As reported in The New England Journal of Medicine by Oliver Sartor, MD, of the School of Medicine, Tulane University, and colleagues, the phase III VISION trial has shown prolonged progression-free and overall survival with lutetium-177–PSMA-617 (LuPSMA) radioligand therapy plus standard care vs standard care alone in heavily pretreated metastatic castration-resistant prostate cancer.1
As stated by the investigators: “Prostate-specific membrane antigen (PSMA) is highly expressed in metastatic castration-resistant prostate cancer. [LuPSMA] is a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the surrounding microenvironment.”
Oliver Sartor, MD
In the open-label trial, 831 patients from sites in North America and Europe were randomly assigned 2:1 between June 2018 and October 2019 to receive LuPSMA at 7.4 GBq every 6 weeks for four to six cycles plus protocol-permitted standard care (n = 551) or standard care alone (n = 280). Patients had received and had disease progression after at least one androgen receptor pathway inhibitor (such as abiraterone or enzalutamide) and one or two taxane regimens and had PSMA-positive gallium-68–labeled PSMA-11 positron-emission tomography/computed tomography scans. Randomization was stratified by baseline lactate dehydrogenase (LDH) level (≤ 260 IU/L vs > 260 IU/L), presence of liver metastases, Eastern Cooperative Oncology Group (ECOG) performance status (0–1 vs 2), and inclusion of an androgen receptor pathway inhibitor in protocol-permitted standard care at the time of randomization.
Protocol-permitted standard care excluded chemotherapy, immunotherapy, radium-223, and investigational drugs (including olaparib, at the time of the trial design). In the LuPSMA group vs standard-care group, the most commonly used protocol-permitted standard care treatments were gonadotropin-releasing hormone analogs (89% vs 84%), glucocorticoids (63% vs 65%), androgen receptor pathway inhibitors (53% vs 68%), and denosumab (35% vs 39%); radiotherapy was received by 15% vs 17%.
The alternate primary endpoints were imaging-based progression-free survival and overall survival (powered for hazard ratios [HRs] of 0.67 at a significance level of .004, and 0.73 at a significance level of .025, respectively). The analysis set for imaging-based progression-free survival (patients who underwent randomization on or after March 5, 2019) consisted of 581 patients, including 385 in the LuPSMA group and 196 in the control group. Overall survival was analyzed among all 831 randomly assigned patients.
Progression-Free and Overall Survival
Median follow-up was 20.9 months. In the imaging-based progression-free survival set, median progression-free survival was 8.7 months in the LuPSMA group vs 3.4 months in the control group (HR = 0.40; 99.2% confidence interval [CI] = 0.29–0.57, P < .001). Among all randomly assigned patients, median overall survival was 15.3 vs 11.3 months (HR = 0.62, 95% CI = 0.52–0.74, P < .001). Analysis of overall survival among the 581 patients in the imaging-based progression-free survival set also showed improved overall survival with LuPSMA (HR = 0.63, 95% CI = 0.51–0.79), with the benefit maintained after adjustment for postprotocol chemotherapy (HR = 0.64, 95% CI = 0.51–0.80).
In the imaging-based progression-free survival set, hazard ratios for progression-free survival in stratification subgroups were 0.44 (95% CI = 0.32–0.61) for LDH ≤ 260 IU/L and 0.37 (95% CI = 0.25–0.53) for LDH > 260 IU/L; 0.28 (95% CI = 0.15–0.53) for liver metastases and 0.43 (95% CI = 0.33–0.57) for no liver metastases; 0.43 (95% CI = 0.33–0.56) for an ECOG performance status of 0 to 1 and 0.18 (95% CI = 0.08–0.38) for an ECOG performance status of 2; and 0.53 (95% CI = 0.37–0.76) among patients with and 0.27 (95% CI = 0.19–0.39) among those without an androgen receptor pathway inhibitor as part of planned standard care.
In the overall survival analysis among all patients, hazard ratios in stratification subgroups were 0.63 (95% CI = 0.50–0.80) for LDH ≤ 260 IU/L and 0.63 (95% CI = 0.48–0.84) for LDH > 260 IU/L; 0.87 (95% CI = 0.53–1.43) for liver metastases and 0.62 (95% CI = 0.51–0.76) for no liver metastases; 0.61 (95% CI = 0.50–0.74) for an ECOG performance status of 0 to 1 and 0.63 (95% CI = 0.35–1.13) for an ECOG performance status of 2; and 0.54 (95% CI = 0.41–0.70) among patients with and 0.68 (95% CI = 0.53–0.87) among those without an androgen receptor pathway inhibitor as part of planned standard care.
The median time to first symptomatic skeletal event was 11.5 vs 6.8 months (HR = 0.50, 95% CI = 0.40–0.62, P < .001). Among 248 patients with measurable target lesions at baseline, complete and partial responses were observed in 9.2% and 41.8% of 184 patients in the LuPSMA group and in 0% and 3% of 64 patients in the control group.
In the total population, grade ≥ 3 adverse events occurred in 52.7% of the LuPSMA group vs 38.0% of the control group, with the most common in the LuPSMA group being anemia (12.9%), thrombocytopenia (7.9%), and lymphopenia (7.8%). The most common adverse events of any grade in the LuPSMA group were fatigue (43.1%), dry mouth (38.8%), and nausea (35.3%).
Serious adverse events occurred in 36.3% vs 27.8% of patients. Adverse events led to discontinuation of LuPSMA in 11.9% of patients. Fatal adverse events occurred in 3.6% of the LuPSMA group and 2.9% of the control group. The time to deterioration in the Functional Assessment of Cancer Therapy–Prostate total score and Brief Pain Inventory–Short Form pain intensity score favored the LuPSMA group.
The investigators concluded: “Radioligand therapy with [LuPSMA] prolonged imaging-based progression-free survival and overall survival when added to standard care in patients with advanced PSMA-positive metastatic castration-resistant prostate cancer.”
DISCLOSURE: The study was funded by Endocyte, a Novartis company. Dr. Sartor holds stock or other ownership interests in AbbVie, Cardinal Health, Clarity Pharmaceuticals, Clovis, GlaxoSmithKline, Lilly, Noria Therapeutics, PSMA Therapeutics, and United Health Group; has served as a consultant or advisor to Advanced Accelerator Applications, Astellas Pharma, AstraZeneca, Bavarian Nordic, Bayer, Blue Earth Diagnostics, Bristol Myers Squibb, Clarity Pharmaceuticals, Clovis, Constellation Pharmaceuticals, Dendreon, EMD Serono, Fusion, Isotopen Technologien Meunchen, Janssen, Myriad Genetics, Noria Therapeutics, Novartis, Noxopharm, Pfizer, Point Biopharma, Progenics, Sanofi, Telix, TeneoBio, and Theragnostics; has received research funding from Janssen, Progenics, and SOTIO; has received institutional research funding from Advanced Accelerator Applications, AstraZeneca, Bayer, Constellation Pharmaceuticals, Dendreon, Endocyte, InVitae, Merck, and Sanofi; has provided expert testimony on behalf of Sanofi; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca, Bayer, Johnson & Johnson, Progenics, and Sanofi.
1. Sartor O, de Bono J, Chi KN, et al: Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. June 23, 2021 (early release online).
Based on the findings of the phase III VISION trial, reported by Sartor et al1 and summarized in this issue of The ASCO Post, lutetium-177–PSMA-617 (LuPSMA) is the first of the prostate-specific membrane antigen–targeted cancer theranostics to demonstrate a survival-prolonging benefit for men with...