Lu-PSMA-617

Lu-PSMA-617, sold under the brand name Pluvicto, is a radiopharmaceutical medication used for the treatment of prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC).^[1][2] Lutetium (¹⁷⁷Lu) vipivotide tetraxetan is a targeted radioligand therapy.^[2][3]

The most common adverse reactions include fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation.^[2][4]

Lu-PSMA-617 is a radioconjugate composed of PSMA-617, a human prostate-specific membrane antigen (PSMA)-targeting ligand, conjugated to the beta-emitting radioisotope lutetium-177, with potential antineoplastic activity against PSMA-expressing tumor cells.^[5] Upon intravenous administration of Lu-PSMA-617, it targets and binds to PSMA-expressing tumor cells.^[5] Upon binding, PSMA-expressing tumor cells are destroyed by ¹⁷⁷Lu through the specific delivery of beta particle radiation.^[5] PSMA, a tumor-associated antigen and type II transmembrane protein, is expressed on the membrane of prostatic epithelial cells and overexpressed on prostate tumor cells.^[5]

Lu-PSMA-617 was approved for medical use in the United States in March 2022,^[2][6] and in the European Union in December 2022.^[4] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.^[7][8]

Lu-PSMA-617 is indicated for the treatment of adults with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy.^[1]

In March 2025, the US Food and Drug Administration expanded the indication for Lu-PSMA-617 to include adults with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer who have been treated with androgen receptor pathway inhibitor therapy and are considered appropriate to delay taxane-based chemotherapy.^[9]

In 2006, scientists from Purdue University designed a targeting ligand that bound with high affinity and specificity to PSMA on prostate cancer cells and patented^[10][11] its ability to target attached radionuclides such as ¹⁷⁷Lu, ^99mTc, ⁶⁸Ga, etc. to prostate cancers. The patents were licensed to Endocyte in 2007. In 2012, scientists at German Cancer Research Center and University Hospital Heidelberg improved the drug's affinity, patented,^[12] and licensed to ABX advanced biomedical compounds, a small German pharmaceutical company, for early clinical development. In 2017, the ABX patent was also acquired by Endocyte^[13] and Endocyte together with the above two sets of patents was acquired by Novartis in 2018.^[14]

Efficacy and safety was initially investigated as a compassionate access treatment in Germany with high tumor targeting and low doses to normal organs.^[15] Physician-scientists from the Peter MacCallum Cancer Centre conducted a phase 2 trial demonstrating high response rates, low toxicity and reduction in pain in men with metastatic castration-resistant cancer who progressed after conventional treatments.^[16] The ANZUP co-operative trials conducted the first randomized, multicentre trial comparing lutetium vipivotide tetraxetan to cabazitaxel chemotherapy.^[17]

Efficacy was evaluated in VISION,^[18] a randomized (2:1), multicenter, open-label trial that evaluated Lu-PSMA-617 plus best standard of care (BSoC) (n=551) or BSoC alone (n=280) in men with progressive, prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer.^[2] All participants received a GnRH analog or had prior bilateral orchiectomy.^[2] Participants were required to have received at least one androgen receptor pathway inhibitor, and 1 or 2 prior taxane-based chemotherapy regimens.^[2] Participants received Lu-PSMA-617 7.4 GBq (200 mCi) every 6 weeks for up to a total of 6 doses plus BSoC or BSoC alone.^[2]

Efficacy was evaluated in PSMAfore (NCT04689828), a randomized, multicenter, open-label trial enrolling 468 participants with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer and progression on one androgen receptor pathway inhibitor, who the investigator considered appropriate for delay of taxane-based chemotherapy.^[9] Participants were randomized (1:1) to receive Lu-PSMA-617 (7.4 GBq [200 mCi] every six weeks for six doses) or a change in androgen receptor pathway inhibitor.^[9] Participants who progressed on the androgen receptor pathway inhibitor arm were allowed to crossover to the experimental therapy.^[9]

The US Food and Drug Administration granted the application for Lu-PSMA-617 priority review and breakthrough therapy designations.^[2]

In October 2022, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Pluvicto, intended for the treatment of prostate cancer.^[19] The applicant for this medicinal product was Novartis Europharm Limited.^[19] Lu-PSMA-617 was approved for medical use in the European Union in December 2022.^[4][20]

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