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
5383 - A pilot trial to investigate the impact of a personalised self-management lifestyle programme using mobile technology on the health and wellbeing of cancer survivors
Presenter: Mary Grace Kelly
Session: Poster Display session 3
Resources:
Abstract
5084 - The BRIGHTLIGHT national survey of the impact of specialist teenage and young adult cancer care on caregivers’ information and support needs
Presenter: Rachel Taylor
Session: Poster Display session 3
Resources:
Abstract
4328 - Life beyond cancer: Occupational health care service support in returning work experienced by cancer survivals
Presenter: Minna Nurmi
Session: Poster Display session 3
Resources:
Abstract
3337 - Investigating the factors related to primary caregivers' burden in oncology patients in Greece
Presenter: Ourania Govina
Session: Poster Display session 3
Resources:
Abstract
3387 - Factors Influencing the Level of Emotional Support from Nurses Perceived by Patients Undergoing Haematopoietic Stem Cell Transplantation in Protective Isolation
Presenter: Michela Piredda
Session: Poster Display session 3
Resources:
Abstract
935 - Progressive Muscle Relaxation and Guided Imagery Techniques and the Way of Coping of Parents of Children with Malignancies: A randomized controlled trial
Presenter: Tsitsi Theologia
Session: Poster Display session 3
Resources:
Abstract
3457 - Pharmacist and Nurse Led Melanoma Immunotherapy Clinic
Presenter: Dharmisha Chauhan
Session: Poster Display session 3
Resources:
Abstract
5160 - Measuring the impact of the Irish Cancer Society's Cancer Information Services
Presenter: Aileen McHale
Session: Poster Display session 3
Resources:
Abstract
4297 - It's Great to Talk
Presenter: Noreen Andersen
Session: Poster Display session 3
Resources:
Abstract
4444 - Impact of Burn-Out Syndrome in Oncology personnel and its improvement through specific interventions
Presenter: Inmaculada Ortega
Session: Poster Display session 3
Resources:
Abstract