177Lu-PSMA-617 Demonstrates Significant rPFS Benefit in PSMA-Positive mCRPC

A statistically significant and clinically meaningful improvement in radiographic progression-free survival (rPFS) was achieved with ¹⁷⁷Lu-PSMA-617 (Pluvicto) treatment in patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) following androgen deprivation therapy (ADT), according to topline findings from the phase 3 PSMAfore study (NCT04689828).¹

With such an rPFS benefit, the study met its primary end point. Moreover, the safety data were consistent with the known safety profile of the agent with no new safety signals observed.

“With the announcement of these positive topline phase 3 results, [¹⁷⁷Lu-PSMA-617 ] becomes the first PSMA-targeted radioligand therapy to demonstrate significant and clinically meaningful benefits for people living with this type of prostate cancer who have not received taxane-based chemotherapy,” said Shreeram Aradhye, MD, president, Global Drug Development and chief medical officer, Novartis, in a press release. “We look forward to discussing the data with healthcare authorities in order to bring this innovative new early treatment option to many more prostate cancer patients sooner after their diagnosis.”

PSMAfore is an open-label, multicenter, randomized study comparing ¹⁷⁷Lu-PSMA-617 to ADT. In the experimental arm, patients are given ¹⁷⁷Lu-PSMA-617 intravenously (IV) once every 6 weeks for 6 cycles with a single IV dose of 8Ga-PSMA-11 lower than 111 MBq or higher than 185 MBq, and best supportive care (BSC). In the control arm, patients receive 68Ga-PSMA-11, ADT, and BSC.²

The study is being conducted at 72 locations worldwide, and up 470 patients will be enrolled. All patients are required to be at least 18 years of age with an ECOG performance status of 0 or 1, histological pathological, and/or cytological confirmed disease, and adequate organ function. In addition, patients must have a castrate level of serum/plasma testosterone (< 50 ng/dL or < 1.7 nmol/L), have progressed only once on a second-generation ADT, and progressive mCRPC with at least 1 metastatic lesion.

Aside from rPFS, the study is looking at multiple secondary end points to determine the efficacy and safety of ¹⁷⁷Lu-PSMA-617 compared with ADT. The secondary end points include overall survival (OS), rPFS2, PFS, PFS2, biochemical response, time to first symptomatic skeletal event, time to radiographic soft tissue progression, time to chemotherapy, quality of life outcomes, and the number of patients with adverse events (AEs).

¹⁷⁷Lu-PSMA-617 is an FDA-approved therapy for adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy, based on results from the phase 3 VISION study (NCT03511664).3In the study, ¹⁷⁷Lu-PSMA-617 achieved statistically significant improvement in the coprimary end points of OS.³

The median OS observed in the VISION study was 15.3 months (95% CI, 14.2-16.9) with the PSMA-directed therapy vs 11.3 months (95% CI, 9.8-13.5 months) with BSC.

The most common AEs observed with ¹⁷⁷Lu-PSMA-617, occurring in at least 20% of patients in the VISION study were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. Laboratory abnormalities occurring in ≥ 30% of patients included deceased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium. In addition, the FDA warns that myelosuppression and renal toxicity may occur due to radiation exposure from the PSMA-directed therapy.

REFERENCES:

_{1. Novartis Pluvicto™ shows statistically significant and clinically meaningful radiographic progression-free survival benefit in patients with PSMA–positive metastatic castration-resistant prostate cancer. News release. Novartis. December 5, 2022. Accessed December 5, 2022. https://bit.ly/3Y0D4mD}

_{2. ¹⁷⁷Lu-PSMA-617 vs. androgen receptor-directed therapy in the treatment of progressive metastatic castrate resistant prostate cancer (PSMAfore). ClinicalTrials.gov. Updated November 8, 2022. Accessed December 5, 2022. https://clinicaltrials.gov/ct2/show/NCT04689828?term=PSMAfore&draw=2&rank=1}

_{3. FDA approves Pluvicto for metastatic castration-resistant prostate cancer. News release. FDA. March 23, 2022. Accessed December 5, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto-metastatic-castration-resistant-prostate-cancer.}