Abstract 1396P
Background
Inhibition of the adenosine 2A receptor (A2AR) diminishes the immunosuppressive effects of adenosine and may complement immune-targeting drugs such as durvalumab (durva) and oleclumab (ole). This phase 2 study evaluated the A2AR antagonist AZD4635 in combination with durva (anti-PD-L1) or ole (anti-CD73) in pts with mCRPC.
Methods
Pts with histologically or cytologically confirmed mCRPC who had progressed ≤6 months prior to enrollment on ≥2 lines of therapy were randomized to Module 1 (AZD4635 75 mg PO QD + durva 1500 mg IV Q4W) or Module 2 (AZD4635 50 mg [first 25 pts] or 75 mg PO QD + ole 1500 mg Q2W for 4 doses, then Q4W). Primary endpoints were objective response rate (ORR) per RECIST v1.1 and prostate-specific antigen (PSA) response rate. Secondary endpoints included radiological progression-free survival (rPFS), overall survival (OS), safety, and pharmacokinetics. PFS by adenosine gene signature was an exploratory endpoint.
Results
Overall, 59 pts were treated (Module 1, n=29; Module 2, n=30). The median number of prior therapies was 4 in both modules. There was 1 confirmed complete response (Module 1) and 2 confirmed PSA responses (1 per module). The most frequent adverse events (AEs) possibly related to study treatment were nausea (38%), fatigue (21%), and decreased appetite (17%) in Module 1; nausea (50%), fatigue (30%), and vomiting (23%) in Module 2. There were no dose-limiting toxicities or serious treatment related AEs in either module. The exposure to AZD4635 was similar in both modules. Efficacy was low in both modules (Module 1 and Module 2, respectively: ORR, 1/29 and 0/30; PSA response, 1/29 and 1/30; median rPFS, 2.33 months [95% CI: 1.58−3.75] and 1.55 months [95% CI: 1.28−4.04]). Median OS was 10.72 months (95% CI: 7.2–NE) in Module 1 and not reached in Module 2. There was no significant difference in PFS based on a 14-gene blood-based adenosine signature (high vs low).
Conclusions
In this heavily pretreated population, AZD4635 with durva or ole demonstrated minimal antitumor activity. Safety profiles of the treatment combinations were manageable and consistent with the known profiles of the individual agents. Exploring alternative dosing in less heavily treated pts may be beneficial.
Clinical trial identification
NCT04089553.
Editorial acknowledgement
Medical writing support, conducted in accordance with Good Publication Practice (GPP3) and the International Committee of Medical Journal Editors (ICMJE) guidelines, was provided by April Suriano, PhD of Oxford PharmaGenesis, Inc., Newtown, PA, and was funded by AstraZeneca.
Legal entity responsible for the study
AstraZeneca.
Funding
AstraZeneca.
Disclosure
E. Lim: Financial Interests, Personal, Stocks/Shares: Pfizer. J. Reeves: Financial Interests, Institutional, Research Grant: Sarah Cannon Research Institute, Eli Lilly, Tesaro, TG Therapeutics, Genentech, Celgene, Merck, Bristol Myers Squibb, Boston Biomedical Inc., AstraZeneca, NovoCure, Calithera Biosciences, Novartis, Guardant Health, Acerta Pharma, Rhizen Pharmaceuticals, Takeda, Onoconova Therapeutics, Sanofi, CTI Biopharma, Eisai, Janssen. D.R. Spigel: Financial Interests, Institutional, Advisory Role, Consulting or Advisory Role: Genentech/Roche, Novartis, Bristol Myers Squibb (Inst), AstraZeneca, Pfizer, GlaxoSmithKline, Takeda, Evelo Therapeutics, Bayer, EMD Serono, Molecular Templates, Amgen, Curio Science, Intellisphere, Ipsen, Jazz Pharmaceuticals, Mirati Therapeutics, PUma Biotechnology, Sanofi/Aventis, Exelixis, Novocure, Regeneron, Lilly, Janssen, Evidera; Financial Interests, Institutional, Research Grant: Genentech/Roach, Novartis, Celgene, Bristol Myers Squibb, Lilly, AstraZeneca, University of Texas Southwestern Medical Center - Simmons Cancer Center, Merck, G1 Therapeutics, Neon Therapeutics, Takeda, Nektar, Celldex, Clovis Oncology, Daiichi Sankyo, EMD Serono, Astellas Pharma, GRAIL, Transgene, Aeglea Biotherapeutics, Ipsen, BIND Therapeutics, Eisai, ImClone Systems, Immunogen, Janssen Oncology, MedImmune, Molecular Partners, Agios, GlaxoSmithKline, Tesaro, Cyteir, Apollomics, Novocure, Elevation Oncology, Calithera Biosciences, Arcus Biosciences, Arrys Ingelheim, Denovo Biopharma, Hutchison MediPharma, Incyte, Kronos Bio, Loxo Oncology, Macrogenics, Molecular Templates, Oncologie, Pfizer, PTC Therapeutics, PureTech, Razor Genomics, Repare Therapeutics, Rgenix, Tizona Therapeutics Inc., Verastem; Financial Interests, Personal, Other, Travel, Accommodations: AstraZeneca, Genentech, Novartis. E. Arrowsmith: Financial Interests, Institutional, Stocks/Shares, employee: OneCology; Financial Interests, Institutional, Other, Travel and Accommodation Expenses: Flatiron Health, OneOncology, Sarah Cannon Research Institute; Financial Interests, Institutional, Research Grant, Research Funding: AstraZeneca, Boehringer Ingelheim, BMS, Calistoga Pharmaceuticals, Celgene, Cephalon, Cougar Biotechnology, Eisai, EMD Serono, Evelo Pharmaceuticals, Exelixis, Genentech, Gilead Sciences, Incyte, Merck, Millennium, Modra Research Institute, Takeda, Clovis Oncology, Lilly, Infinity Pharmaceuticals, Janssen Research & Development. D.J. George: Financial Interests, Personal, Other, Consultant: Advanced Accelerator Applications SA/Novartis, Aveo Pharmaceuticals, Eisai, IdeoOncology, Merck Sharp & Dohme, Myovant Sciences, Inc., Propella Therapeutics, RevHealth, LLC, Seattle Genetics, WebMD, Xcures; Financial Interests, Personal, Other, Sr. Editor: American Association for Cancer Research; Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Advisory Board, CAPI-281 Steering Committee member: AstraZeneca; Financial Interests, Personal, Invited Speaker, and Consultant: Bayer H/C Pharmaceuticals, Exelixis, Inc.; Financial Interests, Personal, Other, Consultant/IDMC member: Janssen Pharmaceuticals; Financial Interests, Personal, Other, Contributor: Medscape Education; Financial Interests, Personal, Other, Honorarium, Consultant: Michael J Hennessey Associates; Financial Interests, Personal, Other, Co-Editor-in-Chief: Millennium Medical Publishing, Clinical Advances in Hematology & Oncology; Financial Interests, Personal, Other, Steering Committee member: NCI Genitourinary (Leidos biomedical Research); Financial Interests, Personal, Other, Consultant, Steering Committee member, Honorarium: Pfizer; Financial Interests, Personal, Other, Consultant, Speaker, Honorarium: Sanofi; Financial Interests, Personal, Other, Honorarium: UroGPO; Financial Interests, Personal, Other, Honorarium, Travel Accommodations: UroToday; Financial Interests, Personal, Expert Testimony: WilmerHale Attorneys; Financial Interests, Institutional, Funding: Astellas, AstraZeneca, Bristol Myers Squibb, Calithera, Exelisix, Janssen Pharmaceuticals, Novartis, Pfizer, Sanofi. G. Pouliot, M. Hattersley, E. Gangl, G. James, J. Thompson, D. Russell, B. Patel, R. Kumar: Financial Interests, Personal, Stocks/Shares, Employee: AstraZeneca. G.S. Falchook: Financial Interests, Institutional, Advisory Board: FujiFilm, Silicon, Navire, Turning Point, Predicine, Inspirna, Regeneron; Financial Interests, Personal, Advisory Board: EMD Serono; Financial Interests, Personal, Invited Speaker: Total Health Conferencing, Rocky Mountain Oncology Society; Financial Interests, Personal, Other, Travel, for work and/or research related to institution, 2015: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel, for work and/or research related to institution, 2011, 2012, 2013: EMD Serono; Financial Interests, Personal, Other, Travel, for work and/or research related to institution, 2018: Fujifilm; Financial Interests, Personal, Other, Travel, for work and/or research related to institution, 2013: Millennium; Financial Interests, Personal, Other, Travel, for work and/or research related to institution, at least once yearly: Sarah Cannon Research Institute (employer); Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Institutional, Invited Speaker: 3-V Biosciences, Abbisko, AbbVie, ABL Bio ADC Therapeutics, Accutar, Aileron, American Society of Clinical Oncology, Amgen, ARMO/Eli Lilly, Artios, AstraZeneca, BeiGene, Bioatla, Bioinvent, Biothera, Bicycle, Black Diamond, Boehringer Ingelheim, Celldex, Celgene, Ciclomed, Curegenix, Curis, Cyteir, Daiichi, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Epizyme, Erasca, Exelixis, Freenome, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, IGM Biosciences, Ignyta, ImmunoGen/MarcoGenics, Incyte, Jacobio, Jounce, Jubilant, Kolltan, Loxo/Bayer, MedImmune, Millennium, Merck, miRNA Therapeutics, Molecular Templates, National Institutes of Health, Navire, NiKang, Novartis, OncoMed, Oncorus, Oncothyreon, Poseida, Precision Oncology, Prelude, PureTech, Pyramid, RasCal, Regeneron, Relay, Rgenix, Ribon, Samumed, Sapience, Seagen, Silicon, Simcha, Sirnaomics, Strategia, Syndax, Synthorx/Sanofi, Taiho, Takeda, Tarveda, Teneobio, Tesaro, Tocagen, Turning Point, U.T. MD Anderson Cancer Center, Vegenics, Xencor. All other authors have declared no conflicts of interest.