Skin rash following Administration of Apalutamide in Japanese patients with Advanced Prostate Cancer: an integrated analysis of the phase 3 SPARTAN and TITAN studies and a phase 1 open-label study

Hiroji Uemura, Yosuke Koroki, Yuki Iwaki, Keiichiro Imanaka, Takeshi Kambara, Angela Lopez-Gitlitz, Andressa Smith, Hirotsugu Uemura, Hiroji Uemura, Yosuke Koroki, Yuki Iwaki, Keiichiro Imanaka, Takeshi Kambara, Angela Lopez-Gitlitz, Andressa Smith, Hirotsugu Uemura

Abstract

Background: A higher incidence of apalutamide-related skin rash has been observed in Japanese patients with prostate cancer (PC).

Methods: This integrated analysis of data of Japanese patients from 2 global Phase 3 studies, SPARTAN ( NCT01946204 ; patients with non-metastatic castration-resistant PC [nmCRPC]) and TITAN ( NCT02489318 ; patients with metastatic castration-sensitive PC [mCSPC]), and the Phase 1 study 56021927PCR1008 ( NCT02162836 ; patients with metastatic CRPC [mCRPC]), assessed clinical risk factors of apalutamide-related skin rash as well as the potential correlation with plasma exposure to apalutamide. Kaplan-Meier method was used for time-to-event analyses. Clinical risk factors for skin rash were assessed using odds ratio.

Results: Data from 68 patients (SPARTAN: n = 34, TITAN: n = 28, 56021927PCR1008: n = 6) receiving apalutamide 240 mg orally once-daily were analyzed. Rash (13 [19.1%]) and maculo-papular rash (11 [16.2%]) were the most frequently reported skin rash. All Grade and Grade 3 skin rash occurred in 35 (51.5%) and 10 (14.7%) patients, respectively. Most (85.7%) skin rash occurred within 4 months of apalutamide initiation and resolved in a median time of 1 month following the use of antihistamines, topical or systemic corticosteroids, with/without apalutamide dose interruptions/reductions. Median time-to-remission of first incidence of rash and maximum grade incidence of rash were 1.0 month (IQR: 0.36-1.81) and 1.0 month (IQR: 0.30-2.43), respectively. No significant clinical risk factors for the incidence of skin rash were observed. Areas under the curve (0-24 h) (AUC0-24, ss) at steady-state of plasma apalutamide concentration were numerically slightly higher in patients with skin rash than those without.

Conclusions: No clinical risk factors for rash could be detected. There is a potential correlation between incidence of skin rash and plasma exposure to apalutamide. In general, apalutamide-related skin rash is easily managed, with appropriate treatment with or without dose adjustment.

Trial registration: Retrospective pooled analysis of NCT01946204 , NCT02489318 , and NCT02162836 .

Keywords: Apalutamide; Japanese; Prostate cancer; Skin rash.

Conflict of interest statement

Dr. Hiroji Uemura received research grants from Janssen Pharmaceutical (during the conduct of the study) and lecture fees/subsidies from Bayer Yakuhin, Limited, Takeda Pharmaceutical Company Limited, AstraZeneca K.K., TAIHO Pharmaceutical Company Limited, Astellas Pharma Inc. and Pfizer Inc.

Dr. Takeshi Kambara has no competing interests.

Dr. Hirotsugu Uemura received lecture fee from Pfizer Japan Inc., Ono pharmaceutical Co., Ltd., Bayer Yakuhin, Limited, Bristol-Myers Squibb, MSD K.K., research fee or grants from TAIHO Pharmaceutical Company Limited, Janssen Pharmaceutical K.K., Mebix, Inc., MSD K.K., Astellas Pharma Inc., Covence, Bayer Yakuhin, Limited, Prexel International Inc., Pfizer Japan Inc. ICON Japan K.K., Ono pharmaceutical Co., Ltd., Daiichi Ssankyo Company Limited, AstraZeneca K. K, EPS Corporation, Green Peptide, PPD-SNBL K.K., Takeda Pharmaceutical Company Limited, Chugai Pharmaceutical Co. Ltd., IQVIA, Mediscience Planning Inc., Osaka Urology Research Foundation, scholarship/encouragement donations from Asahi Kasei Corporation, Kissei Pharmaceutical Co., Ltd., Novartis Pharmaceutical, Pfizer Japan Inc., Astellas Pharma Inc., Ono pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Sanofi K.K., Daiichi Sankyo Co., Ltd.

The following authors are full-time employees of Janssen Pharmaceutical K.K. of Johnson & Johnson: Yosuke Koroki, Yuki Iwaki, and Keiichiro Imanaka; and Janssen Research and Development: Andressa Smith and Angela Lopez-Gitlitz.

Figures

Fig. 1
Fig. 1
Flow diagram representing patient recruitment from SPARTAN, TITAN and PCR1008 studies
Fig. 2
Fig. 2
Kaplan-Meier plot for Time-to-Remission of First Incidence of rash (All Grade). Event: remission of first incidence of rash. Censor: not remission of first incidence of rash at the end of follow-up
Fig. 3
Fig. 3
Kaplan-Meier plot for Time-to-Remission of Maximum Grade Incidence of rash (All grade). Event: remission of maximum Grade incidence of rash. Censor: not remission of maximum Grade incidence of rash at the end of follow-up
Fig. 4
Fig. 4
Plasma-Exposure and Incidence of Rash: Pooled results of Japanese patients from SPARTAN and TITAN studies. a) Apalutamide, b) N-desmethyl apalutamide. Relationships between incidence of rash (by grade) and the plasma exposure (AUC0–24, ss) to apalutamide or N-desmethyl apalutamide were explored using boxplots

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