New results from the phase 3 VISION trial showed that in heavily pretreated patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC), 177Lu-PSMA-617 plus standard of care (SOC) delayed worsening of health-related quality of life (HRQoL) and pain compared with SOC alone.1 No new or unexpected safety concerns were noted, reported Karim Fizazi, MD, PhD, Medical Oncologist at Gustave Roussy and Professor of Oncology at the University of Paris-Saclay in Villejuif, France, during the 2021 European Society for Medical Oncology (ESMO) congress.
The VISION (NCT03511664) study was an open-label prospective trial carried out in 831 mCRPC patients previously treated with at least one androgen receptor pathway inhibitor and one or two taxane regimens with PSMA positive lesions on gallium-68 labeled PSMA-11 PET/CT scanning. PSMA (prostate-specific membrane antigen) is highly expressed on prostate cancer cells and is a known independent biomarker of poor prognosis in prostate cancer. In VISION, patients were randomized in a 2:1 ratio to receive standard of care (SOC) alone or with 177Lu-PSMA-617, an investigational radioligand therapy that delivers beta-particle radiation selectively to PSMA positive cancer cells and the surrounding microenvironment. Protocol-permitted SOC excluded chemotherapy, immunotherapy, radium-223, and investigational drugs.
The main results of VISION, which were presented at the 2021 annual meeting of the American Society of Clinical Oncology (ASCO) and published shortly thereafter,2 showed significant improvements in both primary endpoints of the trial. After a median follow-up of 20.9 months, compared with SOC alone, 177Lu- PSMA-617 plus SOC was associated with significantly improved overall survival (15.3 vs 11.3 months, HR for death, 0.62, P<.0.001) and significantly prolonged radiographic progression-free survival (rPFS) (8.7 vs 3.4 months, HR for progression or death 0.40, P<0.001).
HRQoL and pain outcomes were included as secondary endpoints of VISION. HRQoL was assessed using the FACT-P (Functional Assessment of Cancer Therapy- Prostate) measure, where the total score is the sum of the scores from a 39-item questionnaire (range 1-156), and pain was assessed by the BPI-SF (Brief Pain Inventory-Short Form) with low scores indicating low levels of pain intensity.
Ad hoc HRQoL and pain time-to-worsening analyses completed using data from the rPFS subset of 581 patients both favored the 177Lu-PSMA-617 arm, Dr. Fizazi reported. Administration of 177Lu-PSMA significantly prolonged time to worsening of HRQoL as measured by FACT-P scores (median 9.7 months 2.4 months with SOC alone) (HR 0.46, 95% CI 0.35-0.61, P<0.001), for a 54% reduction, and time to worsening pain as measured by BPI-SF (median 14.3 months vs 2.9 months) with SOC alone arm (HR 0.45, 95% CI 0.33-0.60, P<0.001), a 55% reduction.
Among the other key secondary endpoints of the study was time to first symptomatic skeletal event, defined as time from randomization to first new pathological bone fracture, spinal cord compression, tumor-related orthopedic surgery, radiation therapy for bone pain, or death. In the same patient subset, the time to this endpoint was significantly increased with 177Lu-PSMA-617 (11. 5 months vs 6.8 months on the control arm; HR 0.50, 95% CI 0.40-0.62, P<0.001) again a highly significant 55% risk reduction, Dr. Fizazi noted.
Additional secondary endpoints included treatment-emergent adverse events. Bone marrow suppression Grade ≥3 was seen in 23.4% of patients who received 177Lu-PSMA-617 plus SOC compared with 6.8% of those whose received SOC alone. Thrombocytopenia (Grade ≥3) was recorded in 7.9% vs 1.0% of patients, respectively. Xerostomia (dry mouth) (all Grade <3) and nausea and vomiting (1.5% Grade ≥3), occurred in 39.3% of 177Lu-PSMA-617 patients compared with 1.0% and 17.1%, respectively in the control patients. Despite a higher percentage of renal toxicity in 177Lu-PSMA-617 patients than in control patients (39.3% vs 17.1%, respectively), the incidence of Grade ≥3 renal toxicity was similar on the two treatment arms (3.4% vs. 2.9%).
These promising study results from the VISION study show that in patients with advanced mCRPC with progression of disease despite androgen receptor pathway inhibition therapy and taxane chemotherapy, targeted radiotherapy utilizing 177Lu-PSMA-617 can serve as a well-tolerated therapeutic option to extend OS, delay rPFS, and delay the time to first symptomatic skeletal event, Dr. Fizazi declared. Additionally, these benefits translate to prolonging patient-reported HRQoL, including delaying the onset of significant pain.
These data further support utilizing 177Lu-PSMA-617 as a third-line management option for patients with mCRPC. There are several challenges that still need to be addressed before 177Lu-PSMA-617 can be used more widely, including improving access to PET imaging and further exploring the utility of 177Lu-PSMA-617 in patients that did not meet initial imaging inclusion criteria for VISION. Future studies will explore the utility of targeted radiotherapy using PSMA ligands in earlier stages of disease, as well as possible combination with other existing therapeutic modalities. Two studies currently evaluating 177Lu-PSMA-617 radioligand therapy in earlier lines of treatment for metastatic prostate cancer are already underway, in the mCRPC pre-taxane setting (PSMAfore) and in the metastatic hormone-sensitive setting (PSMAddition).
Akhil Abraham Saji, MD is a urology resident at New York Medical College/ Westchester Medical Center. His interests include urology education and machine learning applications in urologic care. He is a founding and current member of the EMPIRE Urology New York AUA section team.
- Fizazi K, Herrmann K, Krause BJ, et al. Health-related quality of life (HRQoL), pain and safety outcomes in the phase III VISION study of 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer. Ann Oncol. 2021;32(Suppl):S627-S628. Abstract 576MO. DOI: 10.1016/j.annonc.2021.08.1089
- Sartor S, de Bono J, Chi KM, et al; VISION investigators. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer, N Engl J Med. 2021;385(12):1091-1103. DOI: 10.1056/NEJMoa2107322