177Lu-PSMA-617 Plus Standard of Care Improves OS in mCRPC

177Lu-PSMA-617 (LuPSMA), a targeted radioligand therapy, plus standard of care (SOC) induced approximately a 40% reduction in the risk of death vs SOC alone in men with progressive PSMA-positive metastatic castration-resistant prostate cancer (mCRPC), according to findings from the phase 3 VISION trial (NCT03511664).¹

The findings, which were presented during a presscast held as part of the 2021 ASCO Annual Meeting, showed that at a median follow-up of 20.9 months, the addition of LuPSMA improved the median overall survival (OS) by 4 months over SOC alone (HR, 0.62). Adding the targeted radioligand therapy also led to a 5.3-month improvement in median radiographic progression-free survival (rPFS), translating to a 60% reduction in the risk of progression or death (HR, 0.40).

“These findings warrant adoption of LuPSMA as a new treatment option in patients with mCRPC, pending FDA approval,” said lead VISION trial author Michael J. Morris, MD, head of the Prostate Cancer Section at Sloan Kettering Cancer Center in New York.

The open-label phase 3 VISION trial (NCT03511664) included 831 patients (1179 initially screened) with progressive PSMA-positive mCRPC who received at least 1 novel androgen axis drug (eg, enzalutamide [Xtandi] or abiraterone acetate [Zytiga]) and were previously treated with 1 to 2 taxane regimens.

PET imaging with ⁶⁸Ga-PSMA-11 was used to determine PSMA positivity. Patient demographics and baseline characteristics were well balanced at baseline.

Patients were randomized in a 2:1 ratio to LuPSMA (7.4 GBq every 6 weeks x 6 cycles; n = 551) plus SOC or SOC alone (n = 280). Individual investigators determined the SOC; however, radium-223 (Xofigo) and cytotoxic chemotherapy were not allowed. The coprimary end points of the trial were OS and rPFS.

The median OS was 15.3 months in the LuPSMA arm versus 11.3 months in the SOC alone arm, translating to a 38% reduction in the risk of death (HR, 0.62; 95% CI, 0.52-0.74; P <.001).The rPFS was 8.7 versus 3.4 months, respectively (HR, 0.40; 99.2% CI, 0.29-0.57; P <.001).

There was also a statistically significant benefit favoring the LuPSMA arm for the key secondary endpoints of objective response rate (ORR), disease control rate (DCR), and time to first symptomatic skeletal event (SSE). The ORRs and DCRs were 29.8% versus 1.7% and 89.0% versus 66.7%, respectively. The median time to first SSE was 11.5 months in the LuPSMA group compared with 6.8 months in the control arm (HR, 0.50).

The safety analysis included 529 patients in the LuPSMA cohort and 205 patients in the control group. The investigators considered LuPSMA treatment to be well tolerated. The most common adverse events (AEs) across all grades occurring in the LuPSMA arm were fatigue (49.1% vs 29.3% in the control arm), bone marrow suppression (47.4% vs 17.6%, respectively), dry mouth (39.3% vs 1%), nausea/vomiting (39.3% vs 17.1%), kidney effects (8.7% vs 5.9%), second primary malignancies (2.1% vs 1%), and intracranial bleeding (1.3% vs 1.5%).

High-grade treatment-emergent AEs occurred in 52.7% of patients receiving LuPSMA compared with 38% of patients treated with SOC alone. The most common grade 3-5 AEs reported in the LuPSMA arm were bone marrow suppression (23.4% vs 6.8% in the control arm), fatigue (7% vs 2.4%, respectively), kidney effects (3.4% vs 2.9%), and nausea/vomiting (1.5% vs 0.5%).

Regarding the next steps with LuPSMA, Morris said, “There are ongoing trials of LuPSMA in patients with prostate cancer at earlier phases of the disease.”

Commenting on the significance of the VISION study results, ASCO President Lori J. Pierce, MD, FASTRO, FASCO, said, “This is an important study, as the patients in this trial had mCRPC, so they had disease that grew even when testosterone in the body had already been reduced to very low levels, despite receiving 1 to 2 prior taxane regimens.”

She added, “This trial shows an alternative to traditional therapies by using radiation targeted to the PSMA antigen. So, it could be delivered directly to the prostate cancer cells, and by doing that, survival was significantly improved. Use of the PSMA radioligand therapy, if it obtains regulatory approval, could indeed become an important treatment option for these patients with refractory disease.

There are currently 2 PSMA PET imaging agents approved for patients with prostate cancer, Ga 68 PSMA-11 and 18F-DCFPyL (Pylarify). Novartis, the manufacturer of LuPSMA, plans to file for FDA approval of the radioligand therapy based on these positive findings from the VISION trial. If approved, LuPSMA would become the first PSMA theranostic approved in prostate cancer.

Reference

1. Morris MJ, De Bono JS, Chi KN, et al. Phase 3 study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). J Clin Oncol. 39, 2021 (suppl 15; abstr LBA4).