Abiraterone Active in Androgen Receptor-Positive Salivary Tumors

A majority of patients with previously treated androgen receptor (AR)-expressing salivary gland cancer (SGC) achieved disease control with abiraterone (Zytiga) plus a luteinizing hormone-releasing hormone (LHRH) agonist, a small phase II trial showed.

Five of 24 patients had partial responses, and 10 others had stable disease for a disease control rate (DCR) of 62.5%. The cohort had a median progression-free survival (PFS) of 3.65 months and median overall survival (OS) of 22.47 months. Prior exposure to androgen deprivation therapy (ADT) did not correlate with response to abiraterone, reported Laura D. Locati, MD, PhD, of the Istituto Nazionale dei Tumori in Milan, and coauthors, in the Journal of Clinical Oncology.

“The primary aim of the trial was reached, demonstrating for the first time to our knowledge that abiraterone acetate combined with LHRH analog is active in castration-resistant, AR-positive patients with SGC,” the authors said of the findings. “The extension of these positive findings in ADT-resistant patients highlights the value of this approach in AR-overexpressing patients with SGC.”

“The assessment of molecular phenotype in these patients could provide further biologic details on mechanisms of response and ADT resistance,” they added. “Patient selection might contribute to improve the treatment efficacy especially for PFS, which currently is still unsatisfactory.”

The author of a related review article credited the study with establishing that “castration-resistant SGC tumors can still be AR-dependent, analogous to castration-resistant PCa [prostate cancer].”

“The molecular basis for castration resistance in SGCs has yet to be fully delineated and may differ from mechanisms relevant for PCa,” stated Alan L. Ho, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City. “The Locati et al. report suggests that increased tumor responsiveness to castrate levels of circulating androgens is a mechanism of resistance to ADT that can be overcome with abiraterone plus ADT for a subset of patients with SGC.”

“Locati et al. and other phase II AR+ SGC studies verify the feasibility of conducting clinical trials for this orphan disease and should expand opportunities to test novel approaches to broaden AR therapy benefit for these patients,” he concluded.

AR expression occurs in more than 90% of salivary duct carcinoma (SDC) and in 20-30% of adenocarcinomas not otherwise specified. ADT activity in SGCs has been recognized for several years, including some complete remissions. An ongoing multicenter randomized trial is comparing ADT and chemotherapy as initial treatment for relapsed/metastatic SGCs, but optimal second-line therapy in castration-resistant patients remains unknown, Locati and coauthors noted.

Two case reports provided evidence of SDC response to abiraterone after progression on ADT, suggesting potential as second-line hormonal therapy. The potential was evaluated in a phase II trial involving 24 patients with AR-expressing SGC that had progressed on ADT. The patients had a median age of 65.8 years, and men accounted for all but one of the patients. Histology was SDC in 19 cases and adenocarcinoma in the remaining five.

Treatment consisted of abiraterone 1 mg, prednisone 10 mg, and an LHRH agonist, continued until disease progression or unacceptable toxicity. The primary endpoint was confirmed objective response, and secondary outcomes included DCR and safety.

The results showed an objective response rate of 21% and stable disease in 41.6% of patients. The median duration of response was 5.82 months. Three patients remained on treatment, and the remaining 21 had discontinued because of progressive disease, the author reported. Median duration of treatment was 3.93 months.

The cohort had a 12-month OS rate of 66.59%, including 74.48% in the patients with SDC. Median survival from diagnosis was 94.31 months.

All but two patients had at least one adverse event (AE). The most common any-grade treatment-related AEs were fatigue (38%), flushing (29%), and hypokalemia (17%). Four drug-related grade 3 AEs occurred: Two cases of fatigue and one each of flushing and supraventricular tachycardia.

As the treatment landscape for advanced prostate cancer has evolved in recent years, some successful paradigms have been adopted in clinical trials of AR-positive SGC, including abiraterone and enzalutamide (Xtandi), the authors noted. In contrast to abiraterone, enzalutamide has demonstrated limited and short-lived activity as first-line treatment and beyond in AR-positive SGC.

Abiraterone and enzalutamide have different mechanisms of action, which could translate into different levels of activity in AR-positive SGC, the authors continued. Enzalutamide is a direct AR antagonist, whereas abiraterone is an androgen biosynthesis inhibitor.

Next-generation sequencing was performed in 15 of the 24 patients, a limitation the authors acknowledged. More extensive biologic characterization of AR-positive SGCs could improve understanding about the role of genomic alterations in ADT sensitivity and resistance.