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Abiraterone Acetate Plus Prednisone and LHRH Analogue is Active and Safe in AR-Expressing, Castration-Resistant Salivary Gland Carcinoma

The primary aim of the phase II study was reached, demonstrating for the first time that abiraterone acetate combined with prednisone and luteinizing hormone-releasing hormone (LHRH) analogue is active in castration-resistant, androgen receptor (AR)-positive salivary gland carcinoma. The objective response rate (ORR) and survival observed with abiraterone are clinically meaningful for a second-line chemotherapy-free approach. No serious safety issues were observed. The findings are reported by Dr. Laura D. Locati of the Head and Neck Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy and colleagues in an article published online on 1 October 2021 in the Journal of Clinical Oncology.

The authors wrote in the study background that salivary duct carcinoma has a remarkable morphologic resemblance and similar molecular profile to high-grade breast ductal carcinoma. Molecularly it is characterised by androgen receptor (AR) expression, mutations in TP53, HRAS, PIK3CA, and HER2 amplification. AR expression is present in more than 90% of salivary gland carcinomas and 20-30% of adenocarcinoma, not otherwise specified. The co-expression of HER2 and AR varies between 35% and 58% of salivary gland carcinomas.

The activity of androgen-deprivation therapy (ADT) in AR-positive salivary gland carcinomas has been established in recent years. Responses have been reported with ADT, including some cases of complete remission. A randomised, prospective, multicentre study is currently ongoing to demonstrate the efficacy of ADT over chemotherapy in patients with relapsed and/or metastatic AR-positive salivary gland carcinoma in the first-line setting.

The optimal second-line treatment in castration-resistant patients is still unknown. In this setting, therapeutic options include targeting specific molecular pathways, e.g. HER2 when present, or cytotoxic chemotherapy. No second-line hormone treatments have been successfully tested in this context.

The study team investigated the activity of abiraterone acetate as second-line treatment in ADT-resistant, AR-positive patients with salivary gland carcinoma. It was a single-institution phase II study. The primary study endpoint was confirmed ORR. Secondary endpoints were disease control rate (DCR), safety, progression-free survival (PFS), and overall survival (OS).

Patients were eligible for enrolment in this single institution study in case of histologic diagnosis of AR-overexpressing salivary gland carcinoma, measurable disease according to RECIST v1.1, clinical and/or radiologic progression on ADT, suppressed serum testosterone, and no limits for the number of previous chemotherapy lines. All patients received abiraterone 1 g daily plus prednisone 10 mg and LHRH analogue until progression or unacceptable toxicities.

From 2015 to 2019, 24 patients with AR-positive salivary gland carcinomas were treated in the study of whom 23 were men; median age was 65.8 years.

The ORR was 21% with 5 partial responses, and DCR was 62.5%. The median duration of response was 5.82 months.

Median PFS was 3.65 months (95% confidence interval [CI] 1.94 to 5.89), and median OS was 22.47 months (95% CI 6.74 to not reached).

Objective response to previous ADT did not correlate with the activity of abiraterone.

Adverse events (AEs) were reported in 22 cases (92%) with grade 3 AEs in 6 patients (25%), of which 2 had fatigue, 1 flushing, 1 supraventricular tachycardia, and 2 non–drug-related AEs. No drug-related grade 4 or 5 AEs were recorded.

Next-generation sequencing was performed in only 15 cases. Thus, a limitation of this study is the lack of extensive biologic characterisation in patients with AR-expressing tumours treated with abiraterone. The biologic profile of these tumours could deep the knowledge about the role of genomic alterations in determining ADT sensitivity or resistance. 

The authors concluded that abiraterone in association with LHRH analogue is active as second-line treatment in AR-expressing, castration-resistant salivary gland carcinomas. The assessment of the molecular phenotype in these patients could provide further biologic details on mechanisms of response and ADT resistance. Patient selection might contribute to improved treatment efficacy, especially in terms of PFS.

Dr. Alan L. Ho of the Department of Medicine, Memorial Sloan Kettering Cancer Center and Department of Medicine Weill Cornell Medical College in New York, NY, US wrote in an accompanied article devoted to understanding of the pathway that analogous to castration-resistant prostate cancer, the observations from this study establish that castration-resistant salivary gland carcinomas can still be AR-dependent.

Salivary gland carcinomas are rare head and neck malignancies that include more than 20 different histologic subtypes for which standard therapies are lacking. This and other phase II studies in AR-positive salivary gland carcinomas verify the feasibility of performing clinical studies in this orphan disease, expanding the opportunities to test novel approaches to broaden AR treatment benefit for these patients.

The study was supported in part by Janssen Pharmaceuticals, Inc.


Locati L, Cavalieri S, Bergamini C, et al. Abiraterone Acetate in Patients With Castration-Resistant, Androgen Receptor–Expressing Salivary Gland Cancer: A Phase II Trial. JCO; Published online 1 October 2021. DOI: 10.1200/JCO.21.00468 

Ho AL. Androgen Receptor Pathway in Salivary Gland Cancer. JCO; Published online 1 October 2021. DOI: 10.1200/JCO.21.01983 



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