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Is TROP2 Just Not What We Thought It Was for Bladder Cancer? Where to Go after TROPiCS-04?

Sacituzumab govitecan is an antibody drug conjugate that targets TROP-2, a cell-surface glycoprotein highly expressed by bladder cancers. The payload on Sacituzumab govitecan is SN-38, the active metabolite of irinotecan. Sacituzumab govitecan offers a progression-free (PFS) and overall survival (OS) benefit in patients with metastatic triple-negative breast cancer who have previously received at least two prior therapies for metastatic disease.1 Subsequently, the TROPiCS-02 trial showed both PFS and OS benefit in patients with confirmed hormone receptor positive and HER2 negative locally-recurrent, inoperable, or metastatic breast cancer.2 These patients had received at least one previous endocrine therapy, a taxane, and a CDK4/6 inhibitor as well as 2 to 4 previous chemotherapy regimens for metastatic disease.

In urothelial bladder cancer, the TROPHY-U-01 phase 2 trial enrolled 113 patients in Cohort 1 who had experienced prior progression after platinum-based chemotherapy and a checkpoint inhibitor.3 The objective response rate was 27% with median PFS and OS of 5.4 and 10.5 months, respectively. Updated survival data confirmed a median PFS and OS of 5.4 and 10.9 months, respectively.4 As a result of the response data, the United States FDA granted accelerated approval for the use of Sacituzumab govitecan- for patients with locally advanced or metastatic urothelial cancer who previously received a platinum-containing chemotherapy and a PD-(L)1 inhibitor.5

The accelerated approval was contingent upon the confirmatory randomized, phase 3 TROPiCS-04 study, also in the similar heavily pre-treated locally advanced or metastatic urothelial cancer population. In this trial, Sacituzumab govitecan was randomized vs. physician’s choice single-agent taxane chemotherapy. On May 30, 2024, Gilead, provided a press release stating that the primary endpoint of OS was not met in the intention-to-treat population.6 Although granular details were not released, we anticipate they will be presented at an upcoming meeting in the near future. However, it was shared that there was a higher number of deaths due to adverse events in the Sacituzumab govitecan compared to the taxane chemotherapy arm. These events were observed early in treatment and related to neutropenic complications, including infection. Of note, growth factor use was not mandated in the trial.

One concern coming after this press release is whether TROP2 is a good bladder cancer target or not, however, this should be an easy question to answer. TROP2 is highly expressed in urothelial bladder cancer, and that includes variant histologic subtypes.7 In a rapid tumor autopsy study, all histologic subtypes, sans neuroendocrine, demonstrated moderate to high TROP2 expression by immunohistochemistry and RNAseq. TROP2 also had both strong cytoplasmic and membrane staining in both primary and metastatic plasmacytoid and squamous variant tumors. Therefore, the expression of TROP2 was unlikely the problem in the TROPiCS-04 trial.

The Sacituzumab govitecan antibody drug conjugate construct, itself, requires careful examination. The stability of the linker, potential toxicity of the payload, and potential off target effects due to high Drug Antibody Ratio (DAR) are all necessary components to consider. These all seem relevant given the toxicities of Sacituzumab include diarrhea and myelosuppression that can result in infectious complications. For the time being, it seems logical to incorporate granulocyte colony-stimulating factor prophylaxis into both standard clinical practice and clinical trials where Sacituzumab govitecan is to be used. It is possible that consistent and early use of growth factors could abrogate any early toxic death results.

With such prophylaxis in place, it is prudent to continue studying Sacituzumab govitecan and other newer TROP2 antibody drug conjugates like dato-datopotamab deruxtecan. There are certainly other disease states and histologic subtypes of bladder cancer where the risk/benefit ratio warrants further investigation, especially when growth factors are implemented. This includes the cisplatin-ineligible patient population in the neoadjuvant setting, where we currently have patients with a very high risk of relapse and no regulatory approved systemic therapies to decrease that risk. Another population with no conventional standard treatment option is for patients who harbor variant bladder cancers, making the risk of potential toxicity more acceptable. Please see below for select trials of TROP2 targeting antibody drug conjugates in clinical trials that are either actively accruing or will be opening to accrual soon for patients in various clinical settings and with multiple bladder cancer histologic subtypes.


Select trials with TROP2 targeting antibody drug conjugates for bladder cancers

  • PRISMA-1 – Perioperative sacituzumab govitecan plus zimberlimab and domvanalimab in patients with cisplatin-ineligible muscle invasive urothelial carcinoma (NCT06133517)
  • SURE-02 – Perioperative Sacituzumab govitecan plus pembrolizumab in patients cisplatin-ineligble muscle invasive urothelial carcinoma (NCT05535218)
  • Neoadjuvant sacituzumab govitecan prior to radical cystectomy for non-urothelial muscle invasive bladder cancer (NCT05581589)
  • Adaptive radiation therapy with concurrent Sacituzumab govitecan for muscle invasive bladder cancer (NCT05833867)
  • Umbrella trial of various neoadjuvant therapies for patients with cisplatin-ineligible muscle invasive urothelial cancer that include cohorts with Sacituzumab govitecan and in combination with pembrolizumab (NCT06341478)
  • SMART – Sacituzumab govitecan with or without atezolizumab in locally advanced unresectable or metastatic rare genitourinary cancers including small cell, squamous cell, adenocarcinoma of the bladder, renal medullary carcinoma and squamous cell carcinoma of the penis (NCT06161532)
  • Phase 1 trial of IDE397 for MTAP-deleted advanced solid tumors in combination with multiple antitumor agents, including Sacituzumab govitecan (NCT04794699)
  • MORPHEUS mUC – Phase 1/2 trial of sacituzumab govitecan plus atezolizumab for metastatic urothelial carcinoma post platinum chemotherapy (NCT03869190)
  • JAVELIN Bladder Medley – Avelumab maintenance therapy in combination with other agents, including Sacituzumab govitecan, for patients with metastatic urothelial carcinoma (NCT05327530)
  • TROPION-PanTumor03 – Datopotamab deruxtecan as monotherapy and in combination for patients with urothelial and metastatic castration-resistant prostate cancer (NCT05489211)
  • Phase 1/2 trial of LCB84, a TROP2 antibody-drug conjugate alone and in combination with an anti-PD-1 antibody for advanced solid tumors (NCT05941507)
  • Phase 1/2 trial of SKB264, a TROP2 antibody-drug conjugate for locally advanced and metastatic solid tumors refractory to available standard therapies (NCT04152499)

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. Bardia A, et al. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med 2021; 384:1529.
  2. Rugo H, et al. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet 2023; 402:1423-33.
  3. Tagawa ST, et al. TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors. J Clin Oncol 2021; 39:2474-85.
  4. Loriot Y, et al. TROPHY-U-01, a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors: updated safety and efficacy outcomes. Ann Oncol 2024; 35: 392-401.
  5. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sacituzumab-govitecan-advanced-urothelial-cancer
  6. https://www.gilead.com/news-and-press/press-room/press-releases/2024/5/gilead-provides-update-on-phase-3-tropics-04-study
  7. Ghali F, et al. Clin Genitourin Cancer 2023; 21:669-78.