LBA36 - A randomised phase II study to evaluate the efficacy and safety of androgen deprivation therapy (ADT) vs chemotherapy (CT) in patients with recurrent and/or metastatic, androgen receptor (AR) expressing, salivary gland cancers

Background

Salivary duct (SDC) and adenocarcinomas (ADC) (ICDO-coding 8140/3) are aggressive cancers. AR expression is almost universal in SDC, rarely in ADC. The standard of care for recurrent, metastatic or unresectable (R/M/U) AR-expressing tumors is CT. To assess the value of ADT, an EORTC-led randomised phase II study was launched.

Methods

Patients (pts) with untreated R/M/U AR expressing SDC and ADC (cohort A) were randomised to receive CT (cisplatin 75 mg/m2 + doxorubicin 60 mg/m2 or carboplatin AUC 5 + paclitaxel 175 mg/m2 q3 weeks for a maximum of 6 cycles) or ADT (bicalutamide 50 mg once daily + triptorelin 3.75 mg q 28 days until progressive disease (PD)). A second single-arm cohort (B) received ADT until PD, and it included pretreated pts. Histology was centrally reviewed. IHC AR staining of >70 % was required. Primary objectives were to show superiority of progression free survival (PFS) of ADT over CT in cohort A, to describe overall response rate (ORR) in cohort B. Translational studies included HER2 and AR regulation mechanisms. A total of 89 pts were enrolled: 60 in cohort A (29 in ADT and 31 in CT) and 29 in cohort B. Cohort B included 54 pts (25 switched from cohort A upon PD). The majority were male (93%). Median age was 65 (35-80y).

Results

Cohort A: mPFS was 4.0 m (95%CI: 3.6-8.7) in the ADT arm and 6.5 m (95%CI: 5.3-8.6) in the CT arm. Neither superiority nor inferiority of ADT over CT were demonstrated. ORR was 23% (ADT) vs 35% (CT). OS hazard ratio, ADT versus CT, was HR=1.91 (95% CI: 0.92-3.98), with one-sided p=0.9580. Adverse events (AE) were 96% vs 67% in the CT and ADT arm respectively; G3-5 AEs were 15% in both arms. HER 2 amplification was detected in 17% of cases evenly distributed in the 2 arms. Cohort B: ORR was 19% with 1 complete response. mPFS was 3.5 m (95%CI: 2.0-5.9) and median OS was 20.2 m (95%CI: 9.8-29.5). G3-5 AE were 4%.

Conclusions

PFS in R/M/U AR expressing SGCs ADT did not prove superior nor inferior. ADT sensitivity is seen independently of treatment sequence, line and HER2 amplification. ADT combined with CT and/or with HER2 inhibitors, depending on HER2 status, might represent a rational approach for future studies.

Clinical trial identification

NCT01969578.

Editorial acknowledgement

Legal entity responsible for the study

EORTC.

Funding

Fonds Baillet Latour; Bluefish International AB; RARECAREnet; The Institute of Cancer Research (CRUK contribution); AIRC.

Disclosure

L.F.L. Licitra: Financial Interests, Personal, Advisory Board, for expert opinion in advisory boards: AstraZeneca, Bayer, BMS, Eisai, MSD, Boehringer Ingelheim, Hoffmann-La Roche Ltd, Novartis, Roche, Debiopharm International SA, Sobi, Incyte Biosciences Italy srl, Doxa Pharma srl, Amgen, Nanobiotics, GSK, Alentis; Financial Interests, Institutional, Research Grant, Funds received by my institution for clinical studies and research activities in which I am involved: AstraZeneca, BMS, Boehringer Ingelheim, Celgene International, Eisai, Exelixis, Debiopharm International SA, Hoffmann-La roche ltd, IRX Therapeutics, Medpace, Merck–Serono, Merck Healthcare KGaA, MSD, Novartis, Pfizer, Roche, Adlai Nortye; Financial Interests, Institutional, Local PI, Funds received by my institution for clinical studies and research activities in which I am involved: Alentis; Non-Financial Interests, Member: AIOM, ASCO, ESTRO, EORTC; Non-Financial Interests, Leadership Role: AIOCC. L.D. Locati: Financial Interests, Personal, Invited Speaker: EISAI, IPSEN, SunPharma, Bayer, Novartis, Seagen; Financial Interests, Personal, Advisory Board: MSD, Merck Serono, Eli Lilly, Roche; Financial Interests, Personal, Other, Scientific consultant: Istituto Gentili Srl; Financial Interests, Institutional, Local PI: EISAI; Financial Interests, Institutional, Funding: Pfizer; Non-Financial Interests, Leadership Role, Endocrine Tumor Group: EORTC; Non-Financial Interests, Advisory Board: AIOM (Italian Association of Medical Oncology), MSGS (Multidisciplinary Salivary Glands Society); Non-Financial Interests, Advisory Role: AIOCC (Associazione Italiana Oncologia Cervico Cefalica). C. Even: Financial Interests, Personal, Advisory Board: BMS, MSD, Innate Pharma, Merck Serono; Financial Interests, Institutional, Advisory Board: F Star Therapeutics, Novartis, Elevar, BICARA, PDS Biotechnology, GSK, MERUS; Financial Interests, Institutional, Local PI: BMS, AstraZeneca, ISA pharmaceutics, MSD, Debiopharma, Ayala, Gilead, GSK, BeiGene, Takeda, Genmab, Seagen, NYKODE; Financial Interests, Institutional, Coordinating PI: BMS, Novartis, Sanofi. A. Psyrri: Financial Interests, Personal, Invited Speaker: MSD, Merck Serono, EPICS; Financial Interests, Personal, Advisory Board: Pfizer, Sanofi, MSD, AstraZeneca, BMS, Leo, Rakuten, eTheRNA immunotherapies, Merck Serono, Seagen, Merus, Merus Pharmaceuticals, GSK; Financial Interests, Personal and Institutional, Local PI: AstraZeneca, Pfizer, GSK, Genesis, Incyte, Amgen, Debiopharm, MSD, Jannsen, Lilly, Regeneron, Sanofi, BI, Roche, Peregrine, Oncolytics Biotech; Financial Interests, Coordinating PI: AstraZeneca; Financial Interests, Personal and Institutional, Steering Committee Member: Iovance, Pfizer, Roche; Financial Interests, Institutional, Steering Committee Member: Kura Oncology; Financial Interests, Steering Committee Member: Kura Oncology; Financial Interests, Personal and Institutional, Funding: Kura Oncology, BMS, Roche, Demo, Amgen, BI, Genesis, BMS, Pfizer, Oncolytics Biotech; Financial Interests, Institutional, Funding: Merck Serono, Pfizer, GSK; Financial Interests, Personal, Other, Educational activity: Medscape, PrimeOncology; Financial Interests, Institutional, Local PI: Novartis, Replimmune; Financial Interests, Personal, Steering Committee Member: GSK, merus pharmaceuticals. P.M. Clement: Financial Interests, Institutional, Invited Speaker: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Board: MSD, AbbVie, Bayer, Rakuten, Merck, Vifor, Leo Pharma, Daiichi Sankyo, Servier; Financial Interests, Institutional, Research Grant, $ 300000: AstraZeneca; Financial Interests, Institutional, Steering Committee Member: AstraZeneca; Financial Interests, Institutional, Local PI: Orbus; Financial Interests, Institutional, Steering Committee Member, < $ 5000: Rakuten; Financial Interests, Local PI: Basilea; Non-Financial Interests, Advisory Role: KCE; Non-Financial Interests, Advisory Role, Advisory role on reimbursement of pharmaceutical specialties in Belgium (substitute member): CTG; Non-Financial Interests, Member: ASCO, EHNS, BANO, SNO, EANO, EORTC, EURACAN, AACR, BSMO; Non-Financial Interests, Leadership Role: VWHHT; Other, Advisory role ad hoc with payment to my institution: EMA. S. Ochsenreither: Financial Interests, Personal, Advisory Board: MSD, BMS, Janssen, Ipsen, Immunocore, Genemab, Pfizer, Pfizer; Financial Interests, Personal, Invited Speaker: MSD, Merck, Immunocore, Janssen; Financial Interests, Personal, Other, Support for travel / meeting: Janssen, Pfizer; Financial Interests, Personal, Other, Support for Travel / meeting: Merck; Financial Interests, Personal, Advisory Board, Patent of T-cell therapy target: Fred Hutchinson cancer Research Center; Financial Interests, Personal and Institutional, Research Grant: Bayer. J. Delord: Financial Interests, Institutional, Advisory Board: Roche, MSD, BMS, Pierre Fabre; Financial Interests, Institutional, Invited Speaker: Merck Serono; Financial Interests, Institutional, Research Grant: BMS, AstraZeneca, Amgen, Genentech, Transgene, MSD. J. Machiels: Financial Interests, Institutional, Advisory Board: Novartis, MSD, Pfizer, Roche, Debio, AstraZeneca, Innate, Nanobiotix, Bayer, Boerhinger Ingelheim, BMS, Pfizer, Cue Pharma, Incyte, Janssen, Johnson & Johnson, ALX Oncology, F-star, Nektar, F-star, Seagen, Astellas, Genmab, Merus, GSK, CureVac; Financial Interests, Institutional, Advisory Board, Education: Merck-Serono; Financial Interests, Institutional, Other, Travel expense: Gilead, MSD, Sanofi; Financial Interests, Institutional, Steering Committee Member: AstraZeneca, MSD; Financial Interests, Institutional, Coordinating PI: MSD, iTeos, eTheRNA; Financial Interests, Institutional, Local PI: Pfizer, Ceylad, MSD, Novartis, Kura, Roche, Lilly, Boehringer, Sanofi-Aventis, Incyte, Bayer, Merck - Serono, Janssen, Johnson & Johnson, Amgen, AbbVie, GalxoSmithKline; Non-Financial Interests, Leadership Role, Chair: EORTC head and neck group. T. Fuereder: Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme, Merck KGaA, Invios, Takeda, Pfizer, Janssen, Amgen, Roche, Boehringer Ingelheim RCV; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Eli Lilly, Sanofi; Financial Interests, Institutional, Funding: Merck Sharp & Dohme, Merck KGaA, Bristol Myers Squibb, Amgen, Roche. A. Joaquim: Financial Interests, Personal, Advisory Board, February 2022: Novartis, Roche; Financial Interests, Personal, Invited Speaker, March and April 2022: GSK; Financial Interests, Personal, Invited Speaker, May 2022: Merck, MSD; Financial Interests, Institutional, Advisory Board, 2023: EISAI; Financial Interests, Personal, Invited Speaker, March 2022: Gilead, Pfizer; Financial Interests, Personal, Other, Scientific consultant. Until April 2022: Novartis; Financial Interests, Personal, Full or part-time Employment: EORTC. E. Venslovaite: Financial Interests, Personal, Full or part-time Employment, I am an employee of: EORTC. All other authors have declared no conflicts of interest.