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TROP2 in View for Prostate Cancer - Hope for a New Imaging and Therapeutic Target

The cell-surface glycoprotein TROP2 (also called TACSTD2) is increasingly recognized as a potential therapeutic target in advanced prostate cancer, owing to its membrane localization, maintained expression in castration-resistant disease, and the development of antibody-drug conjugates (ADCs) designed to exploit this antigen. In a recent transcriptomic analysis of 634 metastatic castration-resistant prostate cancers (mCRPC), TACSTD2 mRNA was found to be broadly expressed across luminal and basal adenocarcinoma subtypes, though relatively lower in neuroendocrine prostate cancer (NEPC).1 Importantly, evidence suggested that prior exposure to androgen-receptor signaling inhibitors and presence of Androgen Receptor Splice Variant 7 (ARv7) did not reduce TACSTD2 expression; in fact, ARv7 positivity was associated with increased expression in some cases.1 These findings support the feasibility of TROP2 as a drug target throughout the prostate cancer spectrum, including treatment‐resistant prostate cancer.

Mechanistic and preclinical work further bolsters the case for TROP2 as actionable. In prostate cancer cell lines and in vivo models, forced TROP2 over‐expression increased proliferation, colony formation, and tumorsphere growth, while TROP2 knock‐down suppressed these malignant phenotypes.2 In addition, TROP2 over-expression induced lineage plasticity toward a neuroendocrine phenotype, accompanied by up-regulation of PARP1, and PARP-inhibitor treatment significantly delayed tumor growth and metastasis in TROP2-driven NEPC models.2 Thus TROP2 is a functional driver of disease and a logical surface antigen for ADC targeting.

Sacituzumab Govitecan (SG) is a TROP2‐directed ADC composed of a humanized anti-TROP2 antibody linked to SN-38, the active metabolite of irinotecan. In both metastatic breast and urothelial carcinoma (mUC), SG provided clinical proof-of-concept for TROP2 targeting. In the phase II TROPHY-U-01 Cohort 1 study of 113 patients with mUC, previously treated with platinum chemotherapy and checkpoint inhibitors, SG achieved an objective response rate (ORR) of 27% (95% CI 19.5-36.6), with median duration of response (DOR) 7.2 months, median progression-free survival (PFS) 5.4 months, and median overall survival (OS) 10.9 months.3 These results led to accelerated FDA approval of SG for patients with mUC who had progressed after platinum-based and checkpoint inhibitor therapy. A subsequent phase II cohort (Cohort 3) combining SG with pembrolizumab demonstrated an ORR of 41% (95% CI 26.3-57.9), median DOR 11.1 months, and median PFS 5.3 months in a heavily pre-treated mUC population.4 However, the confirmatory randomized, phase 3 TROPiCS-04 trial comparing SG with physician’s-choice taxane chemotherapy failed to meet its primary endpoint of overall survival, and as a result, the FDA withdrew SG’s approval for metastatic urothelial carcinoma in late 2024. This sequence of events may partially have been due to the lack of necessitation of prophylactic growth factors in the TROPiCS-04 trial, and resultant challenges from febrile neutropenia and infectious etiologies.

Early data presented from the phase 1/2 IMMU-132-01 basket trial included some patients with mCRPC. With a limited number of prostate cancer patients, 1/11 (9.1%) had a complete response while 4/11 (36.4%) had stable disease.5 Meanwhile, a phase II study (NCT03725761) is evaluating SG in men with mCRPC who have progressed on next-generation androgen-receptor-directed therapies.6 We eagerly await reports from this trial.

Building on this foundation, next-generation TROP2-ADCs such as Datopotamab Deruxtecan (Dato-DXd) are now advancing into clinical development. Dato-DXd is an ADC consisting of an anti-TROP2 antibody conjugated to a potent topoisomerase I inhibitor payload (DXd) via a cleavable linker. It has demonstrated preclinical activity in multiple TROP2-expressing epithelial tumor models.7 The ongoing phase II protocol TROPION-PanTumor03 (NCT05489211) includes a dedicated mCRPC cohort evaluating Dato-DXd both as monotherapy and in combination strategies.8

Emerging work in molecular imaging adds a further dimension. Recent development of TROP2-targeted PET tracers has enabled non-invasive in vivo assessment of TROP2 expression across lesions and whole-body disease burden. In a prospective study of 90 patients with 15 tumor types, including 12 with prostate cancer, using the tracer 68Ga‑MY6349 PET/CT, compared with a paired 68Ga-PSMA-11 scan, the tumor-to-background contrast was superior for TROP2 imaging.9 These data speculate that TROP2 PET may help identify patients with sufficient antigen expression to benefit from TROP2-directed therapy. A dedicated multicenter diagnostic trial (NCT06696326) is now recruiting to evaluate 68Ga-MY6349 PET/CT in prostate cancer for diagnosis, staging, and treatment selection.10 This imaging paradigm supports the concept of patient-selection for TROP2-ADCs and may enhance precision medicine by identifying heterogeneity of target expression within and between disease sites.

Taken together, TROP2 meets all major criteria for a viable therapeutic target in prostate cancer: cell-surface accessibility, sustained expression in advanced disease, a mechanistic role in tumor growth and lineage plasticity, demonstrated feasibility of drug-target engagement, and now the feasibility of non-invasive imaging to assess expression. The early success of TROP2-directed ADCs in other epithelial cancers, combined with the initiation of prostate-specific trials and companion imaging, positions this pathway as a promising future therapeutic strategy for men with advanced prostate cancer. As ongoing trials mature, biomarker-driven patient selection (including TROP2 PET) and combination strategies will be critical to fully realize the therapeutic potential of TROP2-targeted therapy in this disease.

Select prostate cancer trials with TROP2 targeting for imaging or therapy that are actively accruing patients

  • TROP2-targeted immunoPET imaging of solid tumors (NCT06851663)
  • 68Ga-MY6349 PET/CT for prostate cancer (NCT06696326)
  • Sacituzumab tirumotecan combined with tagitanlimab for aggressive variant and neuroendocrine prostate cancer (NCT07179783)
  • TROPION-PanTumor03 – Dato-Dxd as monotherapy and in combinations for patients with advanced solid tumors (NCT05489211)
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Sperger JM, Helzer KT, Stahlfeld CN, et al. Expression and Therapeutic Targeting of TROP-2 in Treatment-Resistant Prostate Cancer. Clin Cancer Res. 2023;29(12):2324-2335. doi:10.1158/1078-0432.CCR-22-1305.
  2. Hsu E, Rice MA, Bermudez A, et al. TROP2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1. Proc Natl Acad Sci USA. 2020;117(4):2032-2042.
  3. Tagawa ST, O’Donnell PH, et al. TROPHY-U-01 Cohort 1: Phase II study of sacituzumab govitecan in metastatic urothelial carcinoma after platinum and checkpoint inhibition. J Clin Oncol. 2021;39(22):2474-2485.
  4. Tagawa ST, O’Donnell PH, et al. Sacituzumab govitecan plus pembrolizumab in metastatic urothelial carcinoma (TROPHY-U-01 Cohort 3) and FDA update following TROPiCS-04 Phase III. J Clin Oncol. 2024;42(12):1415-1425.
  5. Bardia A, Messersmith WA, Kio EA, et al. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial. Ann Oncol. 2021;32(6):746-756.
  6. ClinicalTrials.gov Identifier: NCT03725761. Sacituzumab govitecan in Patients With Metastatic Castration-Resistant Prostate Cancer Progressing on Second-Generation AR-Directed Therapy.
  7. Preclinical Activity of Datopotamab Deruxtecan (Dato-DXd), an ADC targeting TROP2. AACR Proceedings 2025.
  8. ClinicalTrials.gov Identifier: NCT05489211. TROPION-PanTumor03: Datopotamab Deruxtecan in Advanced Solid Tumors (including mCRPC).
  9. Chen H, Wang Z, Fan W, et al. 68Ga-MY6349 PET/CT imaging to assess TROP2 expression in multiple types of cancer including prostate. J Clin Invest. 2025;135(1):e185408.
  10. ClinicalTrials.gov Identifier: NCT06696326. Multicenter Study Evaluating the Diagnostic Value of 68Ga-MY6349 PET/CT for Prostate Cancer.