A Randomized Trial of Bicalutamide in Non-Muscle Invasive Bladder Cancer

PRIMARY OBJECTIVE:

I. To compare epidermal growth factor receptor (EGFR) messenger ribonucleic acid (mRNA) expression measured by reverse transcriptase polymerase chain reaction (rt-PCR) in normal appearing urothelium adjacent to tumor (measured as a ratio relative to urothelium and lamina-propria specific markers) in participants treated with anti-androgen therapy versus (vs.) participants given NSD.

SECONDARY OBJECTIVES:

I. To determine effect of bicalutamide on EGFR expression (by rtPCR) in the subgroup of patients whose normal appearing urothelium adjacent to tumor expresses the androgen receptor (AR) (at least "1" by immunohistochemistry [IHC] score).

II. To correlate AR expression in adjacent urothelium (by IHC score) with EGFR expression by rtPCR in participants randomized to bicalutamide versus NSD.

III. Comparison of toxicity in participants randomized to bicalutamide versus NSD.

EXPLORATORY OBJECTIVES:

I. Comparison of AR and EGFR (and possibly phosphorylated EGFR [pEGFR]) staining levels (low, moderate, high; by immunocytology) in pre-treatment vs. post-treatment bladder wash cytology.

II. To compare expression of direct androgen response gene (ADAR)-2 measured by rtPCR in normal appearing adjacent (to tumor) urothelium that does and does not express AR (by IHC), in participants randomized to bicalutamide versus NSD.

III. Ki-67 expression (by IHC) in normal appearing urothelium adjacent to tumor in participants randomized to bicalutamide versus NSD.

IV. Subgroup analysis of Ki-67 expression in the AR+ subgroup. V. Differences in expression of AR, EGFR, pEGFR, and Ki-67 (by semi-quantitative IHC) in tumor in participants randomized to bicalutamide versus NSD.

VI. Comparison of demographics of two groups. VII. Change in EGFR expression by rt-PCR in tumor in participants randomized to bicalutamide versus NSD.

VIII. Morbidities of treatment (breast tenderness, sexual or urinary side effects, seizure[s], depression, abnormal liver function tests [LFTs]).

IX. Comparison of pre vs. post intervention urinary biomarkers (CxBladderTM) in both groups, examining the 5 RNAs (by rtPCR) that make up the test, both as a group and each RNA separately.

X. Fibroblast growth factor receptor 3 (FGFR3) mutation analysis in deoxyribonucleic acid (DNA) extracted from formalin fixed paraffin embedded (FFPE) blocks from neighboring normal urothelium and tumor tissue in participants randomized to bicalutamide versus NSD.

XI. Define changes in the tumor immune microenvironment pre- and post-bicalutamide through liquid biopsies of blood and urine using high-dimensional flow cytometry.

XII. Analyze tumor (biopsy specimen) immune microenvironment via multiplex immunofluorescence and spatial transcriptomics.

XIII. Compare AR, EGFR, and pEGFR in biopsies of tumors done at index cystoscopy vs. TURBT in participants randomized to bicalutamide versus NSD. (Optional) XIV. Other exploratory markers such as changes in the urinary microbiome in bladder cancer participants randomized to bicalutamide versus NSD.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Patients receive bicalutamide orally (PO) once daily (QD) on days 1-21. Patients undergo TURBT on day 21. Up to 28 days of bicalutamide prior to TURBT is permitted in the absence of unacceptable toxicity. Patients undergo blood and urine sample collection throughout the study. Patients may optionally undergo tumor biopsy at baseline.

ARM 2: Patients receive NSD PO QD on days 1-21. Patients undergo TURBT on day 21. Up to 28 days of NSD prior to TURBT is permitted in the absence of unacceptable toxicity. Patients undergo blood and urine sample collection throughout the study. Patients may optionally undergo tumor biopsy at baseline.

After completion of study treatment, patients are followed up 20-30 days after TURBT.

Inclusion criteria

• Biologic male adults (>= 18 years old)

• Note: Because no dosing or adverse event (AE) data are currently available on the use of bicalutamide in participants < 18 years of age, children are excluded from this study but will be eligible for future pediatric trials, if applicable
• Have suspected non-muscle invasive bladder carcinoma (NMIBC) on clinic-based cystoscopy or imaging as viewed by an American Urological Association (AUA) board-certified urologist
• Have had cross sectional imaging of the abdomen and pelvis (computed tomography [CT] or magnetic resonance imaging [MRI] with or without contrast) within 6 months prior to enrollment with no signs of upper tract urothelial cancer (UC), invasive, nor metastatic disease

• Note: If adenopathy or upper tract abnormalities are identified, a negative biopsy and or ureteroscopy is required prior to enrollment
• Newly suspected, diagnosed, or occasionally recurrent bladder cancer (BC)

• Note: Occasional recurrence is defined as =< 2 prior NMIBC episodes in the 18 months preceding cystoscopy where the index tumor was identified
• Participants with single and multiple tumor lesions
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1
• Total bilirubin =< 1.5 x institutional upper limit of normal (note: in participants with Gilbert's syndrome, if total bilirubin is > 1.5 x upper limit of normal, measure direct and indirect bilirubin and if direct bilirubin is =< 1.5 x upper limit of normal, participants may be eligible)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2 × institutional upper limit of normal
• Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2 × institutional upper limit of normal
• Urine Culture < 50,000 colonies/cc of 1 or more organisms (if found and treated and a confirmed negative culture obtained off antibiotics before study drug is started, they will be eligible)
• Serum Testosterone >= 250 ng/dL
• Thyroid stimulating hormone (TSH) within institutional normal
• White blood cell count (WBC) >= 0.5 × institutional lower limit of normal
• The effects of bicalutamide on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, men who are having sex must wear a condom when engaging in any activity that allows for passage of ejaculate to another person throughout the course of the study and 130 days after receiving last dose of study intervention. Male participants should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak. Additionally, men must agree to not donate sperm for the purpose of reproduction during the study and for a minimum of 130 days after receiving the last dose of study intervention
• Ability to understand and the willingness to sign a written informed consent document

Exclusion criteria

• Participants who have had a previous exposure to sex hormone (e.g., exogenous androgens) or anti-androgenic therapies (e.g., luteinizing hormone-releasing hormone [LHRH] agonists, LHRH antagonists, 5 alpha reductase-inhibitors, abiraterone or other anti-androgens) within 6 months of accrual
• Participants taking Coumarin derivative anticoagulation (e.g., warfarin). Other anticoagulation medications are allowed.
• Participants receiving any other investigational agents.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to bicalutamide.
• History of prior or concurrent muscle invading UC, or concurrent prostatic urethral, urethral, or upper tract UC or non-urothelial bladder cancer
• History of radiation therapy to the pelvis, prostate or prostatic bed, or rectum
• Any condition (uncontrolled intercurrent illness, psychiatric illness, or social situation) for which, in the opinion of the investigator, participation would not be in the best interest of the participant (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
• Participants with severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, uncontrolled hypertension, recent arterial or venous thromboembolic events (e.g. pulmonary embolism, cerebrovascular accident including transient ischemic attacks) for which anticoagulation therapy is ongoing, or clinically significant ventricular arrhythmias.
• In the opinion of the investigator, participant has underlying uncontrolled hypertension, high cholesterol, or diabetes.
• Allergy or hypersensitivity to bicalutamide, or excipients, unable or unwilling to take ADT.
• Plans to father a child while enrolled in this study or within 130 days after the last dose of study intervention.