PCa Commentary | Volume 209 – January 2026

Posted by Edward Weber, MD | January 2026

Pluvicto (177 Lutetium PSMA) — Advanced To “Up Front” in Multiple Combinations

The initial VISION Trial of Pluvicto enrolled men with advanced metastatic prostate cancer who had been heavily pretreated. Nearly 50% of men benefited from a PSA reduction of >50%. Median overall survival for Pluvicto-treated men was 15.3 months compared to 11.3 months for the best standard of care. It was recognized that in advanced disease, many men had already developed resistance to treatment, and many no longer expressed the cell-surface PSMA antigen, the target for Pluvicto. These trials using Pluvicto in earlier stages of disease before the disadvantageous mutations had developed. This Commentary will review the many current trials moving Pluvicto “upfront.”

There is an unmet need for Lu-177 therapy in combination up front in treatment schemas, particularly for the overall 172,000 men diagnosed yearly with metastatic hormone-sensitive prostate cancer, in roughly in 20 – 30% of newly diagnosed patients. Even with the best current treatment, progression occurs rapidly in these men to metastatic castration-resistant prostate cancer (mCRPC).

Pluvicto is an early example of a category of treatment termed “radioligand therapy” (RLT) targeting the PSMA antigen, and new versions of RLT are currently under extensive investigation. The radioligand 225 Actinium-PSMA is next in line, and Lead 212-PSMA is a promising nuclide under evaluation.

The PSMA antigen has 707 amino acids in the extracellular domain, 24 spanning the membrane, and 19 within. Upon ligating with an amino acid pocket in the chain, the lutetium complex is internalized. Over 7 or more days, Lutetium emits high-energy electrons (Beta particles) which cause DNA damage within the recipient cell and nearby cells, resulting in cell death. RLT might be considered intracellular radiation.

New Regimens of 177 Lutetium in Combination:

The International trial “PSMAddition” enrolled men with metastatic hormone-sensitive PC. 177Lu was combined in 557 men with an androgen receptor pathway inhibitor (ARPI), mainly Zytiga, plus ADT. This was compared to standard ADT/ARPI in another 557 men. The regimen was 6 weeks of treatment repeated 6 times. The trial is ongoing, but at the first analysis, the radiographic-free survival (rPFS) for the combination was 25% better (P=002), and overall survival was superior by 16%. Novartis data has been submitted to the FDA, and approval for clinical use is expected by year’s end.

The “PSMAfore” trial compared 177Lu PSMA alone to an alternative androgen receptor pathway inhibitor in men with mCRPC after progression on first-line hormone suppression before docetaxel therapy.

This is a clinically relevant trial, since conventionally after a man fails an initial hormone therapy (i.e., Xtandi or Zytiga), he is then switched to an alternative ARPI, although with diminished response compared to the usual robust response to the first agent.

Interim analysis at a follow-up of 7.3 months reported that the median radiographic-free survival (PFS) for LuPSMA was 60% better than the alternate hormone therapy: 12 months for LuPSMA vs 5.6 months for ARPI change. (Sartor. Ann of Oncol 2023). Dry mouth occurred in ~60% and anemia in ~30% in the LuPSMA group. Final results from this trial will likely guide future therapy in men with metastatic CRPC.

Based on the success of the VISION trial and the expectation of increased efficacy of LuPSMA when moved forward in disease progression, LuPSMA has been combined in trials with many other agents. As the trials yield results, they will likely be offered as treatment regimens. An overview of some of the many combinations under study is listed below:

• 177 LuPSMA + enzalutamide was studied as 1st-line therapy in men with high-risk metastatic CRPC. Early results of this Australian study (The Lancet Oncology, March 2025) show the combination’s mOS was 34 vs 26 months for enzalutamide alone. The combination was superior in terms of general quality of life, physical function, pain control, and caused less fatigue.
• 177L uPSMA + olaparib (LUPARP) was tested in heavily pretreated men as second-line therapy in mCRPC without the need for mutated BRCA-like genes. As reported at the 2023 ASCO Annual Meeting, PSA dropped 62% in 50% and 90% in 48% of men.
• 177 LuPSMA was given in two adjuvant cycles before radiation therapy targeted all lesions in oligorecurrent metastatic hormone-sensitive PC. (The LUNAR trial; Journal of Clin Oncol, November 2025). At 22 months follow-up, the combination doubled PFS: 17 months vs 7.4 months.
• 177 LuPSMA is under study in combination with Bipolar Androgen Therapy (BAT) in a trial sponsored by Dr. Mike Schweizer, Fred Hutchinson Cancer Institute. The trial is open to “any patient who has progressed after a novel hormone therapy (e.g., abiraterone, enzalutamide) and has minimal cancer symptoms (e.g., is pain free).”
• 177 LuPSMA is being tested at UCLA in patients with mCRPC who received prior treatment with ARPIs in a regimen using a single priming dose of LuPSMA followed by pembrolizumab immunotherapy I.V. every 3 weeks (NCT05766371) (Cancer Network November 2023). Laurence Fong, MD, UCSF, commented: “Findings from the phase 1 study show that a single dose of 177Lu-PSMA-617 combined with immunotherapy can have durable responses that are similar to those achieved with currently accepted treatment with 6 doses of 177Lu-PSMA-617.”

BOTTOM LINE:

Combinations of 177 LuPSMA with other agents will profoundly expand and improve therapeutic options as the many trials testing them work through evaluation.

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