in 8%; and dry mouth (not high grade), in 39%. High-grade renal side effects were observed in 3.5% of the experimental arm and 2.9% of the control arm.

“LuPSMA is currently being studied in earlier stages of prostate cancer,” Dr. Morris noted.

Clarifying the Dropout Rate

During the question-and-answer session following his presentation, Dr. Morris cited two reasons for the high dropout rate initially: First, in sites where the partnership between nuclear medicine and medical oncology was not strong, there was a breakdown in communication. These patients had very advanced disease and required medical oncology as well as nuclear medicine. Second, this therapy was available internationally, and a small number of patients randomly assigned to the standard of care arm dropped out.

“Our measures helped reduce the dropout rate and rebalance the equipoise, so patients understood the intent and design of the trial,” Dr. Morris explained. 

DISCLOSURE: The VISION study was funded by Endocyte. Dr. Morris has served as a consultant or advisor to Advanced Accelerator Applications, Athenex, Bayer, Curium, Endocyte, Exelixis, Johnson & Johnson, Lantheus, NCCN, Novartis, ORIC Pharmaceuticals, and Progenics; has received institutional research funding from Bayer, Corcept Therapeutics, Endocyte, Janssen, Progenics, Roche/Genentech, and Sanofi; and has been reimbursed for travel, accommodations, or other expenses by Endocyte and Fujifilm. Dr. Pierce holds other ownership interests in PFS Genomics, holds intellectual property in PFS Genomics and UpToDate, and has held uncompensated relationships with Bristol Myers Squibb and Exact Sciences.

REFERENCE

1. Morris MJ, De Bono JS, Chi KN, et al: Phase III study of lutetium-177–PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). 2021 ASCO Annual Meeting. Abstract LBA4. Presented June 6, 2021.