Efficacy and Safety Exposure–Response Relationships of Apalutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer

Abstract

Purpose: To evaluate the relationship between exposure of apalutamide and its active metabolite, N-desmethyl-apalutamide, and selected clinical efficacy and safety parameters in men with high-risk nonmetastatic castration-resistant prostate cancer. Patients and Methods: An exploratory exposure-response analysis was undertaken using data from the 1,207 patients (806 apalutamide and 401 placebo) enrolled in the SPARTAN study, including those who had undergone dose reductions and dose interruptions. Univariate and multivariate Cox regression models evaluated the relationships between apalutamide and N-desmethyl-apalutamide exposure, expressed as area under the concentration-time curve at steady state, and metastasis-free survival (MFS). Univariate and multivariate logistic regression models assessed the relationship between apalutamide and N-desmethyl-apalutamide exposure and common treatment-emergent adverse events including fatigue, fall, skin rash, weight loss, and arthralgia. Results: A total of 21% of patients in the apalutamide arm experienced dose reductions diminishing the average daily dose to 209 mg instead of 240 mg. Within the relatively narrow exposure range, no statistically significant relationship was found between MFS and apalutamide and N-desmethyl-apalutamide exposure. Within apalutamide-treated subjects, skin rash and weight loss had a statistically significant association with higher apalutamide exposure. Conclusions: The use of apalutamide at the recommended dose of 240 mg once daily provided a similar delay in metastases across the SPARTAN patient population, regardless of exposure. The exploratory exposure-safety analysis supports dose reductions in patients experiencing adverse events.

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

“…However, the results should be interpreted with caution due to the limited sample size. The exposure-response modeling analysis for SPARTAN study based on whole study population was reported in a separate article [10].…”

Apalutamide‐associated skin rash in patients with prostate cancer: Histological evaluation by skin biopsy

“…There is no difference in metastasis-free survival between the initial dose of 240 mg of apalutamide and the adjusted dose. 4 These results suggest that dose reduction or discontinuation of apalutamide does not have a negative effect on its efficacy. In a phase III clinical study of apalutamide, body weight was lower in the Japanese population (median 61.9 kg) compared to the global population (median 1,11 The initial dose of 240 mg of apalutamide may be too high for Japanese patients.…”

“…Of note, the skin rash has a statistically significant association with a higher dose of apalutamide, or its active metabolite exposure. 4 In addition, the frequency of the skin rash is much higher during treatment with apalutamide than with other antiandrogens. 10 These findings prompted us to consider that the apalutamide-associated skin rash might not be attributed to allergic reactions, but a structure-specific, off-target pharmacological reaction.…”

“…[1][2][3] In most cases, the rash is dose-dependent, and requires dose reduction or discontinuation during treatment in the affected cases. 4 However, the mechanism of this common adverse event remains elusive, and limited histopathological information hampers further understanding. We present two representative cases of apalutamide-associated skin rash that was evaluated histologically.…”

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

“…The exposure-response modeling analysis for SPARTAN study based on whole study population was reported in a separate article. [10] Recently, the National Comprehensive Cancer Network (NCCN) guidelines were updated to recommend apalutamide or enzalutamide, another second-generation antiandrogen, in patients with nmCRPC with background ADT therapy.…”