PMID- 38430405
OWN - NLM
STAT- MEDLINE
DCOM- 20240304
LR  - 20240403
IS  - 1432-0851 (Electronic)
IS  - 0340-7004 (Print)
IS  - 0340-7004 (Linking)
VI  - 73
IP  - 4
DP  - 2024 Mar 2
TI  - A phase 2 study of AZD4635 in combination with durvalumab or oleclumab in 
      patients with metastatic castration-resistant prostate cancer.
PG  - 72
LID - 10.1007/s00262-024-03640-6 [doi]
LID - 72
AB  - BACKGROUND: Inhibition of the adenosine 2A receptor (A(2A)R) diminishes the 
      immunosuppressive effects of adenosine and may complement immune-targeting drugs. 
      This phase 2 study evaluated the A(2A)R antagonist AZD4635 in combination with 
      durvalumab or oleclumab in patients with metastatic castration-resistant prostate 
      cancer. METHODS: Patients with histologically/cytologically confirmed disease 
      progressing within 6 months on >/= 2 therapy lines were randomly assigned to either 
      Module 1 (AZD4635 + durvalumab) or Module 2 (AZD4635 + oleclumab). Primary 
      endpoints were objective response rate per RECIST v1.1 and prostate-specific 
      antigen (PSA) response rate. Secondary endpoints included radiological 
      progression-free survival (rPFS), overall survival, safety, and pharmacokinetics. 
      RESULTS: Fifty-nine patients were treated (Module 1, n = 29; Module 2, n = 30). 
      Median number of prior therapies was 4. One confirmed complete response by RECIST 
      (Module 1) and 2 confirmed PSA responses (1 per module) were observed. The most 
      frequent adverse events (AEs) possibly related to AZD4635 were nausea (37.9%), 
      fatigue (20.7%), and decreased appetite (17.2%) in Module 1; nausea (50%), 
      fatigue (30%), and vomiting (23.3%) in Module 2. No dose-limiting toxicities or 
      treatment-related serious AEs were observed. In Module 1, AZD4635 geometric mean 
      trough concentration was 124.9 ng/mL (geometric CV% 69.84; n = 22); exposures 
      were similar in Module 2. In Modules 1 and 2, median (95% CI) rPFS was 2.3 
      (1.6 -3.8) and 1.5 (1.3- 4.0) months, respectively. Median PFS was 1.7 versus 
      2.3 months for patients with high versus low blood-based adenosine signature. 
      CONCLUSION: In this heavily pretreated population, AZD4635 with durvalumab or 
      oleclumab demonstrated minimal antitumor activity with a manageable safety 
      profile. CLINICAL TRIAL: gov identifier: NCT04089553.
CI  - (c) 2024. The Author(s).
FAU - Falchook, Gerald S
AU  - Falchook GS
AD  - Drug Development Unit, Sarah Cannon Research Institute at HealthONE, Denver, CO, 
      USA. Gerald.Falchook@sarahcannon.com.
FAU - Reeves, James
AU  - Reeves J
AD  - Florida Cancer Specialists South, Sarah Cannon Research Institute, Fort Meyers, 
      FL, USA.
FAU - Gandhi, Sunil
AU  - Gandhi S
AD  - Florida Cancer Specialists South, Sarah Cannon Research Institute, St. 
      Petersberg, FL, USA.
FAU - Spigel, David R
AU  - Spigel DR
AD  - Tennessee Oncology, Sarah Cannon Research Institute, Nashville, TN, USA.
FAU - Arrowsmith, Edward
AU  - Arrowsmith E
AD  - Tennessee Oncology, Sarah Cannon Research Institute, Nashville, TN, USA.
FAU - George, Daniel J
AU  - George DJ
AD  - Duke Cancer Institute, Durham, NC, USA.
FAU - Karlix, Janet
AU  - Karlix J
AD  - Sarah Cannon Research Institute, Gainesville, FL, USA.
FAU - Pouliot, Gayle
AU  - Pouliot G
AD  - Oncology R&D, AstraZeneca, Waltham, MA, USA.
FAU - Hattersley, Maureen M
AU  - Hattersley MM
AD  - Oncology R&D, AstraZeneca, Waltham, MA, USA.
FAU - Gangl, Eric T
AU  - Gangl ET
AD  - BioPharma R&D, AstraZeneca, Boston, MA, USA.
FAU - James, Gareth D
AU  - James GD
AD  - Medical Statistics Consultancy Ltd, London, UK.
FAU - Thompson, Jeff
AU  - Thompson J
AD  - Oncology R&D, AstraZeneca, Waltham, MA, USA.
FAU - Russell, Deanna L
AU  - Russell DL
AD  - Oncology R&D, AstraZeneca, Waltham, MA, USA.
FAU - Patel, Bhavickumar
AU  - Patel B
AD  - Oncology R&D, AstraZeneca, Cambridge, UK.
FAU - Kumar, Rakesh
AU  - Kumar R
AD  - Oncology R&D, AstraZeneca, Gaithersburg, MD, USA.
FAU - Lim, Emerson
AU  - Lim E
AD  - Medical Oncology & Hematology-LHCP, Corewell Health Medical Group, Grand Rapids, 
      MI, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT04089553
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20240302
PL  - Germany
TA  - Cancer Immunol Immunother
JT  - Cancer immunology, immunotherapy : CII
JID - 8605732
RN  - 28X28X9OKV (durvalumab)
RN  - EC 3.4.21.77 (Prostate-Specific Antigen)
RN  - 0 (Antineoplastic Agents)
RN  - K72T3FS567 (Adenosine)
RN  - 0 (Antibodies, Monoclonal)
SB  - IM
MH  - Male
MH  - Humans
MH  - *Prostatic Neoplasms, Castration-Resistant
MH  - Prostate-Specific Antigen
MH  - *Antineoplastic Agents/therapeutic use
MH  - Fatigue
MH  - Adenosine
MH  - Nausea/drug therapy
MH  - *Antibodies, Monoclonal
PMC - PMC10908633
OTO - NOTNLM
OT  - A2AR antagonist
OT  - AZD4635
OT  - Adenosine
OT  - Durvalumab
OT  - Metastatic castration-resistant prostate cancer
OT  - Oleclumab
COIS- Gerald S. Falchook: Royalties (self): Wolters Kluwer (2014-present); Advisory 
      role (to institution): Fujifilm (2018), Silicon (2020, 2021), Navire (2021), 
      Turning Point (2021), Predicine (2021), Inspirna (2021), Regeneron (2021) 
      Advisory role (self): EMD Serono (2010, 2011); Speakers honorarium for CME: Total 
      Health Conferencing (2019), Rocky Mountain Oncology Society (2020); Travel (self, 
      for work or research related to institution): Bristol Myers Squibb (2015), EMD 
      Serono (2011, 2012, 2013), Fujifilm (2018), Millennium (2013), Sarah Cannon 
      Research Institute Research funding [to institution, for any trial for which I 
      have been the PI (ever) or subinvestigator (minimum last 4 years): 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, 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/MacroGenics, Incyte, Jacobio, Jounce, 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, Silicon, Simcha, Sirnaomics, Strategia, Syndax, 
      Synthorx/Sanofi, Taiho, Takeda, Tarveda, Teneobio, Tesaro, Tocagen, Turning 
      Point, U.T. MD Anderson Cancer Center, Vegenics, Xencor. James Reeves: None. 
      Sunil Gandhi: None. David Spigel: None. Edward Arrowsmith: Tennessee Oncology 
      Stock. Other Ownership Interests: One Oncology Research Funding: AstraZeneca, 
      Boehringer Ingelheim, Bristol Myers Squibb, Calistoga Pharmaceuticals, Celgene, 
      Cephalon, Chorus, Cougar Biotechnology, Eisai, EMD Serono, Evelo Biosciences, 
      Exelixis, Genentech, Gilead Sciences, Incyte, Merck Sharp & Dohme, Millennium, 
      Modra Pharmaceuticals, Novartis, Oncogenex, Onyx, Peloton Therapeutics, Pfizer, 
      Sarah Cannon Research Institute, Takeda, Clovis Oncology, Lilly, Infinity 
      Pharmaceuticals, Janssen Research & Development Travel, Accommodations, Expenses: 
      Flatiron Health, OneOncology, Sarah Cannon Research Institute. Other 
      Relationship: Sarah Cannon Research Institute. Daniel J. George: Consultant for 
      Astellas, AstraZeneca, Bayer H/C Pharmaceuticals, BMS, Constellation 
      Pharmaceuticals, Exelixis, Inc, Flatiron, IdeoOncology (formerly Nexus), Janssen 
      Pharmaceuticals, Merck Sharp & Dohme, Michael J Hennessey Associates, Myovant 
      Sciences, Inc, Physician Education Resource LLC, Pfizer, PlatformQ, Propella 
      TX-Consultant (formerly Vizuri), RevHealth, LLC, Sanofi, Seattle Genetics, WebMD, 
      and Xcures. Speaker's honorarium for Bayer H/C Pharmaceuticals, EMD Serono, 
      Exelixis, Inc, Ipsen, Michael J Hennessey Associates, Pfizer, Sanofi, UroGPO, and 
      UroToday. Advisory Role (self and institution) for Astellas, AstraZeneca, Capio 
      Biosciences, and Modra Pharmaceuticals B.V. Travel accommodations from Bayer H/C 
      Pharmaceuticals, Exelixis, Inc, Sanofi, and UroToday. Research funding (self and 
      institution) from AstraZeneca, Astellas, BMS, Calithera (institution only), 
      Exelixis, Inc, Janssen Pharmaceuticals, Novartis (institution only), Pfizer, and 
      Sanofi. Steering Committee for Astrazeneca, Bayer H/C Pharmaceuticals, BMS, 
      Leidos Biomedical Research Inc, Nektar Therapeutics, and Pfizer. Sr Editor for 
      American Association for Cancer Research and Co-Editor-in-Chief for Millennium 
      Medical Publishing, Clinical Advances in Hematology & Oncology. Independent 
      contractor for Axess Oncology. Independent Data Monitoring Committee for Janssen 
      Pharmaceuticals. Janet Karlix: None. Gayle Pouliot: Employee of AstraZeneca and 
      may own stock or stock options. Maureen M. Hattersley: Employee of AstraZeneca 
      and may own stock or stock options. Eric T Gangl: Employee of AstraZeneca and may 
      own stock or stock options. Gareth D James: Contractor for AstraZeneca. Jeff 
      Thompson: Employee of AstraZeneca and may own stock or stock options. Deanna 
      Russell: Employee of AstraZeneca and may own stock or stock options. Bhavickumar 
      Patel: Employee of AstraZeneca and may own stock or stock options. Rakesh Kumar: 
      Employee of AstraZeneca and may own stock or stock options. Emerson Lim: None.
EDAT- 2024/03/02 12:50
MHDA- 2024/03/04 06:48
PMCR- 2024/03/02
CRDT- 2024/03/02 11:14
PHST- 2023/09/22 00:00 [received]
PHST- 2024/01/22 00:00 [accepted]
PHST- 2024/03/04 06:48 [medline]
PHST- 2024/03/02 12:50 [pubmed]
PHST- 2024/03/02 11:14 [entrez]
PHST- 2024/03/02 00:00 [pmc-release]
AID - 10.1007/s00262-024-03640-6 [pii]
AID - 3640 [pii]
AID - 10.1007/s00262-024-03640-6 [doi]
PST - epublish
SO  - Cancer Immunol Immunother. 2024 Mar 2;73(4):72. doi: 10.1007/s00262-024-03640-6.