1. Fuerst, Mark L.

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An investigational targeted radiotherapy significantly improves radiographic progression-free survival (PFS) and prolongs overall survival (OS) compared to standard of care therapy in men with advanced-stage metastatic castration-resistant prostate cancer (CRPC).

Metastatic Prostate ... - Click to enlarge in new windowMetastatic Prostate Cancer. Metastatic Prostate Cancer

Despite recent therapeutic advances, metastatic CRPC remains incurable. Current treatment options include chemotherapy, androgen receptor blockers, and targeted therapies. However, these therapies are not durable and the vast majority of men die within 5 years of diagnosis.


Prostate-specific membrane antigen (PSMA) is a transmembrane protein that is highly expressed in approximately 80 percent of patients with prostate cancer, including in metastatic disease. With that high expression, PSMA is an "excellent target for PET imaging," said lead author Michael J. Morris, MD, who is the head of the Prostate Cancer Section at Memorial Sloan Kettering Cancer Center in New York. Lutetium-labeled PSMA-617 (177Lu-PSMA-617) is a radioactive compound that binds to prostate cancer cells expressing PSMA, enabling targeted delivery of radiation to the tumor and surrounding microenvironment, he said at a press briefing during the 2021 ASCO Annual Meeting.


"PSMA-617 targets PSMA with high affinity and delivers a payload of 177lutetium, a beta-particle-emitting radioactive metal. When the drug carrying the 177lutetium payload binds to PSMA, the whole molecule is internalized by the cell, and the cell is then exposed to a lethal dose of radiation and dies," Morris explained.


About the Study

Morris presented the results of the VISION trial (Abstract LBA4), an international, randomized, open-label Phase III study evaluating 177Lu-PSMA-617 in men with PSMA-positive metastatic CRPC previously treated with next-generation androgen receptor signaling inhibition and 1-2 taxane regimens. A total of 831 patients were randomized to receive 177Lu-PSMA-617 7.4 GBq every 6 weeks for 6 cycles plus standard of care (551 patients) or standard of care only (280 patients). Standard of care was determined by the investigator, but excluded cytotoxic chemotherapy and radium-223. The primary endpoints were radiographic PFS and OS.


Median study follow-up was 20.9 months at the data cut-off of January 27, 2021. Treatment groups were balanced in terms of demographics and baseline characteristics, Morris noted.


Key Findings

Results show the addition of 177Lu-PSMA-617 to standard of care significantly improved radiographic PFS, with a median of 8.7 months, as compared with standard of care alone, with a median of 3.4 months. OS was also significantly improved, with the median 15.3 months versus 11.3 months, respectively.


All key secondary endpoints were statistically significant between the treatment arms in favor of 177Lu-PSMA-617 plus standard of care, including overall response rate (29.8% vs. 1.7%), disease-control rate (89% vs. 66.7%), and time to first symptomatic skeletal event (median time, 11.5 vs. 6.8 months; HR, 0.50).


The most common adverse events observed during the trial included fatigue (49.1% for treatment arm vs. 29.3% for control arm), bone marrow suppression (47.4% vs. 17.6%), dry mouth (39.3% vs. 1%), and nausea/vomiting (39.3% vs. 17.1%).


A higher rate of high-grade treatment-emergent adverse events was observed with 177Lu-PSMA-617 (52.7%) versus standard of care alone (38%). These events included bone marrow suppression (23.4% vs. 6.8%), including anemia (13%) and platelet count decline (8%) in the treatment arm; fatigue (7% vs. 2.4%); and renal effects (3.4% vs. 2.9%). No cases of dry mouth were high-grade and only 1.5 percent of nausea/vomiting cases were high-grade.


"The therapy was well-tolerated. There were no unexpected or concerning safety signals," said Morris.


In conclusion, "Adding 177Lu-PSMA-617 to safely combine standard of care in patients with metastatic CRPC after androgen receptor pathway inhibition and chemotherapy extended OS and delayed radiographic disease progression. These findings warrant adoption of 177Lu-PSMA-617 as a new treatment option in patients with metastatic CRPC, pending regulatory review and approval," Morris noted.


He added that 177Lu-PSMA-617 is under investigation in patients with earlier stage prostate cancer.


ASCO President Lori J. Pierce, MD, a radiation oncologist, professor, and Vice Provost for Academic and Faculty Affairs at the University of Michigan, commented: "This novel targeted radiotherapy could fill a significant need for patients with metastatic CRPC that has progressed despite chemotherapy and targeted antiandrogen therapy. The success of this treatment highlights the importance of investigating alternatives to traditional types of cancer therapies."


Mark L. Fuerst is a contributing writer.