VISION Trial Research Review

Introduction

Metastatic castration-resistant prostate cancer (mCRPC) remains associated with limited survival following progression on androgen receptor pathway inhibitors (ARPI) and taxane-based chemotherapy. Despite the availability of multiple life-prolonging systemic therapies, treatment options after progression on these agents have historically provided modest clinical benefit.

Prostate-specific membrane antigen (PSMA) is highly expressed in most prostate cancers and has emerged as a therapeutic target for radioligand therapy. Lutetium-177–PSMA-617 is a radiolabeled small molecule designed to deliver beta-emitting radiation selectively to PSMA-expressing tumor cells. The VISION trial was conducted to evaluate whether the addition of lutetium-177–PSMA-617 to standard of care would improve survival outcomes in patients with PSMA-positive mCRPC who had previously received ARPIs and taxane chemotherapy.

Study Design

VISION was an international, randomized, open-label, phase 3 trial. A total of 831 patients were randomized in a 2:1 ratio to receive lutetium-177–PSMA-617 plus protocol-permitted standard of care (SOC) or SOC alone. Eligible patients had PSMA-positive mCRPC confirmed by PSMA PET imaging. Patients were required to have received at least 1 ARPI and 1 or 2 prior taxane regimens. Adequate organ function and castrate levels of testosterone were required. Patients with PSMA-negative lesions on imaging were excluded.

Lutetium-177–PSMA-617 was administered at a dose of 7.4 GBq every 6 weeks for up to 6 cycles. Standard of care excluded chemotherapy, immunotherapy, radium-223, and investigational agents. The trial had 2 primary end points: overall survival (OS) and radiographic progression-free survival (rPFS) assessed by blinded independent central review. Secondary end points included objective response rate (ORR), disease control rate, time to symptomatic skeletal events, and safety.

Efficacy Results

At the time of primary analysis, lutetium-177–PSMA-617 plus SOC demonstrated statistically significant improvements in both primary end points. Median overall survival was 15.3 months in the lutetium-177–PSMA-617 group compared with 11.3 months in the SOC group (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.52 to 0.74; P <.001). Median radiographic progression-free survival was 8.7 months in the lutetium-177–PSMA-617 group compared with 3.4 months in the SOC group (HR, 0.40; 95% CI, 0.29 to 0.57; P <.001).

Key Secondary Outcomes:

• Objective response rate (RECIST-evaluable population): 29.8% with lutetium-177–PSMA-617 vs 1.7% with SOC
• Disease control rate: Data reported; specific percentages not specified here
• Time to symptomatic skeletal events: Statistically significant delay observed; detailed hazard ratio not specified in this summary

All reported secondary end points with prespecified statistical testing favored the investigational arm.

Safety Profile

Adverse events were more frequent in the lutetium-177–PSMA-617 group compared with SOC alone. Common adverse events of any grade in the lutetium-177–PSMA-617 arm included fatigue (43%), dry mouth (38%), nausea (35%), anemia (32%), and decreased appetite. Hematologic toxicities were observed, including anemia and thrombocytopenia. Grade ≥3 adverse events occurred in 52.7% of patients receiving lutetium-177–PSMA-617 and 38% of patients receiving SOC alone. Grade ≥3 anemia occurred in 12.9%, thrombocytopenia in 7.9%, and leukopenia in 7.8% of patients treated with lutetium-177–PSMA-617.

Adverse events leading to treatment discontinuation occurred in 11% of patients in the lutetium-177–PSMA-617 group and 2% in the SOC group.

Conclusion

In patients with PSMA-positive mCRPC previously treated with ARPIs and taxane chemotherapy, the addition of lutetium-177–PSMA-617 to SOC improved OS and rPFS compared with SOC alone. Higher rates of hematologic and nonhematologic adverse events were observed in the investigational arm, including increased rates of grade ≥3 toxicities and treatment discontinuations.

Source

Sartor O, de Bono J, Chi KN, et al. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021;385(12):1091–1103. doi:10.1056/NEJMoa2107322.