Lutetium Lu 177 Vipivotide Tetraxetan Generates rPFS Improvement in PSMA+ mHSPC

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Lutetium Lu 177 vipivotide tetraxetan (Pluvicto; formerly ¹⁷⁷Lu-PSMA-617) plus hormone therapy yielded a statistically significant and clinically meaningful radiographic progression-free survival (rPFS) benefit vs hormone therapy alone in patients with prostate-specific membrane antigen (PSMA)–positive metastatic hormone-sensitive prostate cancer (mHSPC), meeting the primary end point of the phase 3 PSMAddition trial (NCT04720157).¹

Topline findings from a prespecified interim analysis of the trial also showed a positive overall survival (OS) trend favoring the lutetium Lu 177 vipivotide tetraxetan arm. Notably, OS is a key secondary end point of the study. Full data will be presented at a future medical meeting.

Novartis, the developer of lutetium Lu 177 vipivotide tetraxetan, also plans to submit an application to the FDA to review data for lutetium Lu 177 vipivotide tetraxetan in this setting during the second half of 2025, pending FDA feedback.

“The progression from mHSPC to castration-resistant disease remains a formidable challenge that can profoundly impact the survival of patients,” Shreeram Aradhye, MD, president of Development and chief medical officer at Novartis, stated in a news release. “These results further strengthen our confidence in [lutetium Lu 177 vipivotide tetraxetan] as a PSMA-targeted radioligand therapy. Following the recent FDA approval based on [findings from the phase 3] PSMAfore trial [NCT04689828] in metastatic castration-resistant prostate cancer [mCRPC], these data suggest using it in an earlier disease setting could advance care and address a significant unmet need for [patients with] HSPC.”

In March 2022, the FDA approved lutetium Lu 177 vipivotide tetraxetan for the treatment of patients with PSMA-positive mCRPC who had previously received other anticancer therapies—including taxane-based therapy and an androgen receptor pathway inhibitor (ARPI)—based on data from the phase 3 VISION trial (NCT03511664).² In March 2025, the FDA expanded the indication for this agent to include patients with PSMA-positive mCRPC who had previously been treated with an ARPI and are cleared to delay taxane-based chemotherapy; this regulatory decision was backed by findings from PSMAfore.³

PSMAddition was an international, open-label, prospective study that enrolled patients at least 18 years of age with PSMA-positive HSPC with histologically or cytologically confirmed adenocarcinoma who had an ECOG performance status of 0 to 2, a life expectancy longer than 9 months, at least 1 documented metastatic bone and/or visceral lesion/soft tissue lesion documented within 28 days prior to random assignment, and adequate organ function.⁴ Patients needed to be treatment naive or minimally treated with a maximum of 45 days of a luteinizing hormone-releasing hormone agonist/antagonists or bilateral orchiectomy with or without first-generation anti-androgen therapy for metastatic prostate cancer prior to informed consent signature; or a maximum of 45 days of CYP17 inhibitor or AR-directed therapy (ARDT) exposure for metastatic prostate cancer prior to informed consent signature.

Trial investigators randomly assigned patients 1:1 to receive lutetium Lu 177 vipivotide tetraxetan plus standard-of-care (SOC) ARPI therapy and androgen deprivation therapy (ADT) vs SOC alone. Lutetium Lu 177 vipivotide tetraxetan was administered intravenously (IV) at 7.4 GBq (+/– 10%) once every 6 weeks (+/– 1 week) for a planned 6 cycles. All patients also received IV ⁶⁸Ga-PSMA-11 at approximately 150 MBq at screening and at the time of centrally confirmed rPD (if applicable), oral ARDT administered continuously per package insert and guideline recommendations, and ADT administered per physician order.

Patients who were randomly assigned to the control arm were permitted to cross over to receive lutetium Lu 177 vipivotide tetraxetan upon confirmed radiographic progression per blinded independent committee review and the discretion of the treating physician.

Additional study end points include PSA90 response, time to development of mCRPC, PFS, PFS2, change in nadir level of PSA lower than 0.2 ng/mL, time to radiographic soft tissue progression, time to first symptomatic skeletal event, overall response rate, disease control rate, duration of response, time to response, quality-of-life outcomes, and safety.

References

1. Novartis Pluvicto demonstrates statistically significant and clinically meaningful rPFS benefit in patients with PSMA-positive metastatic hormone-sensitive prostate cancer. News release. Novartis. June 2, 2025. Accessed June 2, 2025. https://www.novartis.com/news/media-releases/novartis-pluvictotm-demonstrates-statistically-significant-and-clinically-meaningful-rpfs-benefit-patients-psma-positive-metastatic-hormone-sensitive-prostate-cancer
2. FDA approves Pluvicto for metastatic castration-resistant prostate cancer. FDA. March 23, 2022. Accessed June 2, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto-metastatic-castration-resistant-prostate-cancer?utm_medium=email&utm_source=govdelivery
3. FDA expands Pluvicto’s metastatic castration-resistant prostate cancer indication. FDA. March 28, 2025. Accessed June 2, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-pluvictos-metastatic-castration-resistant-prostate-cancer-indication