Abiraterone With Dalpiciclib in Salivary Gland Carcinoma

A Prospective, Open-Label, Single-Arm, Phase II Clinical Study of Abiraterone Combined With Dalpiciclib in Patients With HER-2-Negative, AR-Positive Recurrent/Metastatic Salivary Gland Carcinoma

This study is a single center, non controlled, prospective phase II clinical trial to evaluate the efficacy and safety of abiraterone combined with dalpiciclib in recurrent/metastatic salivary gland carcinoma patients with AR positive and Her-2 negative. The participants would receive abiraterone combined with dalpiciclib until termination criteria are met.

Salivary gland malignancy (SGM) accounts for 1%-5% of all head-and-neck malignancies, with an overall incidence of approximately 0.4-13.5 per 100 000 persons. The vast majority are epithelial neoplasms, while mesenchymal-origin tumors are relatively rare. SGM exhibits a broad spectrum of histological appearances and diverse biological behaviors. Currently, surgical resection and radiotherapy remain the mainstay of curative-intent therapy for SGM. Nevertheless, one distinct feature of salivary gland malignancy is the potential occurrence of "dedifferentiation" during tumor progression, accompanied by increased malignant potential. Once dedifferentiation develops, salivary gland malignancy is highly prone to recurrence and metastasis.

For recurrent and/or metastatic salivary gland malignancy, drug development has advanced slowly owing to its low incidence, leaving clinicians with limited therapeutic options. The optimal systemic treatment for recurrent/metastatic salivary gland carcinoma (R/M SGC) remains undefined. Clinically, combination chemotherapy, HER2-targeted inhibitors, and androgen-deprivation therapy (ADT) are among the available approaches; however, treatment responses vary, and high-level clinical trial evidence comparing different therapeutic strategies is lacking. Salivary gland malignancy comprises numerous pathological subtypes with substantial heterogeneity, and molecular profiles differ markedly across subtypes, which directly determines treatment response and prognosis.

Androgen receptor (AR) represents one of the key biomarkers for recurrent and/or metastatic salivary gland malignancy. Nevertheless, AR expression varies considerably across histological subtypes of salivary gland carcinoma (SGC): AR positivity reaches up to 98% in salivary duct carcinoma (SDC), 30% in adenocarcinoma, not otherwise specified (AC NOS), and as low as 15% and 5% in acinic cell carcinoma and mucoepidermoid carcinoma (MEC), respectively. Prospective phase II trials have investigated the efficacy of androgen-deprivation therapy (ADT) combined with bicalutamide (complete androgen blockade, CAB) in AR-positive SDC. That trial enrolled 36 pretreated patients with AR-positive SGC (94% SDC, 6% AC NOS) who received leuprorelin plus daily bicalutamide 80 mg for complete androgen blockade. The objective response rate (ORR) was 41.7% (95%CI: 25.5%-59.2%), median progression-free survival (mPFS) was 8.8 months (95%CI: 6.3-12.8 months), and median overall survival (mOS) was 30.5 months (95%CI: 16.8-not reached). Collectively, these findings are consistent with prior retrospective analyses evaluating ADT for R/M SGC. Boon E et al. reported a retrospective series of 35 patients with advanced/recurrent AR-positive SDC receiving first-line ADT, yielding a partial response (PR) rate of 18%, mPFS of 4 months (95%CI: 3-5 months), and mOS of 17 months (95%CI: 10-24 months). Consistent survival benefits were also observed in the adjuvant setting: a retrospective analysis by Van Boxtel et al. demonstrated significant improvements in overall survival (OS) and disease-free survival (DFS) among high-risk patients with AR-positive SDC treated with adjuvant ADT/complete androgen blockade (OS: HR = 0.064, 95%CI: 0.005-0.764, P = 0.030; DFS: HR = 0.138, 95%CI: 0.025-0.751, P = 0.022). Emerging evidence suggests biological parallels between salivary gland malignancy and prostate as well as breast cancer, which may provide novel therapeutic opportunities for SGC.

Combination regimens of CDK4/6 inhibitors plus endocrine therapy have achieved breakthroughs in hormone-dependent malignancies, particularly breast and prostate cancer. In breast cancer, such combinations constitute core therapeutic options for hormone-receptor-positive, HER2-negative disease, and are explicitly recommended in 2024 ASCO and CSCO guidelines. The MonarchE trial has firmly established the efficacy of abemaciclib combined with endocrine therapy in high-risk early-stage breast cancer. At a median follow-up of 54 months, the abemaciclib-containing group showed a 32% reduction in the risk of invasive cancer recurrence or death versus endocrine monotherapy (HR = 0.680, 95%CI 0.599-0.772), with absolute improvements of 7.6% in 5-year invasive-disease-free survival and 6.7% in distant-recurrence-free survival. Guidelines recommend 2 years of abemaciclib plus at least 5 years of endocrine therapy for node-positive patients at high recurrence risk. The phase III NATALEE trial of ribociclib plus endocrine therapy reported a 3-year invasive-disease-free survival rate of 90.4% in stage II-III hormone-receptor-positive, HER2-negative early breast cancer, representing a 3.3% absolute improvement over endocrine monotherapy (HR = 0.75, 95%CI 0.62-0.91, P = 0.003), alongside significant gains in distant-metastasis-free survival. In prostate cancer, exploration of CDK4/6 inhibitors combined with ADT lags behind breast cancer but has demonstrated clear synergistic potential. As an androgen-driven malignancy, prostate cancer exhibits AR-driven activation of the CDK4/6-cyclin D1 axis, furnishing the molecular rationale for this combination strategy. Early-phase clinical studies indicate that CDK4/6 inhibitors (e.g., abemaciclib, ribociclib) combined with ADT prolong progression-free survival and induce substantial tumor burden reduction in metastatic hormone-sensitive prostate cancer, potentially conferring extra benefit for patients with suboptimal responses to ADT alone. These data provide critical references for therapeutic exploration in AR-positive SGC.

This study is a single center, non controlled, prospective phase II clinical trial to evaluate the efficacy and safety of abiraterone combined with dalpiciclib in recurrent/metastatic salivary gland carcinoma patients with AR positive and Her-2 negative. The participants would receive abiraterone combined with dalpiciclib until termination criteria are met.

Inclusion Criteria:

• - Aged 18-75 years, male or female;
• Patients with histopathologically confirmed salivary gland malignancy of the head and neck: recurrent/metastatic disease without curative-intent therapeutic options (surgery/radiotherapy), or unresectable locally-advanced disease, with at least one measurable lesion (≥10 mm on spiral CT, complying with RECIST version 1.1);
• HER-2-negative and AR-positive status determined by immunohistochemistry (IHC);
• Availability of evaluable tumor tissue (paraffin-embedded specimen obtained within the past 2 years or fresh tumor tissue);
• ECOG performance status of 0 or 1;
• Expected survival ≥12 weeks;
• Adequate major-organ function within 2 weeks prior to study treatment initiation, meeting the following criteria:
• Bone marrow: haemoglobin ≥100 g/L, white blood cell count ≥4.0 × 10⁹/L or absolute neutrophil count ≥2.0 × 10⁹/L, platelet count ≥100 × 10⁹/L, in the absence of transfusion or colony-stimulating factor support;
• Liver: total serum bilirubin ≤1.5 × upper limit of normal (ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5 × ULN;
• Kidney: serum creatinine ≤1.5 × ULN OR creatinine clearance ≥60 mL/min; blood urea nitrogen ≤200 mg/L;
• Urine protein: negative; if urine protein is 1+, 24-hour total urinary protein must be <500 mg;
• Glucose: within normal range; or patients with diabetes with stable glycaemic control under ongoing management;
• Cardiac function: no myocardial infarction within 1 year; no unstable angina; no symptomatic severe arrhythmia; no cardiac insufficiency;
• For women of child-bearing potential: negative serum pregnancy test within 7 days before the first dose of study drug. Men with reproductive potential and women at risk of pregnancy must use highly-effective contraceptive measures throughout the study (e.g., oral contraceptives, intrauterine device, sexual abstinence, or barrier contraception combined with spermicide), and continue contraception for 12 months after treatment completion;
• Subjects voluntarily participate in this study, provide written informed consent, demonstrate good compliance, and are willing to complete follow-up assessments;
• Patients for whom the investigator judges treatment may confer clinical benefit.

Exclusion Criteria:

• - Patients with prior exposure to anti-androgen therapy or CDK4/6 inhibitors.
• Patients receiving ongoing anti-neoplastic treatment.
• Patients who have participated in, or are participating in, another investigational drug/therapy clinical trial within 4 weeks prior to the first dose of study drug.
• Patients who received haematopoietic stimulating factors, such as granulocyte-colony-stimulating factor (G-CSF) or erythropoietin, within 1 week before the first administration of study drug.
• Positive serology for human immunodeficiency virus (HIV) antibody or *Treponema pallidum* antibody.
• Patients with active hepatitis B or hepatitis C:
• HBsAg-positive or HBcAb-positive subjects with detectable HBV DNA (value above the upper limit of normal);
• Subjects with positive HCV antibody and detectable HCV RNA (value above the upper limit of normal).
• Symptomatic and clinically significant pleural effusion or ascites requiring therapeutic intervention.
• Active pulmonary disease (interstitial pneumonia, pneumonitis, obstructive pulmonary disease, asthma) or history of active pulmonary tuberculosis.
• Presence of any uncontrolled clinical conditions, including but not limited to:
• Persistent or active (severe) infection;
• Poorly-controlled diabetes mellitus;
• Cardiac disease (New York Heart Association (NYHA) class III/IV congestive heart failure or cardiac conduction block).
• Occurrence of any of the following events within 6 months prior to first-dose administration: deep-vein thrombosis or pulmonary embolism; myocardial infarction; severe or unstable arrhythmia or angina pectoris; percutaneous coronary intervention, acute coronary syndrome, coronary artery bypass grafting; cerebrovascular accident, transient ischaemic attack, cerebral embolism.
• Prior history of stem-cell transplantation or solid-organ transplantation.
• History of substance abuse of psychotropic agents without successful abstinence, or history of psychiatric disorders.
• Other severe, acute or chronic medical conditions or laboratory abnormalities which, in the investigator's judgement, may increase risks associated with study participation or confound the interpretation of study results.
• Patients deemed by the investigator to have poor compliance, or with other conditions rendering them unsuitable for trial participation.
• Patients with a history of another malignancy within the past five years.