Darolutamide Alone and in Combination With Goserelin in Androgen Receptor-Positive Salivary Gland Carcinoma: Results From the Phase II DISCOVARY Trial.
The combination of darolutamide and goserelin showed a higher objective response rate and longer progression-free survival compared to darolutamide alone in patients with androgen receptor-positive salivary gland carcinoma.
Where it sits
this study against the rest of the goserelin corpusSummary and findings
This study measured the efficacy and safety of darolutamide, both as monotherapy and in combination with goserelin, in patients with androgen receptor-positive salivary gland carcinoma. The trial involved 57 patients, with darolutamide administered at 600 mg orally twice daily and goserelin at 3.6 mg subcutaneously once every 28 days. The combination therapy showed a higher objective response rate compared to monotherapy.
Abstract
<h4>Purpose</h4>Salivary gland carcinoma (SGC), particularly salivary duct carcinoma (SDC), is a rare and aggressive malignancy with no standard systemic treatment. Androgen receptor (AR) expression is frequently detected in SDC, which suggests inhibition of the AR pathway as a therapeutic strategy. We conducted a prospective phase II trial of the efficacy and safety of darolutamide, a second-generation AR signaling inhibitor, as monotherapy or in combination with goserelin, in patients with AR-positive unresectable locally advanced (LA) or recurrent/metastatic (R/M) SGC.<h4>Methods</h4>DISCOVARY was a multicenter, single-arm, phase II trial conducted in Japan. Patients with unresectable LA or R/M AR-positive SGC were enrolled into two sequential cohorts, a monotherapy cohort (darolutamide 600 mg orally twice daily) and a combination cohort (darolutamide plus goserelin 3.6 mg subcutaneously once every 28 days). The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), safety, and health-related quality of life.<h4>Results</h4>Fifty-seven patients were enrolled (monotherapy, n = 24; combination, n = 33). In the monotherapy cohort, the confirmed ORR was 8.3% (90% CI, 1.5 to 24.0) and the median PFS was 5.7 months. In the combination cohort, ORR was 45.2% (90% CI, 29.7 to 61.3) and the median PFS was 13.1 months. Twelve-month OS rates were 91.3% and 87.0%, respectively. Most adverse events were grade 1 or 2 in severity, with no treatment-related deaths. Quality of life was preserved. No clear association between AR expression level or Ki-67 index and treatment response was evident in exploratory analysis.<h4>Conclusion</h4>Darolutamide demonstrated antitumor activity in AR-positive SGC, with numerically more favorable outcomes with goserelin. Darolutamide plus goserelin may represent a chemotherapy-sparing option in this rare malignancy.
Background
The study addresses the lack of standard systemic treatment for salivary gland carcinoma, particularly salivary duct carcinoma, which is aggressive and often androgen receptor-positive. Prior knowledge indicates that androgen receptor expression is common in this type of cancer, suggesting that targeting this pathway could be beneficial. This trial is significant as it explores the efficacy of darolutamide, a second-generation androgen receptor inhibitor, alone and in combination with goserelin in this rare malignancy.
Methods
This was a multicenter, single-arm, phase II trial involving patients with unresectable locally advanced or recurrent/metastatic androgen receptor-positive salivary gland carcinoma. A total of 57 patients were enrolled, with 24 receiving darolutamide alone and 33 receiving darolutamide in combination with goserelin. The primary outcome measure was the objective response rate, while secondary outcomes included progression-free survival, overall survival, safety, and quality of life.
Results
The primary endpoint showed a confirmed objective response rate of 45.2% (90% CI, 29.7 to 61.3) in the combination cohort. The median progression-free survival was 13.1 months for the combination therapy and 5.7 months for monotherapy. Twelve-month overall survival rates were reported as 91.3% for monotherapy and 87.0% for combination therapy. Adverse events were predominantly grade 1 or 2, with no treatment-related deaths.
Interpretation
The findings suggest that the combination of darolutamide and goserelin may offer improved outcomes compared to darolutamide alone, particularly in terms of objective response rate and progression-free survival. However, the clinical significance of the observed effect sizes should be interpreted cautiously, given the small sample size and lack of a control group. The exploratory analysis did not find a clear association between androgen receptor expression levels or Ki-67 index and treatment response, which may limit the understanding of the treatment's mechanisms.
Key findings
- Confirmed ORR of 8.3% (90% CI, 1.5 to 24.0) in the monotherapy cohort, n=24.
- Confirmed ORR of 45.2% (90% CI, 29.7 to 61.3) in the combination cohort, n=33.
- Median PFS of 5.7 months in the monotherapy cohort.
- Median PFS of 13.1 months in the combination cohort.
- Twelve-month OS rates of 91.3% for monotherapy and 87.0% for combination therapy.
Limitations
- Single-arm trial with no control group.
- Small sample size (n=57).
- Short follow-up duration.
- Exploratory analysis showed no clear association between AR expression and treatment response.