Abstract 2214
Background
ENZA and APA are androgen receptor inhibitors approved for treatment of castration-resistant prostate cancer (CRPC) and nonmetastatic CRPC, respectively. Their chemical structures differ with ENZA having 2-cyanophenyl and dimethyl moieties and APA 2-cyanopyridyl and cyclobutyl moieties. In the SPARTAN clinical trial, APA treatment was reported to be associated with an increased incidence of skin rash compared with the placebo group, which was not observed with ENZA in the PROSPER trial in a similar patient population; therefore, we examined their in vitro chemical reactivity and hypersensitivity potential in an MDAM.
Methods
To assess possible reactivity of cyanopyridine, in vitro studies examining the chemical stability in buffer (+/- glutathione) and covalent binding to proteins (eg, bovine serum albumin [BSA]) were evaluated. For the MDAM, C57BL/6 mice were injected subcutaneously with APA, ENZA, or RD162 (Analogue 1), daily for 3 days at 25, 50, or 100 mg/kg/day. Brachial lymph nodes were harvested on day 6 and lymph node cellularity was analyzed by flow cytometry.
Results
The 2-cyanopyridine moiety of APA was found to be chemically reactive with the thiol nucleophile glutathione, resulting in rearranged thiazoline products. Radiolabeled APA, but not ENZA, was shown to react with mouse and human plasma proteins. Thiol nucleophiles decreased the extent of covalent binding to the model protein BSA while amine and alcohol nucleophiles had no effect, suggesting a reaction with cysteine sulfhydryl groups of proteins. In the MDAM, dose-dependent higher lymph node cellularity was observed for the APA groups (compared with the vehicle control), suggesting immune activation. ENZA and Analogue 1 demonstrated substantially less covalent binding activity and no change in lymph node cellularity (compared with vehicle) in the MDAM.
Conclusions
These data support the hypothesis that the 2-cyanopyridine moiety present in APA, but absent in ENZA or Analogue 1, may react with cysteine residues in proteins to form haptens that may trigger an immune response leading to the increased incidence of skin rash clinically observed in patients treated with APA, but not with ENZA.
Clinical trial identification
Editorial acknowledgement
Medical writing and editorial assistance funded by Pfizer Inc. was provided by Ira Mills, PhD, and Michele Salernitano from Ashfield Healthcare Communications.
Legal entity responsible for the study
Pfizer Inc. and Astellas Pharma, Inc.
Funding
Pfizer Inc. and Astellas Pharma, Inc.
Disclosure
M. Guha: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. C. Ji: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. X. Zhu: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. J. Whritenour: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. M. Hemkens: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. S. Tse: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. G.S. Walker: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. E. Evans: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. N.K. Khan: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. M.B. Finkelstein: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. E. Callegari: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc.. R..S. Obach: Shareholder / Stockholder / Stock options, Employee: Pfizer Inc..
Resources from the same session
4868 - Evaluation of markers associated with efficacy of abiraterone acetate plus prednisone (AAP) in patients (pts) with castration-sensitive prostate cancer (mCSPC) from the LATITUDE study
Presenter: Kim Chi
Session: Poster Display session 3
Resources:
Abstract
4837 - LRP2, a potential new biomarker for Chinese younger aged intrahepatic cholangiocarcinoma patients
Presenter: Xiaoliang Shi
Session: Poster Display session 3
Resources:
Abstract
1286 - Reanalysis of the efficacy of molecular targeted agents (MTAs) given in the randomized trial SHIVA01 according to the ESMO ESCAT scale of actionability
Presenter: Aurelie Moreira
Session: Poster Display session 3
Resources:
Abstract
2736 - Comparison of Platforms for Determining Tumor Mutational Burden (TMB) From Blood Samples in Patients With Non-Small Cell Lung Cancer (NSCLC)
Presenter: Jonathan Baden
Session: Poster Display session 3
Resources:
Abstract
5045 - Comprehensive Pan-Cancer analysis of somatic mutations in drug transporters to reveal acquired and intrinsic drug resistance in 3149 metastatic cancer patients
Presenter: Sander Bins
Session: Poster Display session 3
Resources:
Abstract
4577 - Pan-Cancer Genomic Landscape of the Cyclin D1/FGF3,4,19 (11q13) Amplicon Including Associations with HPV Status, and ESR1 and AR Alterations
Presenter: Jennifer Johnson
Session: Poster Display session 3
Resources:
Abstract
5366 - Co-occurrence of NTRK fusions with other genomic biomarkers in cancer patients
Presenter: Xiaolong Jiao
Session: Poster Display session 3
Resources:
Abstract
4084 - Prospective comparative study of next-generation sequencing on fine needle aspirations versus core needle biopsies in cancer patients included in SHIVA02 trial
Presenter: Julien Masliah-Planchon
Session: Poster Display session 3
Resources:
Abstract
6017 - First national External Quality Assessement for the interpretation of somatic variants: assessment of 25 variants in colorectal, lung, ovarian cancers and melanoma in France
Presenter: Etienne Rouleau
Session: Poster Display session 3
Resources:
Abstract
2283 - Prospective testing of circulating tumor DNA in metastatic breast cancer facilitates clinical trial enrollment and precision oncology
Presenter: Andjelija Bujak
Session: Poster Display session 3
Resources:
Abstract