Efficacy and safety of apalutamide in Japanese patients with nonmetastatic castration-resistant prostate cancer: a subgroup analysis of a randomized, double-blind, placebo-controlled, Phase-3 study

Uemura, Hiroji; Satoh, Takefumi; Tsumura, Hideyasu; Arai, Gaku; Imanaka, Keiichiro; Shibayama, Kazuhiro; Fujii, Koji; Rooney, Brendan; Lopez-Gitlitz, Angela; Espina, Byron M.; Pérez-Ruixo, Carlos; Small, Eric J.; Smith, Matthew R.

doi:10.1016/j.prnil.2020.05.002

Cited by 20 publications

(32 citation statements)

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“…Apalutamide-related skin rash has been observed in previous studies, with a higher incidence of skin rash observed in the Japanese subpopulation compared to overall global population. In the global SPARTAN and TITAN studies, and the Japanese subpopulation analysis from these studies [5], [Uemura et al, International Journal of Urology, submitted], Grade 3 rash (covering > 30% of the body surface) was observed more frequently with apalutamide [3,4]. In the current integrated analysis, the incidence of Grade 3 rash (14.7%) was also higher than in the global SPAR TAN and TITAN studies (combined incidence, 5.8%).…”

Section: Discussionmentioning

confidence: 47%

“…Interestingly, the subgroup analysis of Japanese patients in both the SPARTAN and TITAN studies showed that a greater proportion of patients treated with apalutamide developed skin rash compared with placebo (SPARTAN subgroup: 56.0% vs 0.0%; TITAN subgroup: 50.0% vs 8.7%) [5], [Uemura et al, International Journal of Urology, submitted], with the incidence in Japanese patients being nearly double the incidence observed in the global populations of the two studies. In a Phase 1 trial (56021927PCR1008, referred hereafter as PCR1008) conducted to study the safety, efficacy and pharmacokinetic (PK) profile of apalutamide in Japanese patients with metastatic CRPC (mCRPC) (NCT02162836) [6], skin rash was observed in 2/6 (33.3%) patients.…”

Section: Introductionmentioning

confidence: 99%

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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

Uemura

Koroki²,

Iwaki³

et al. 2020

BMC Urol

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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.

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Section: Discussionmentioning

confidence: 47%

Section: Introductionmentioning

confidence: 99%

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

Uemura

Koroki²,

Iwaki³

et al. 2020

BMC Urol

Self Cite

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show abstract

“…Apalutamide-related skin rash has been observed in previous studies, with a higher incidence of skin rash observed in the Japanese subpopulation compared to overall global population. In the global SPARTAN and TITAN studies, and the Japanese subpopulation analysis from these studies [5], [Uemura et al, International Journal of Urology, submitted], Grade 3 rash (covering >30% of the body surface) was observed more frequently with apalutamide. [3,4] In the current integrated analysis, the incidence of Grade 3 rash (14.7%) was also higher than in the global SPARTAN and TITAN studies (combined incidence, 5.8%).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the subgroup analysis of Japanese patients in both the SPARTAN and TITAN studies showed that a greater proportion of patients treated with apalutamide developed skin rash compared with placebo (SPARTAN subgroup: 56.0% vs 0.0%; TITAN subgroup: 50.0% vs 8.7%) [5], [Uemura et al, International Journal of Urology, submitted], with the incidence in Japanese patients being nearly double the incidence observed in the global populations of the two studies. In a Phase 1 trial (56021927PCR1008, referred hereafter as PCR1008) conducted to study the safety, e cacy and pharmacokinetic (PK) pro le of apalutamide in Japanese patients with metastatic CRPC (mCRPC) (NCT02162836) [6], skin rash was observed in 2/6 (33.3%) patients.…”

Section: Introductionmentioning

confidence: 99%

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

Uemura

Koroki

Iwaki

et al. 2020

Preprint

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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 hours) (AUC 0-24, 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.

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“…reported the survival advantage of combined androgen blockade with vintage drugs for Japanese metastatic prostate cancer patients 4 . In the current Japanese subgroup analysis of the TITAN trial, although there are trends toward the clinical benefit of the upfront apalutamide treatment arm compared with a placebo, no significant difference was observed in terms of rPFS or OS 5 . However, the major limitation was that clinical trials were not designed to calculate the statistical significance in the Japanese subgroup.…”

mentioning

confidence: 93%

Editorial Comment to Apalutamide for metastatic, castration‐sensitive prostate cancer in the Japanese population: A subgroup analysis of the randomized, double‐blind, placebo‐controlled phase 3 TITAN study

Sakamoto

2020

Int J of Urology

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A paradigm shift has taken place in the treatment strategy of prostate cancer, especially in de novo metastatic prostate cancer. The CHAARTED trial in 2015 1 and the LATTITUDE trial in 2017 2 proposed the clinical benefit of early intensive treatment with docetaxel or abiraterone in de novo metastatic prostate cancer. These two studies also defined the specific risk group among metastatic prostate cancer patients, such as high-volume and high-risk patients, which should benefit from upfront treatment. In the year 2020, the ENZAMET, ARCHES and TITAN trials released the results of randomized control trials. Among the several novel findings, one of the distinguished points might be that these trials allowed entry of any metastatic prostate cancer regardless of risk criteria. The benefit of upfront treatment with androgen receptor axis-targeted agents for overall survival (OS) was shown in the ENZAMET trial and TITAN trial, whereas the benefit in radiographic progressionfree survival (rPFS) was shown in the ARCHES trial. These results guide us toward upfront treatment with androgen receptor axis-targeted agents in de novo metastatic prostate cancer. Now, androgen receptor axis-targeted agents do not mainly apply to metastatic castration-resistant prostate cancer, but also cover metastatic hormone-sensitive prostate cancer. One of the open questions is "How to translate the results of the global randomized control trials in the Asian population, including Japanese." Fukagai et al. demonstrated that Japanese advanced prostate cancer patients showed a favorable response rate to androgen deprivation therapy compared with that of white patients. 3 Kadono et al. reported the survival advantage of combined androgen blockade with vintage drugs for Japanese metastatic prostate cancer patients. 4 In the current Japanese subgroup analysis of the TITAN trial, although there are trends toward the clinical benefit of the upfront apalutamide treatment arm compared with a placebo, no significant difference was observed in terms of rPFS or OS. 5 However, the major limitation was that clinical trials were not designed to calculate the statistical significance in the Japanese subgroup. Therefore, the result of no significant P-value does not represent the absence of clinical significance. When looking at the hazard ratio (HR) between the Japanese subgroup and the overall population, the HR of OS was rather similar between the Japanese subgroup and the overall

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Efficacy and safety of apalutamide in Japanese patients with nonmetastatic castration-resistant prostate cancer: a subgroup analysis of a randomized, double-blind, placebo-controlled, Phase-3 study

Cited by 20 publications

References 11 publications

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

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

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

Editorial Comment to Apalutamide for metastatic, castration‐sensitive prostate cancer in the Japanese population: A subgroup analysis of the randomized, double‐blind, placebo‐controlled phase 3 TITAN study

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