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[177Lu]Lu-PSMA-617 plus immune checkpoint inhibition in mCRPC

Researchers reported the first study of multiple-cycle combination therapy, with PSA responses and disease control observed in a subset of men with metastatic castration-resistant prostate cancer and a manageable adverse event profile.

  • Shahneen Sandhu, MBBS; Anthony M Joshua, PhD; Louise Emmett, MD; Mathias Bressel, MSc; Angelyn Anton, MBBS; Lavinia Spain, MBBS; et al.

  • April 1, 2026

  • The Lancet Oncology
  • The Lancet Oncology, Volume 27, Issue 4, Pages 470–479
  • 10.1016/S1470-2045(26)00017-3

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Evidence before this study

We searched PubMed and MEDLINE for peer-reviewed studies published up to July 31, 2025, using the search terms (and related search terms) “immune checkpoint inhibitors” and “radioligand”, “PSMA”, or “Prostate Specific Membrane Antigen”. Abstracts from leading urology, medical oncology, and nuclear medicine congresses were also reviewed. [Lu]Lu-PSMA-617, a radiolabelled small molecule that delivers beta particle radiation targeted to PSMA-expressing prostate cancer cells, is an established therapy for metastatic castration resistant prostate cancer (mCRPC); however, both de novo and acquired resistance remain common. Optimising [Lu]Lu-PSMA-617 combination strategies to improve outcomes is a critical clinical priority. Preclinical studies suggest that radiotherapy can potentiate immune checkpoint inhibition via induction of immunogenic cell death. Clinically, one trial investigated the activity of a single cycle of [Lu]Lu-PSMA-617 together with immune checkpoint inhibition in patients with mCRPC and showed responses in a subset of patients.

Added value of this study

To our knowledge, this is the first study to investigate the safety and activity of multiple cycles of [Lu]Lu-PSMA-617 in combination with immune checkpoint inhibition in patients with mCRPC. We observed deep PSA responses and durable disease control (radiographic progression-free survival and overall survival), with a manageable profile of adverse events consistent with known toxicities of individual therapies administered alone. Our study provides clinical evidence that multiple cycles of [Lu]Lu-PSMA-617 in conjunction with immune checkpoint inhibition is feasible and achieves durable clinical benefit in a meaningful subset of patients without excess harms.

Implications of all the available evidence

These results contribute crucial clinical evidence to the rapidly evolving field of radioligand therapy in multiple cancers, including those deemed to be immunologically cold. Ongoing correlative biomarker analyses will be essential to identify molecular determinants of response and resistance, define which patients derive the greatest benefit and to inform future biomarker-enriched trials.

Source: The Lancet Oncology

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