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A Phase 2 Trial of Darolutamide plus Leuprolide Acetate in Advanced Androgen Receptor Positive Salivary Gland Cancer

Award Number: R01FD008542
ORGANIZATION: FOOD AND DRUG ADMINISTRATION
OPDIV: FDA
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2030

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A Phase 2 Trial of Darolutamide plus Leuprolide Acetate in Advanced Androgen Receptor Positive Salivary Gland Cancer - PROJECT SUMMARY/ABSTRACT Salivary gland cancers (SGCs) are rare tumors that constitute ~5% of all head and neck malignancies. They include >20 histologies, each with distinct biologic and clinical characteristics. Recurrent and/or metastatic (R/M) SGCs are incurable, and effective treatments are lacking. Molecular profiling studies have established that the androgen receptor (AR) is expressed in a high proportion of the SGC histology called salivary duct carcinoma (SDC; 70–89% AR+). Therapeutically targeting AR using androgen-deprivation therapy (ADT) plus an antiandrogen (known as combined androgen blockade [CAB]) has been shown to be clinically effective against SDCs. However, trials to date have yielded variable overall response rates and limited durations of benefit and were conducted outside the United States. To establish for the first time that targeting AR is effective in a US cohort, and to improve upon the efficacy observed in prior studies, we are now conducting a National Cancer Institute-sponsored phase II trial. This trial evaluates the second-generation antiandrogen darolutamide (daro) + ADT in unresectable/locally advanced or R/M AR+ SGCs (NCT05669664). Daro and its metabolites bind and inhibit AR more effectively than prior antiandrogens tested in patients with SGC. We hypothesize that daro + ADT will provide more effective AR inhibition than other AR-targeted therapies evaluated in SGCs to date, translating to higher efficacy. Success in this clinical trial will be essential for supporting US approval of this combination for AR+ SGCs. The biology of AR targeting in SGC tumors is likely distinct from that in other tumor types. To better understand the impact of AR inhibition in SGC tumor cells and the tumor microenvironment (TME), we will evaluate clinical trial outcomes in conjunction with the analysis of serial tumor and plasma biospecimens from the daro + ADT trial to achieve 3 specific aims: Aim 1: Determine the clinical efficacy of daro + ADT in AR+ SGC. The primary endpoint of the trial is best overall response rate. Secondary clinical endpoints include PFS, overall survival, and safety/tolerability. Aim 2: Analyze AR pathway inhibition achieved with daro + ADT in AR+ SGC tumors. We will 1) use current AR transcriptomic signatures and AR immunohistochemistry to verify AR inhibition by daro + ADT in patients with SGC tumors, and 2) develop an SGC-specific signature that more precisely captures the impact of AR inhibition in SGCs. Aim 3: Investigate adaptive changes with AR inhibition that may impact daro + ADT efficacy in AR+ SGC tumors. In preclinical models of AR+ SGCs, AR inhibition can alter intratumor heterogeneity and increase HER2 signaling pathway activation. The efficacy of AR inhibition in prostate cancer may also be influenced by its modulation of the immune TME and acquired genetic alterations. We will examine whether these adaptive changes occur in SGC tumors and cell-free DNA to impact daro + ADT efficacy. These studies will nominate biomarkers associated with daro + ADT efficacy and suggest rational therapeutic combinations that will inform novel strategies to improve AR targeting that can be tested in future trials.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $2,583,632 )
2026	2026	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Food and Drug Administration Research	000	1	9/28/2026	NEW	$2,583,632
														Subtotal = $2,583,632

Grand Total All Awards = $2,583,632

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A Phase 2 Trial of Darolutamide plus Leuprolide Acetate in Advanced Androgen Receptor Positive Salivary Gland Cancer

Award Number: R01FD008542

ORGANIZATION: FOOD AND DRUG ADMINISTRATION

OPDIV: FDA

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2030

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