Why This Study Matters
Salivary gland carcinoma (SGC) is a rare, heterogeneous group of head and neck malignancies, accounting for roughly 5–7% of head and neck cancers. Salivary duct carcinoma (SDC), an aggressive subtype, carries a median overall survival typically under two years once the disease is unresectable or has spread. No systemic therapy is currently approved for SGC, leaving cytotoxic chemotherapy — modestly effective and often poorly tolerated — as the default option.
Androgen receptor (AR) expression is present in roughly 70–90% of SDC tumors, but AR-targeted monotherapy, including first-generation antiandrogens and the second-generation inhibitor enzalutamide, has shown only limited efficacy. That backdrop motivated the DISCOVARY investigators to test darolutamide — a potent, second-generation AR signaling inhibitor already established in prostate cancer — both alone and combined with the LHRH agonist goserelin, a strategy known as combined androgen blockade (CAB).
Study Design
DISCOVARY was a prospective, open-label, multicenter, phase II study conducted at 12 institutions in Japan. Rather than randomizing patients, the trial used a sequential, non-randomized two-cohort design: a darolutamide monotherapy cohort enrolled from April 2020 to February 2021, followed by a darolutamide-plus-goserelin combination cohort enrolled from October 2022 to August 2023. Because the cohorts were developed sequentially rather than as a single comparative study, the authors are explicit that cross-cohort comparisons are descriptive and exploratory only — the trial was not designed or powered to formally compare the two regimens.
| Cohort | Regimen | Enrollment Window | Primary Endpoint Assessment |
|---|---|---|---|
| Monotherapy (n = 24) | Darolutamide 600 mg orally twice daily | April 2020 – February 2021 | Investigator-assessed ORR |
| Combination (n = 33) | Darolutamide 600 mg BID + goserelin 3.6 mg subcutaneously every 28 days | October 2022 – August 2023 | Independent central review (ICR)-assessed ORR |
Patient Population
Eligible patients were adults (age ≥20 years) with histologically confirmed, AR-positive, unresectable locally advanced or recurrent/metastatic SGC, ECOG performance status 0–2, and at least one measurable lesion by RECIST v1.1. No prior AR inhibitor, CYP17 inhibitor, GnRH analog, or other androgen-deprivation therapy was permitted.
Of 57 patients enrolled (24 monotherapy, 33 combination), two combination-cohort patients were later found centrally AR-negative and excluded from the efficacy analysis set, leaving a modified full analysis set (mFAS) of 31 patients for combination-cohort efficacy results; all 57 enrolled patients were included in the safety analysis. Most patients in both cohorts were male, had ECOG PS 0, and had distant metastases — most commonly in the lungs, distant lymph nodes, and bone — with the parotid gland as the most common primary tumor site. The combination cohort included a higher proportion of salivary duct carcinoma histology (97.0% vs. 66.7%) and fewer male patients (78.8% vs. 95.8%) than the monotherapy cohort.
Primary Endpoint Results
| Outcome | Monotherapy (n = 24, FAS) | Combination (n = 31, mFAS) |
|---|---|---|
| Complete response (CR) | 0 (0.0%) | 1 (3.2%) |
| Partial response (PR) | 2 (8.3%) | 13 (41.9%) |
| Stable disease (SD) | 11 (45.8%) | 6 (19.4%) |
| Progressive disease (PD) | 9 (37.5%) | 10 (32.3%) |
| Not evaluable (NE) | 2 (8.3%) | 1 (3.2%) |
| ORR — primary endpoint | 8.3% (90% CI, 1.5–24.0) | 45.2% (90% CI, 29.7–61.3) |
| Disease control rate (DCR) | 54.2% | 64.5% |
| Clinical benefit rate (CBR) | 41.7% | 51.6% |
| Median duration of response | 14.7 mo (95% CI, 14.4–15.1) | 18.2 mo (95% CI, 11.3–NR) |
The ORR figures above reflect the assessment method pre-specified for each cohort (investigator assessment for monotherapy; independent central review for combination). Reciprocal secondary assessments were also reported in the source: ORR by independent central review was 20.8% in the monotherapy cohort, and ORR by investigator was 45.2% in the combination cohort — a reminder that the assessment method, not just the regimen, shapes the reported response rate.
Subgroup Analyses
The source article reports subgroup findings only in qualitative or descriptive terms — it does not provide subgroup-specific hazard ratios, confidence intervals, or P-values, and none are presented here. Among 5 combination-cohort patients previously treated with HER2-targeted therapy, the best overall response to study treatment was a partial response in 3 patients, stable disease in 1, and progressive disease in 1. Exploratory analyses did not identify a clear association between response and prior systemic therapy, AR expression level, or Ki-67 labeling index, and the authors describe these findings as exploratory. No objective response was observed among evaluable patients with AR positivity below 70%, though the source notes this subgroup was small. Concordance between local and central AR assessment in the combination cohort was 93.9% (31 of 33 patients; 95% CI, 79.8–99.3).
Safety Profile
Both regimens were generally well tolerated, with no treatment-related deaths in either cohort. Grade ≥3 adverse events occurred more often with monotherapy (37.5%, 9/24) than with the combination (18.2%, 6/33). Endocrine-related adverse events were mostly grade 1–2; gynecomastia (20.8%) was reported only in the monotherapy cohort, which the authors suggest may reflect goserelin's suppression of testosterone-related effects in the combination cohort.
| Adverse Event | Monotherapy (n = 24) | Combination (n = 33) |
|---|---|---|
| Grade ≥3 AEs (any) | 9 (37.5%) | 6 (18.2%) |
| Gynecomastia (any grade) | 5 (20.8%) | 0 (0.0%) |
| Malaise (any grade) | 2 (8.3%) | 3 (9.1%) |
| Serious treatment-related AEs | 3 events in 2 patients (anaphylaxis, drug eruption, rhabdomyolysis) | 3 patients (hypersensitivity/pyrexia; DIC) |
| Grade 4–5 AEs | 1 grade 4 (laryngeal edema); no grade 5 | None |
| Permanent discontinuation (serious TRAEs) | 3 patients | 2 (darolutamide), 1 (goserelin) |
Health-related quality of life, assessed by EQ-5D-5L and the EQ-VAS, was generally preserved in both cohorts. Mean EQ-VAS scores improved modestly in the combination cohort but generally remained below the reported minimal important difference threshold (5 points) in the monotherapy cohort; no consistent, clinically meaningful deterioration was observed in any EQ-5D-5L domain.
Interpretation and Broader Context
DISCOVARY is the first prospective trial of darolutamide, alone or combined with androgen deprivation, in AR-positive salivary gland carcinoma. The combination cohort's numerically higher response rate and longer progression-free survival support combined androgen blockade as a potential chemotherapy-sparing option, particularly in HER2-negative disease or when HER2-directed therapy is not appropriate.
With the limitations of the phase II design and inherent challenges with cross-trial comparisons, these promising results expand the therapeutic armamentarium for this rare disease.
— Jonathan W. Friedberg, MD, Editor-in-Chief, Journal of Clinical Oncology (commentary accompanying the DISCOVARY publication)
The authors are careful to frame these results as hypothesis-supporting rather than confirmatory: because the two cohorts were enrolled sequentially rather than randomized, and the study was not powered for formal between-cohort comparison, differences in enrollment period, histology mix, HER2 status, and AR-testing methodology could all have contributed to the numerically better outcomes seen with the combination. HER2 status was not prospectively collected, which the authors note limits HER2-stratified analysis. Randomized data have not established endocrine therapy as superior to chemotherapy in the first-line recurrent/metastatic setting, so these findings are presented as supporting further evaluation of darolutamide plus goserelin rather than establishing superiority over chemotherapy or other combined-androgen-blockade regimens.
Limitations
DISCOVARY's central limitation is its design: the monotherapy and combination cohorts were enrolled sequentially rather than randomized, roughly 18 months apart, and the trial was not powered for a formal between-cohort comparison — so the combination's numerically higher response rate is a descriptive, exploratory finding rather than a controlled result. The two cohorts also differed in histology mix (97.0% vs. 66.7% salivary duct carcinoma) and sex distribution, either of which could confound a cross-cohort comparison, and HER2 status was not prospectively collected, limiting HER2-stratified analysis. The trial was conducted at 12 sites in a single country (Japan) with a small combination-cohort efficacy population (mFAS n = 31), and the study was open-label with no control arm. Subgroup analyses of prior therapy, AR expression level, and Ki-67 index are explicitly described by the authors as exploratory, with no hazard ratios, confidence intervals, or significance testing reported.
In this non-randomized, two-cohort phase II trial, adding goserelin to darolutamide produced a substantially higher response rate (45.2% vs. 8.3%) and longer progression-free survival (13.1 vs. 5.7 months) than darolutamide alone in AR-positive salivary gland carcinoma, with no treatment-related deaths in either cohort. Because the cohorts were enrolled sequentially rather than randomized and the trial was not powered for a formal comparison, the authors describe combined androgen blockade as a promising, chemotherapy-sparing option warranting further study rather than an established standard of care.