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Therapeutic Targeting of Prostate-Specific Membrane Antigen Could Limit Its Potential as Benchmark Imaging - Beyond the Abstract

The emergence of target-based molecular imaging has the potential to revolutionize how cancer is diagnosed, staged, and treated. In the field of solid tumor theranostics, prostate cancer leads the way with the rapid uptake of Prostate Cancer Specific Membrane Antigen (PSMA) PET scans and PSMA-targeted radiopharmaceuticals like 177Lu-PSMA-617. Prostate Cancer Working Group 41 puts forth a strategy for future trials to utilize PSMA imaging as an investigational clinical trial endpoint, while acknowledging a lack of data clearly defining what those endpoints are. Similarly, a recent NCI Working Group on Biochemically Recurrent Prostate Cancer2 indicated that there was insufficient evidence to fully support the clinical value of PSMA PET endpoints in the rapidly evolving BCR space.

Indeed, phase 3 trials are already emerging with PSMA endpoints (e.g., NCT05794906). The drive to promote PSMA PET as the heir apparent imaging platform in prostate cancer has led the field to overlook how therapeutic targeting of PSMA antigen may alter PSMA imaging sensitivity over time. Current and future trials are moving 177Lu-PSMA-16 to earlier stages of disease, and newer PSMA-targeted therapies are under active investigation. However, there is a key gap in data about the impact of PSMA-targeted therapies on post-treatment PSMA PET scans. Unlike FDG PET, which provides functional measurement of tumor metabolism, PSMA PET measures the expression of a surface protein. Loss of target antigen is a known resistance mechanism to targeted cancer therapies and could promote the emergence of heterogeneous “PSMA Dark” disease.

This potential outcome raises key questions the field has broadly ignored: How does treating PSMA+ prostate cancer with 177Lu-PSMA-617 affect subsequent PSMA imaging? What will late-stage tumors look like after progressively earlier and more effective PSMA-targeted therapeutics? Could targeted therapeutics impact the accuracy/sensitivity of PSMA-based imaging that utilizes the same surface target? Could the most clinically relevant prostate cancer in a patient after PSMA-based therapeutic targeting be PSMA Dark disease? This article raises key questions to consider as 177Lu-PSMA-617 moves earlier in the prostate cancer disease course, before heralding PSMA imaging as the benchmark imaging strategy of the future.

Written by: Melissa L. Abel,1 Adam Sharp,2 Edwin M. Posadas,3 Fatima Karzai,1 Frank I. Lin,4 Peter L. Choyke,4 Ravi A. Madan1

  1. Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.
  2. Institute of Cancer Research, Royal Marsden NHS Foundation Trust, London, UK.
  3. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  4. Molecular Imaging Branch, National Cancer Institute, Bethesda, MD, USA.
References:

  1. Armstrong et al., Trial design and objectives for prostate cancer: Recommendations from the Prostate Cancer Clinical Trials Working Group 4 (PCWG4). J Clin Oncol 44, 162. 2026. DOI: 10.1200/JCO.2026.44.7_suppl.16.
  2. Einstein et al. National Cancer Institute's Working Group on Biochemically Recurrent Prostate Cancer: Clinical Trial Design Considerations. J Clin Oncol. 2025 Dec;43(34):3672-3683. doi: 10.1200/JCO-25-01693.
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