Carlos Perez-Ruixo,1 Oliver Ackaert,1 Daniele Ouellet,2 Caly Chien,2 Hiroji Uemura,3 David Olmos,4 Paul Mainwaring,5 Ji Youl Lee,6 Margaret K. Yu,7 Juan-Jose Perez-Ruixo,1 Matthew R. Smith,8 Eric J. Small?
1Janssen Research & Development, Antwerp, Belgium; 2Janssen Research & Development, Spring House, PA, USA; 3Yokohama City University Medical Center, Yokohama, Japan; 4Spanish National Cancer Research Centre (CNIO), Madrid, and Hospitales Universitarios Virgen de la Victoria y Regional, Institute of Biomedical Research in Málaga (IBIMA), Spain; 5Centre for Personalised Nanomedicine, University of Queensland, Brisbane, Australia; 6Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea, Republic of (South); 7Janssen Research & Development, Los Angeles, CA, USA; 8Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA; 9Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
Objectives: Apalutamide (APA; ERLEADA®), an orally administered selective androgen receptor inhibitor,1 is approved for the treatment of men with non-metastatic castration-resistant prostate cancer (nmCRPC) based on the pivotal phase 3 clinical study SPARTAN, which studied apalutamide plus androgen deprivation therapy (ADT).2 We sought to understand the relationship between exposure to APA and its active metabolite N-desmethyl-apalutamide (N-APA) and selected clinical efficacy and safety endpoints to support APA dosing recommendations in men with high risk nmCRPC.
Methods: Data from 1207 subjects (806 APA 240 mg and 401 placebo) in the SPARTAN study were included in the exposure-response (ER) analysis. Using a population PK model developed in NONMEM® software,3 exposures of APA and N-APA were quantified as the area under the concentration–time curve at steady state (AUC0-24h,ss) at the average daily dose received up to the day of metastastic progression or adverse event. Univariate and multivariate Cox regression models evaluated the relationships between APA and N-APA AUC0-24h,ss and the primary outcome of the study, metastatis free survival (MFS) and were adjusted by pre-specified stratification factors (prostate-specific antigen doubling time, bone-sparing agent use, locoregional disease status) and other potential prognostic factors (age, ECOG performance status). In the multivariate Cox regression analysis, the impact of apalutamide and N-desmethyl-apalutamide exposure on MFS, was assessed by the hazard ratio (HR) and its 95% confidence interval (CI). Univariate and multivariate logistic regression models assessed the relationship between APA and N-APA AUC0-24h,ss and common treatment emergent adverse events (TEAEs): fatigue, fall, skin rash, weight decrease, and arthralgia. The corresponding odds ratio (OR), 95% CI, χ² and p-values were calculated. Additionally, a sensitivity analysis was conducted by including and excluding placebo subjects in the exposure-safety analysis.
Results: Both the univariate and multivariate Cox regression showed no statistically significant relationship between MFS, APA, and N-APA when categorized by quartiles of exposure (median AUC0-24h,ss of 78.1, 98.8, 116.1, and 143.5 µg·h/mL for quartiles 1, 2, 3 and 4, respectively) or when used as a continuous variable (AUC0-24h,ss range of 13.8 to 280µg·h/mL), suggesting that differences in APA and N-APA exposure within the range observed in SPARTAN are not associated with clinically relevant differences in MFS.
The univariate and multivariate logistic regression analysis demonstrated that within the exposure range observed in men treated with APA, the exposure-TEAEs relationship was statistically significant for skin rash and weight decrease. Using Li’s method, APA exposure explained 57% and 38.8% of the effect on rash and weight decrease, respectively.4
Conclusions: The exposure-response analyses demonstrated that differences in APA and N-APA exposure with a starting dose of 240-mg daily are not expected to be associated with clinically relevant differences in MFS in men with nmCRPC. The exposure-safety analysis supports the dose reductions to 180 or 120 mg/day in subjects who experienced AEs, such as rash.
References:
[1] Clegg NJ, Wongvipat J, Joseph JD, et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res 2012; 72: 1494-503.
[2] Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 2018; 378: 1408-18.
[3] NONMEM 7.1.0 Users Guides (1989-2009). Beal SL, Sheiner LB, Boeckmann AJ, and Bauer RJ (eds). Icon Development Solutions, Ellicott City, MD.
[4] Li Z, Meredith MP, Hoseyni MS. A method to assess the proportion of treatment effect explained by a surrogate endpoint. Stat Med. 2001; 20: 3175-88.
Reference: PAGE 28 (2019) Abstr 8935 [www.page-meeting.org/?abstract=8935]
Poster: Drug/Disease Modelling - Oncology