Despite advances in the management of castration-resistant prostate cancer (CRPC) and availability of several therapeutic options with the potential to prolong survival, patients with metastatic disease continue to have poor prognosis. A promising molecular target for diagnostic imaging and targeted therapy is prostate-specific membrane antigen (PSMA), a membrane-bound enzyme (carboxypeptidase) that is selectively overexpressed on prostate cancer cells. The radioligand ¹⁷⁷lutetium (Lu)-PSMA-617 is a small molecule that targets PSMA with high affinity and delivers β-particle-emitting ¹⁷⁷Lu via receptor-mediated endocytosis. This leads to DNA damage and cell death.

During the plenary session at ASCO 2021, results from the randomized, open-label, phase III VISION study of ¹⁷⁷Lu-PSMA-617 in patients with mCRPC were presented by Dr Michael J Morris (Memorial Sloan Kettering Cancer Center, New York, US). Results were also published in the New England Journal of Medicine on June 23. In this trial, patients with PSMA-positive mCRPC (on gallium-68 PSMA PET-CT scans), previously treated with at least one second-generation androgen receptor signaling inhibitor and 1 – 2 taxane regimens were randomly assigned to receive either ¹⁷⁷Lu-PSMA-617 (7.4 GBq every 6 weeks for 4 – 6 cycles) plus standard of care (SOC), or SOC alone. SOC was the choice of treating physicians; however, it could not include chemotherapy, immunotherapy, radium-223 or investigational agents, due to safety concerns over combinations with ¹⁷⁷Lu-PSMA-617. Median follow-up was 20.9 months. The co-primary endpoints were radiographic progression-free survival (rPFS analysis set; n=581) and overall survival (OS in all randomized patients; n=831). Among patients in the rPFS analysis set, the risk of radiographic progression or death was reduced by 60% with ¹⁷⁷Lu-PSMA-617 treatment (hazard ratio [HR], 0.4; P<0.001); median rPFS was 8.7 versus 3.4 months. For OS, the risk of death was reduced by 38% (HR, 0.62; P<0.001), and median OS was prolonged from 11.3 months to 15.3 months. The survival benefits were generally consistent across all subgroups except in those that included a low number of patients, which resulted in wide confidence intervals. Response rates also significantly favored the ¹⁷⁷Lu-PSMA-617 arm, with an independent review committee-determined overall response rate of 29.8% versus 1.7%. Furthermore, a decrease by ≥50% of prostate-specific antigen (PSA) levels was seen in 46% of the 177Lu-PSMA-617 arm and 7% of the SOC arm.”. More grade ≥3 treatment-related adverse events (TRAEs) occurred in patients who received ¹⁷⁷Lu-PSMA-617 plus SOC compared with SOC treatment (52.7% versus 38%), with the most common TRAEs being hematologic toxicity, in particular anemia (12.9%). The most frequent AEs of any grade related to ¹⁷⁷Lu-PSMA-617 were fatigue, dry mouth, and nausea. Adverse events led to discontinuation of ¹⁷⁷Lu-PSMA-617 in 11.9% of patients. Deaths related to TRAEs were reported in 5 patients (0.9%) in the ¹⁷⁷Lu-PSMA-617 arm and none in the SOC arm.

Dr Morris concluded that the findings from the VISION trial warrant the adoption of ¹⁷⁷Lu-PSMA-617 as a new treatment option for patients with mCRPC who have progressed after androgen receptor pathway inhibitor therapy and chemotherapy. Dr Mary-Ellen Taplin (Harvard Medical School, Boston, Massachusetts, US), the abstract discussant, noted this was a highly positive trial, although she had hoped for a longer survival improvement. Nevertheless, she concluded that if ¹⁷⁷Lu-PSMA-617 receives FDA approval ‘’this therapy will add to our armamentarium of palliative systemic treatment options for mCRPC.’’

References

Morris M, et al. ASCO 2021; Abstract LBA04.

Sartor O, et al. N Engl J Med. 2021 June 23. [Online ahead of print].