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The Next Revelation in Prostate Cancer Therapy? Antibody Drug Conjugates

Antibody drug conjugates (ADCs) have now worked their way into the standard treatment of many malignancies, including urothelial carcinoma. We already have FDA approvals for both Enfortumab vedotin1 and Sacituzumab govitecan2 for patients with advanced urothelial carcinoma. Some of the advantages of this class of agents include high objective response rates, reasonable durability, and acceptable adverse event profiles, as the chemotherapeutic payload is delivered directly to the target to decrease systemic toxicity.

One of the greatest advantages of ADCs are their ability to treat tumors in anatomic locations that portend a poor prognosis, for example, liver metastases. Another potential advantage is the “bystander effect” that allows tumors with potentially “spotty” expression of the target antigen to still respond, as cytotoxic payload may be released into the tumor microenvironment and induce local cell death. This may be especially relevant and demonstrated in the HER2 low-expressing breast cancer patients that received trastuzumab deruxtecan.3 The same potential is there for disitamab vedotin, an ADC that targets HER2, which is fully being explored in urothelial carcinoma and a topic that we will discuss in a future Urotoday Clinical Trials Portal article.

It stands to reason that if you have a highly expressed target antigen that is not excreted into the circulation, there is potential for ADC antineoplastic therapeutic development. One could postulate that the first decade of this century of antineoplastic agents for various cancers was dominated by tyrosine kinase inhibitors, while the previous decade was dominated by immune-oncology agents. Perhaps, this current decade will be that of ADCs? If so, we should work hard to develop therapeutics for our most common cancer in genitourinary oncology, prostate cancer.

A couple of months ago, I proposed B7H3 (PD-L2) as a therapeutic target for prostate cancer, and most of the ongoing therapeutic developments aimed at this target are using ADC constructs.4 I will not go into detail, here, on why B7H3 may be an attractive target for prostate cancer or the details surrounding those ADC constructs. They were previously summarized, and the ongoing trials can be accessed by going to that article. However, there are many other potential targets that one might deem attractive for ADC direction toward prostate cancer. For example, current clinical trials open for enrollment of patients with prostate cancer include antigen targets like prostate specific membrane antigen (PSMA), trophoblast cell-surface antigen 2 (TROP2), CD46, and tissue factor.

Given recent PET imaging and therapeutic data surrounding PSMA, attempts to target it with an ADC seem obvious. With the supply chain and production challenges of 177Lu-vipivotide textraxetan,5 the demand for PSMA targeted therapies is abound, making the below ARX517 trial (NCT04662580) highly attractive.

TROP2 is another target that is being targeted both with Sacituzumab govitecan (NCT03725761 and NCT0438132), with FDA approvals already in breast and bladder cancer, and with datopotamab deruxtecan (NCT05489211 and NCT04644068). TROP2 is a cell surface glycoprotein that is highly expressed in metastatic castration-resistant prostate cancer, and increased expression is a poor prognostic characteristic.6 In prostate cancer, TROP2 also likely has a role in differentiation to the neuroendocrine phenotype, which is a well-known resistance mechanistic pathway in response to androgen pathway inhibition. Since TROP2 expression has a strong role in the resistance of prostate cancer to androgen targeting therapies, castration-resistant prostate cancer may be an ideal setting for the use of TROP2-targeting ADCs.

Please see below for select trials of some ADCs where patients with prostate cancer are one of the key target populations.

Select Trials with ADCs for patients with prostate cancer

  • ARX517, targeting PSMA (NCT04662580)
  • Sacituzumab govitecan (NCT03725761)
  • ARC-6 - Sacituzumab govitecan with etrumadenant with or without zimberelimab (NCT0438132))
  • Datopotamab deruxtecan (Dato-DXd), targeting TROP2, in combination with various agents (NCT05489211)
  • PETRA – AZD5305 (PARP inhibitor) combination with Datopotamab deruxtecan (also includes patients with bladder cancer) (NCT04644068)
  • FOR46, targeting CD46, in combination with enzalutamide (NCT05011188)
  • EWEL-101 – XB002, targeting tissue factor, monotherapy or in combination with nivolumab or bevacizumab (also includes patients with urothelial carcinoma) (NCT04925284)
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. Center for Drug Evaluation and Research. FDA Grants Regular Approval to Enfortumab Vedotin-Ejfv for Locally Adv, U.S. Food and Drug Administration.
  2. Center for Drug Evaluation and Research (no date a) FDA Grants Accelerated Approval for Sacituzumab Govitecan, U.S. Food and Drug Administration.
  3. Modi S, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med 2022; 387:9-20. 
  4. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012; 367:1783-91.
  5. Yu EY.  Bladder Preservation – A New Age of Sparing Bladders That Includes Immunotherapy? Urotoday Clinical Trials Portal; May 2, 2023.
  6. Is B7-H3 (PD-L2) the Target We Need for Prostate Cancer to Come into the Antibody Drug Conjugate Era? UroToday.
  7. Sartor O, et al. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 2021; 385:1091-103.
  8. Shen M, et al. Trop2 Expression in Extramammary Paget’s Disease and Normal Skin. Am J Clin Exp Urol 2021; 9:73-87.