Background
Phase II single-arm, open-label trial. N=36 patients with androgen receptor (AR)-positive recurrent/metastatic (R/M) or locally advanced unresectable salivary gland carcinoma (SGC). Enrolled at a single Japanese institution (IUHW Mita Hospital), 2011–2016. AR positivity defined as IHC ≥10% nuclear staining. 94% of enrolled patients had salivary duct carcinoma (SDC); 6% adenocarcinoma NOS. SDC is the SGC subtype most commonly AR-positive (~70–80% of cases). No prior systemic therapy required. First prospective phase II study of androgen deprivation in AR+ SGC.
Interventions and follow up
Arm A: Combined androgen blockade (CAB): leuprorelin acetate 3.75 mg subcutaneous q4wk + bicalutamide 80 mg oral daily until PD or unacceptable toxicity
Primary endpoint: Overall response rate (ORR)
mFollow up: Not stated
Primary endpoint: Overall response rate (ORR)
mFollow up: Not stated
Results
ORR: 41.7% (95% CI 25.5–59.2%); 15/36 patients
Clinical benefit rate (CR+PR+SD ≥6 months): 75.0% (95% CI 57.8–87.9%)
mPFS: 8.8 months (95% CI 6.3–12.3 months)
mOS: 30.5 months (95% CI 16.8 months – NR)
Clinical benefit rate (CR+PR+SD ≥6 months): 75.0% (95% CI 57.8–87.9%)
mPFS: 8.8 months (95% CI 6.3–12.3 months)
mOS: 30.5 months (95% CI 16.8 months – NR)
Adverse events
Main adverse events: Grade 3 elevated liver transaminases: 2 patients. Grade 3 elevated creatinine: 2 patients. One patient discontinued due to AE. Overall toxicity was manageable and substantially milder than conventional chemotherapy. Hot flashes, fatigue, sexual dysfunction expected from ADT.
Conclusions
Combined androgen blockade with leuprorelin + bicalutamide achieved a 41.7% ORR, 75% clinical benefit rate, and 30.5-month median OS in AR-positive SDC — outcomes comparable to or better than conventional chemotherapy with substantially lower toxicity. This trial established CAB as the preferred first-line treatment for AR+/HER2-negative SGC.
Key Limitations
Key Limitations: Single-center, single-arm design without randomized comparator. N=36 is very small; CIs are wide. SDC dominated (94%) — results in non-SDC AR+ histologies (e.g., adenocarcinoma ex pleomorphic adenoma, myoepithelial carcinoma) are uncertain. AR positivity defined as ≥10% — optimal IHC threshold is debated. No biomarker analysis identified predictors of response within AR+ tumors. Whether LHRH agonist is necessary (vs AR antagonist alone) is unclear. Bicalutamide dose used (80 mg) is higher than the standard 50 mg commonly used in Japan for prostate cancer.
Clinical Context
Fushimi 2018 established CAB as the foundational treatment for AR+/HER2-negative SDC. Current practice: in HER2+ AR+ SDC, HER2-targeted therapy (trastuzumab + docetaxel) is preferred; in HER2-negative AR+ SDC, CAB is first-line. Enzalutamide and abiraterone are under investigation as more potent AR-targeted approaches. The DUCT study (randomized phase II, dutasteride added to CAB) is ongoing. NCCN and ESMO recommend AR-targeted therapy (ADT) for AR+/HER2-negative SDC.
References
References: Fushimi C et al, Ann Oncol 2018 (primary)