Abstract CT085: Targeting androgen signaling in urothelial carcinoma
Authors: Araoye Mojisola , Mega Anthony , Lagos Galina G. , Carneiro Benedito , Khaleel Sari , Golijanin Dragan , HOLDER SHELDON L. 
Published: April 2024

Abstract
Background: Men are 3-4 times more likely to develop urothelial carcinoma (UC) than women, even after accounting for differences in smoking and occupational exposures. A potential cause for this difference may be androgen signaling.
Testosterone receptors are present in up to 53% of UC in men and women. Androgen signaling promotes proliferation and chemotherapy resistance, while blocking androgen has been shown to sensitize UC to chemotherapy. When exposed to a chemical carcinogen, castrated male mice and androgen receptor (AR) knockout mice are less likely to develop UC. Additionally, men taking testosterone lowering agents for prostate cancer, who are concurrently treated for UC, have a 50% lower UC recurrence rate than men with normal testosterone signaling. In a study of 9 men and 1 woman with metastatic UC, all patients were treated with gemcitabine/cisplatin and concurrent enzalutamide. Patients’ testosterone levels were not medically lowered. Importantly, dihydrotestosterone, the native ligand for the AR, has higher affinity for the AR than enzalutamide. Interestingly, the only woman in the study (with presumably low dihydrotestosterone levels) had a complete response to therapy. No other complete responses were observed.
The standard therapy for non-metastatic muscle invasive UC is chemotherapy followed by cystectomy. Currently this results in about a 35% pathologic complete response (pCR) rate. pCR is associated with improved overall survival. In our study (TASUC; NCT05839119), we add degarelix to standard neoadjuvant chemotherapy to treat men and women who have AR positive UC.
Methods:
The main eligibility criteria are:
(1) Muscle-invasive urothelial carcinoma of the bladder (2) AR positive disease by nuclear staining on immunohistochemistry (3) pT2 - T4, N0 - N1, M0 (Stage II or IIIA disease) (4) Eligible for cisplatin-based chemotherapy (5) Eligible for cystectomy
In this single-arm study, all patients receive standard of care gemcitabine/cisplatin neoadjuvant chemotherapy (4 cycles) with the addition of monthly degarelix during chemotherapy. The primary outcome is pCR rate at cystectomy. We are employing a Simon 2-stage minmax design. In stage I we will enroll 20 patients. If there are at least 7 pCRs (35%) we will enroll an additional 12 patients in stage II, for a total of 32 patients. This design will provide 80% statistical power to detect a change in pCR rate from 35% to 50% with a significance level of less than 0.20. If we observe at least 14 pCRs (of 32 patients) the study will be considered positive and we will plan a follow-up randomized, controlled phase II (or phase III) study.
Exploratory outcomes include correlation of AR positivity with proliferation at diagnosis, identification of oncogenic androgen response elements from matched pre- and post- treatment tissue, and identification of gene signatures associated with pCR. We will also measure 2- and 5-year disease free survival.
TASUC opened to accrual on October 2, 2023 and is actively recruiting.
Citation Format: Mojisola Araoye, Anthony Mega, Galina G. Lagos, Benedito Carneiro, Sari Khaleel, Dragan Golijanin, SHELDON L. HOLDER. Targeting androgen signaling in urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT085.