As reported in The New England Journal of Medicine by Oliver Sartor, MD, and colleagues, the phase III VISION trial has shown prolonged progression-free and overall survival with lutetium-177–PSMA-617 (Lu-177–PSMA-617) radioligand therapy plus standard care vs standard care alone in previously treated metastatic castration-resistant prostate cancer.

Oliver Sartor, MD

As stated by the investigators: “Prostate-specific membrane antigen (PSMA) is highly expressed in metastatic castration-resistant prostate cancer. [Lu-177–PSMA-617] is a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the surrounding microenvironment.”

Study Details

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 Lu-177–PSMA-617 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). Protocol-permitted standard care excluded chemotherapy, immunotherapy, radium-223, and investigational drugs. Patients had received at least one androgen receptor pathway inhibitor and one or two taxane regimens and had PSMA-positive gallium-68–labeled PSMA-11 positron-emission tomography/computed tomography scans.

The alternate primary endpoints were imaging-based progression-free survival and overall survival (powered for hazard ratios [HRs] of 0.67 and 0.73, respectively). The analysis set for imaging-based progression-free survival consisted of 581 patients, including 385 in the Lu-177–PSMA-617 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, the median progression-free survival was 8.7 months in the Lu-177–PSMA-617 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).

An analysis of overall survival among the 581 patients in the imaging-based progression-free survival set showed improved overall survival with Lu-177–PSMA-617 (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).

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 response were observed in 9.2% and 41.8% of 184 patients, respectively, in the Lu-177–PSMA-617 and in 0% and 3% of 64 patients, respectively, in the control group.

Adverse Events

In the total population, grade ≥ 3 adverse events occurred in 52.7% of the Lu-177–PSMA-617 group vs 38.0% of the control group, with the most common in the Lu-177–PSMA-617 group being anemia (12.9%), thrombocytopenia (7.9%), and lymphopenia (7.8%). The most common adverse events of any grade in the Lu-177–PSMA-617 group were fatigue (43.1%), dry mouth (38.8%), and nausea (35.3%). Adverse events led to discontinuation of Lu-177–PSMA-617 in 11.9% of patients. Fatal adverse events occurred in 3.6% of the Lu-177–PSMA-617 group and 2.9% of the control group. Fatal adverse events were considered related to treatment in five patients in the Lu-177–PSMA-617 group, with causes consisting of pancytopenia in two patients, bone marrow failure in one, subdural hematoma in one, and intracranial hemorrhage in one.

The time to deterioration in the Functional Assessment of Cancer Therapy–Prostate (FACT–P) total score and Brief Pain Inventory–Short Form (BPI-SF) pain intensity score favored the Lu-177–PSMA-617 group.

The investigators concluded: “Radioligand therapy with [Lu-177–PSMA-617] 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. For full disclosures of the study authors, visit nejm.org.