The addition of 117Lu-PSMA-617, a radionuclide therapy that targets prostate-specific membrane antigen (PSMA), to standard-of-care treatment resulted in a 38% reduction in the risk for death versus standard of care alone in men with progressive PSMA-positive metastatic castration-resistant prostate cancer (mCRPC), according to findings from the phase 3 VISION clinical trial, which were presented during a plenary session at the American Society of Clinical Oncology (ASCO) 2021 virtual annual meeting.
At a median follow-up of 20.9 months, the risk for radiographic progression or death was 60% lower in patients who received 117Lu-PSMA-617 compared with those who received best standard of care alone.
“These findings warrant adoption of 117Lu-PSMA-617 as a new treatment option in patients with mCRPC, pending FDA approval,” said lead investigator Michael J. Morris, MD, Section Head, Prostate Cancer, Genitourinary Oncology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center, New York City.
117Lu-PSMA-617 is one of several investigational therapies that target PSMA, which is expressed on the surface of metastatic prostate cancer cells but not on normal tissue.
The open-label, randomized, phase 3 VISION trial included 831 patients (1179 initially screened) with progressive PSMA-positive mCRPC who had received ≥1 novel androgen receptor–directed therapies (enzalutamide [Xtandi] or abiraterone acetate [Zytiga]) and were previously treated with 1 to 2 taxane regimens.
PET imaging with 68Ga-PSMA-11 was used to determine PSMA positivity. At baseline, all patients were PSMA-positive, and demographics and disease characteristics were well-balanced. Previous treatment with radium-223 was not allowed.
Patients were randomized in a 2:1 ratio to physicians’ choice of best standard of care either with or without 4 to 6 cycles of 117Lu-PSMA-617 at a dose of 7.4 GBq every 6 weeks. The co-primary end points of the trial were overall survival (OS) and radiographic progression-free survival (PFS).
The median OS was 15.3 months in the 117Lu-PSMA-617 arm versus 11.3 months in the control arm, representing a 38% reduction in the risk for death (P <.001). The radiographic PFS was 8.7 versus 3.4 months, respectively, a 40% reduction in risk for disease progression or death (P <.001).
A statistically significant benefit was observed with 117Lu-PSMA-617 for the key secondary end points of time to first symptomatic skeletal event, objective response rate, and disease control rate. The median time to first symptomatic skeletal event was 11.5 months in the 117Lu-PSMA-617 arm compared with 6.8 months in the control arm. The objective response rates and disease control rates were 29.8% versus 1.7% and 89.0% versus 66.7%, respectively.
Safety was analyzed in 529 patients in the 117Lu-PSMA-617 arm and 205 patients in the control arm. 117Lu-PSMA-617 treatment was well-tolerated. The most frequently reported adverse events (AEs) of any grade in the 117Lu-PSMA-617 arm were fatigue (49.1% vs 29.3% in the control arm), bone marrow suppression (47.4% vs 17.6%, respectively), dry mouth (39.3% vs 1%, respectively), nausea/vomiting (39.3% vs 17.1%, respectively), kidney effects (8.7% vs 5.9%, respectively), second primary malignancies (2.1% vs 1%, respectively), and intracranial bleeding (1.3% vs 1.5%, respectively).
High-grade treatment-emergent AEs were reported in 52.7% of patients in the 117Lu-PSMA-617 arm and 38% of patients treated with standard of care alone. The most common grade 3/5 AEs with 117Lu-PSMA-617 were bone marrow suppression (23.4% vs 6.8% in the control arm), fatigue (7% vs 2.4%, respectively), kidney effects (3.4% vs 2.9%, respectively), and nausea/vomiting (1.5% vs 0.5%, respectively). There were 5 treatment-related deaths in the 117Lu-PSMA-617 arm versus none in the control arm.
Commenting on the VISION trial, ASCO President Lori J. Pierce, MD, FASTRO, FASCO, said, “This is an important study, as the patients in this trial had mCRPC, so they had disease that grew even when testosterone in the body had already been reduced to very low levels, despite receiving 1 to 2 previous taxane regimens.”
“This trial shows an alternative to traditional therapies by using radiation targeted to the PSMA antigen. So, it could be delivered directly to the prostate cancer cells, and by doing that, survival was significantly improved. Use of the PSMA radioligand therapy, if it obtains regulatory approval, could indeed become an important treatment option for these patients with refractory disease,” she added.