Phase II Study of Enzalutamide for Patients With Androgen Receptor–Positive Salivary Gland Cancers (Alliance A091404)

Abstract

PURPOSE The androgen receptor (AR) is expressed (+) in a subset of salivary gland cancers (SGCs). This phase II trial evaluated the efficacy of the antiandrogen enzalutamide in AR+ SGC. METHODS Patients with locally advanced/unresectable or metastatic AR+ SGCs were enrolled. Enzalutamide (160 mg) was given orally once daily. The primary end point was the best overall response rate per RECIST v1.1 within eight cycles. Confirmed responses in ≥ 5 of 41 patients would be considered promising. Secondary end points were progression-free survival, overall survival, and safety. RESULTS Forty-six patients were enrolled; 30 (65.2%) received prior systemic therapy, including 13 (28.3%) with AR-targeted drugs. Of seven (15.2%) partial responses (PRs), only two (4.3%) were confirmed per protocol and counted toward the primary end point. Twenty-four patients (52.2%) had stable disease; 15 (32.6%) had progression of disease as best response. Twenty-six patients (56.5%) experienced tumor regression in target lesions; 18 (39.1%) had partial response/stable disease ≥ 6 months. Tumor regressions were observed in female patients (5 of 6 [83.3%]) and those who received prior AR– (6 of 13 [46.2%]) or human epidermal growth factor receptor 2–targeted therapies (5 of 8 [62.5%]). Three patients remained on treatment at data cutoff (duration, 32.2-49.8 months). The median progression-free survival was 5.6 months (95% CI, 3.7 to 7.5); the median overall survival was 17.0 months (95% CI, 11.8 to 30.0). The most common adverse events were fatigue, hypertension, hot flashes, and weight loss. Total and free testosterone levels increased by a mean of 61.2% and 48.8%, respectively, after enzalutamide. CONCLUSION Enzalutamide demonstrated limited activity in AR+ SGC, failing to meet protocol-defined success in part because of a lack of response durability. Strategies to enhance the efficacy of antiandrogen therapy are needed.

‘Toxic Masculinity’: What Is Known about the Role of Androgen Receptors in Head and Neck Squamous Cell Carcinoma

“…Currently, in the treatment of prostate cancer, new-generation nonsteroidal antiandrogens such as abiraterone acetate, enzalutamide, apalutamide, and darolutamide also are used [ 123 ]. Enzalutamide monotherapy treatment was used for AR+ SDC patients in a phase II trial in which only 15% of patients (7/46) had a partial response and 2/46 patients maintained the response until 8 weeks [ 124 ]. On the other hand, in the first published report of SDC responding to abiraterone, a 10-month progression-free survival was described in one patient [ 125 ].…”

Survival benefit of HER2-targeted or androgen deprivation therapy in salivary duct carcinoma

“…This result was similar to that recently reported in the phase II study of enzalutamide. 33 Therefore, HER2targeted therapy can be recommended prior to ADT for HER2-positive/AR-positive SDC. These findings support the treatment algorithm for systemic therapy in patients with SDC advocated by Sousa et al 36 Conversely, the OS2 and PFS2 of patients who received ADT were not inferior to those of patients who received HER2targeted therapy.…”

“…35 Furthermore, selecting appropriate treatment for HER2-positive/AR-positive patients with SDC, who account for 21-62% of patients with SDC, 19,38,39 is another unresolved issue. 10,12,32,33,36,37 Compared to the previously recommended systemic therapy, a high response rate for HER2targeted therapy and more tolerable adverse events for ADT can be expected, although this is an indirect comparison.…”

The Therapeutic Landscape of Salivary Gland Malignancies—Where Are We Now?

“…Seen the involvement of the above-mentioned targets in SGMs, there is strong rationale for the development and testing of specific inhibitors as anti-cancer therapy in SGMs. Multiple clinical studies, of which the majority phase II studies (listed in Table 3 ), have been conducted in order to determine the effectiveness of these inhibitors in heterogeneous populations of SGMs [ 81 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 ].…”

“…The same holds true for therapies directed at the AR. Despite the strong rationale, ORR for enzalutamide (non-steroidal AR antagonist), abiraterone acetate (androgen biosynthesis inhibitors) and leuprorelin acetate + bicalutamide (gonadotropin-releasing hormone receptor agonist + non-steroidal AR antagonist) was only 15%, 21% and 42%, respectively [ 113 , 119 , 131 ]. The combination of leuprorelin acetate + bicalutamide did although result in a clinical benefit of 75% and a statistically significant increase in three-year disease-free survival (48% versus 28%).…”