Apalutamide-induced rash and relative dose intensity in metastatic castration-sensitive prostate cancer: a multicenter Japanese cohort study

Introduction

The advent of androgen receptor signaling inhibitors (ARSIs) has markedly reshaped the therapeutic landscape of metastatic castration-sensitive prostate cancer (mCSPC) (1). Over the past two decades, treatment strategies have progressed from androgen deprivation therapy (ADT) alone, or combined androgen blockade (CAB), toward the integration of ARSIs, chemotherapy, and their combinations, selected according to tumor burden and patient characteristics (2,3). While triplet therapy consisting of ADT, docetaxel, and an ARSI has demonstrated efficacy, particularly in patients with high-volume disease, current international guidelines generally endorse the ARSI plus ADT doublet as the preferred standard of care for mCSPC (4,5).

Among those that are available, apalutamide with ADT has shown clear superiority over placebo plus ADT (6). However, a notably higher incidence of dermatologic adverse events has been reported in Japanese patients (51.5%) (7) compared to subjects in the pivotal SPARTAN (23.8%) (8) and TITAN (27.1%) (6) trials. According to previous studies, the smaller body size of Japanese patients may contribute to increased circulating levels of apalutamide (9,10), but those studies were limited by relatively small sample sizes and the inclusion of both metastatic castration-resistant prostate cancer (mCRPC) and mCSPC populations. Moreover, the potential impact of treatment modification, such as dose reduction or discontinuation, on relative dose intensity (RDI) and its influence on outcomes specifically in the mCSPC setting have not been elucidated.

To address this gap, we focused specifically on patients with mCSPC. We identified clinical and demographic factors associated with the development of apalutamide-induced skin-related adverse events, and examined whether modifications in dose intensity, particularly treatment interruption or dose reduction, affected RDI and oncological outcomes during apalutamide therapy. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-635/rc).

Methods

Patients

We utilized the JIKEI-YAYOI Prostate Cancer Database (11-14). This retrospective, multicenter cohort study included consecutive patients with mCSPC who received apalutamide in combination with ADT at 4 university hospitals and 15 affiliated general hospitals between February 2018 and April 2023. Patients were excluded if they initiated apalutamide at a reduced starting dose [180 mg/day (n=4) or 120 mg/day (n=2)]; only those who commenced treatment at the full standard dose of 240 mg/day were included. Ultimately, 95 patients fulfilled the eligibility criteria and were included in the analysis. Apalutamide was administered orally at 240 mg once daily in 4-week cycles, in combination with ADT using a luteinizing hormone-releasing hormone (LH-RH) analog.

Clinicopathologic data and study outcomes

The primary endpoint was the incidence of apalutamide-induced skin rash and its clinical determinants in patients with mCSPC receiving apalutamide plus ADT as first-line systemic therapy. Clinical and demographic data were retrospectively collected from electronic medical records. Patients were classified into low- and high-volume groups according to the CHAARTED criteria, in which high-volume disease was defined as the presence of visceral metastases or four bone lesions with at least one location beyond the vertebral body and pelvis (15). Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cutoff values for age and body mass index (BMI) in predicting rash development, with Youden’s index [maximum (sensitivity + specificity − 1)] applied to identify thresholds.

The secondary endpoint was the effect of the RDI of apalutamide during treatment on oncological outcomes. The efficacy of apalutamide was assessed by evaluating progression-free survival (PFS), defined as the time to castration-resistant prostate cancer (CRPC) in patients with mCSPC. The time to CRPC progression was defined as the time from initial apalutamide administration to earlier progression detected through imaging or prostate-specific antigen progression, according to the Prostate Cancer Clinical Trials Working Group 3 criteria (16). Patients without progression were censored at the time of death, treatment discontinuation, or last documented follow-up. To clarify the clinical relevance of RDI, outcomes after permanent discontinuation of apalutamide were not considered; therefore, we focused specifically on the treatment period during which apalutamide was administered. RDI was calculated as: total cumulative administered dose of apalutamide/(240 mg × total treatment period). Patients were categorized into three groups according to RDI: RDI =1.00, RDI ≥0.75 and <1.00, and RDI <0.75.

Statistical analysis

Continuous parametric variables are presented as medians with interquartile ranges (IQRs). The chi-square test, Mann-Whitney U test, and Kruskal-Wallis test were used for statistical comparisons between groups or among the groups depending on the characteristics of the data. Univariate logistic regression analyses were conducted to predict the occurrence of skin rash. The cumulative incidences of rash and disease progression were estimated using the Kaplan-Meier method. Predictors of progression were assessed using Cox proportional hazards regression. A two-sided P value <0.05 was considered statistically significant. All statistical analyses were conducted using STATA software, version 13.1 (StataCorp, College Station, TX, USA).

Ethics statement

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Institutional Review Board of The Jikei University School of Medicine (approval No. 33-260[10878]). Given the retrospective nature of the study, the requirement for individual informed consent was waived by the Institutional Review Board.

Results

Patient demographics

In total, 95 patients were included in the study. Among them, 38 (40%) developed rash during apalutamide treatment (Table 1). The median age of the overall cohort was 74 years (IQR, 69–78 years), and the median duration of apalutamide administration was 14 months (IQR, 5–25 months). Significant differences were observed between patients with and without rash: those in the rash group were older and had a lower BMI compared to those in the no-rash group (P=0.048 and 0.049, respectively).

Cumulative incidence of rash and risk factors for rash

During apalutamide treatment, rash occurred in 38 patients, of whom 24 (63.2%) underwent dose reduction (including those who subsequently required treatment discontinuation), whereas 14 patients (36.8%) discontinued apalutamide without prior dose reduction. Among the patients who developed a rash, 13 (34.2%) experienced grade 3 events. The median time to onset of any-grade rash was 2 months (IQR, 2–4 months), and that of grade 3 rash was 3 months (IQR, 2–4 months; Table 2). The cumulative incidence curves demonstrated that the majority of both any-grade and grade 3 rash events occurred within the first 3 months of treatment (Figure 1A,1B). Regarding treatment exposure, 37.7% of patients were able to continue apalutamide at the full dose throughout follow-up. Overall, 8.5% of patients had their doses reduced and 29.5% and 24.2% had their treatments discontinued due to adverse events and disease progression, respectively (Figure 1C).

Figure 1 Incidence of rash and treatment status during apalutamide therapy. (A) Cumulative incidence of any-grade rash. (B) Cumulative incidence of grade 3 rash. (C) Treatment status during apalutamide therapy, including full-dose continuation, dose reduction, and discontinuation. AE, adverse event.

When age and BMI were analyzed as continuous variables in logistic regression, both age [odds ratio (OR) =1.07, P=0.048] and BMI (OR =0.89, P=0.049) emerged as independent predictors of rash (Table S1). ROC curve analysis identified a BMI of 19.7 kg/m² and 68 years of age as exploratory cutoff values for predicting rash occurrence (Figure 2A,2B). The incidence of any-grade rash increased stepwise with the number of risk factors (age ≥68 years and BMI ≤19.7 kg/m²), with rates of 7.7%, 38.1%, and 68.4% for no, one, and two risk factors, respectively (Figure 2C). A similar trend was observed for grade 3 rash (0.0%, 14.3%, and 21.1% for 0, 1, and 2 risk factors, respectively) (Figure 2D).

Figure 2 Risk factors for rash occurrence. (A) ROC curve of BMI for rash occurrence. The red point represents the optimal cutoff with the highest Youden index value (J=0.23; sensitivity =86%, specificity =37%). The AUC was 0.61. (B) ROC curve of age at rash occurrence. The red point represents the optimal cutoff with the highest Youden index value (J=0.25; sensitivity =95%, specificity =30%). The AUC was 0.62. (C) Incidence of any-grade rash according to the number of risk factors (age ≥68 years and BMI ≤19.7 kg/m² as cutoff values). (D) Incidence of grade 3 rash according to the number of risk factors (age ≥68 years and BMI ≤19.7 kg/m² as cutoff values). AUC, area under the curve; BMI, body mass index; ROC, receiver operating characteristic.

Outcome analysis according to RDI

The RDI of apalutamide was calculated for each patient and categorized into three groups: RDI =1.00, RDI ≥0.75 to <1.00, and RDI <0.75 (Figure 3A). The baseline characteristics for the three groups are summarized in the Table S2, with no significant differences observed among the groups.

Figure 3 RDI of apalutamide and progression-free survival. (A) Distribution of RDI values during apalutamide treatment. (B) Kaplan-Meier curves of progression-free survival stratified by RDI categories. RDI, relative dose intensity.

Kaplan-Meier analysis was performed to compare the PFS between patients who underwent dose reduction and those who continued treatment at the full dose. No significant difference in PFS was detected between the groups (P=0.23; Figure 3B). Furthermore, in multivariable analysis, the RDI of apalutamide was not identified as an independent predictor of clinical progression (Table 3).

Discussion

We investigated both the timing and clinical determinants of apalutamide-associated cutaneous adverse events. In line with previous observations, skin toxicities most frequently developed within the first 2 or 3 months after treatment initiation. Low BMI and advanced age were independent predictors of rash. Importantly, the cumulative incidence increased according to the number of risk factors, with the highest risk observed in patients who were both older and had a lower BMI. Furthermore, by evaluating the RDI during apalutamide treatment, we were able to assess the potential impact of dose interruptions and reductions on treatment continuation and tolerability.

In a previous, real-world, Japanese cohort, 55 of 119 patients (46.2%) developed apalutamide-associated rash, representing the highest incidence reported worldwide to date (17). In our cohort, rash occurred in 40% of patients, largely consistent with previous reports. Notably, although China is also located in East Asia, the incidence of rash among Chinese patients seems to be lower than that in Japanese cohorts (7,17,18). A plausible explanation is the smaller body sizes of Japanese patients, which may lead to greater systemic exposure when receiving the same fixed dose of apalutamide (10,19,20). These findings highlight the particular clinical importance of evaluating risk factors for rash in Japanese patients. Our results corroborate these observations by confirming that a low BMI is a predictive factor and further extend current knowledge by identifying advanced age as an additional determinant. This aligns with previous studies that have reported a correlation between older age and apalutamide-induced rash (10,21). Prophylactic use of moisturizing lotion has been recommended to reduce rash risk (22), and the association between age and rash in our study may reflect age-related changes in skin integrity and susceptibility to cutaneous toxicity. Furthermore, pharmacokinetic analyses from a post hoc evaluation of the TITAN trial revealed that higher apalutamide exposure was significantly associated with increased rates of rash and pruritus (23), implying that full-dose therapy may be excessive in susceptible patients. This raises an important clinical consideration: whether dose reduction or initiating treatment at a reduced dose (e.g., 180 mg/day) could mitigate rash risk while maintaining therapeutic efficacy.

In this study, we evaluated the impact of RDI on oncological outcomes. Unlike previous studies that have primarily examined baseline body weight or initial dose adjustments (7,17), we directly assessed the consequences of treatment interruptions and dose reductions during apalutamide therapy. We did not find a significant association between decreased RDI and disease progression, implying that temporary dose modifications in response to adverse events may not compromise therapeutic benefits. Our results support a previous study that found that reduced RDI, even when adjusted for body surface area, did not significantly affect oncological outcomes (21). Similarly, Suzuki et al. (20) identified 3.33 mg/kg as the optimal cutoff dose predicting rash occurrence and reported no significant difference in PFS between patients treated with <3.33 mg/kg and those treated with ≥3.33 mg/kg, thereby supporting the feasibility of dose reduction in selected patients. Nonetheless, a key limitation of these studies is that all patients initially received the full 240-mg daily dose, which precludes assessment of whether starting at a reduced dose might influence PFS. However, Oishi et al. (24) reported no difference in the time to castration resistance between patients initiated on full-dose versus reduced-dose apalutamide, and a recent systematic review further suggested that reduced-dose ARSI-doublet therapy, including apalutamide, does not adversely affect PFS or overall survival (25). Collectively, these findings indicate that early dose reduction in patients at higher risk for adverse events may represent a reasonable, individualized strategy to balance toxicity management with preservation of oncological efficacy.

This study had several limitations. First, its retrospective design is subject to inherent selection bias. Second, the relatively small sample size and limited follow-up period may restrict the generalizability of our findings. Third, follow-up was censored at the time of apalutamide discontinuation; therefore, outcomes after treatment cessation, including overall survival beyond disease progression, could not be evaluated. Fourth, we were unable to account for potential confounders such as comorbidities and concomitant medications. Finally, racial and pharmacogenomic differences warrant caution when extrapolating these results beyond Japanese populations. Prospective studies with larger cohorts and longer follow-up times are required to validate the clinical utility of dose-reduction strategies in mCSPC.

Conclusions

Using age ≥68 years and BMI ≤19.7 kg/m² as cutoffs, we identified a subgroup of patients at elevated risk for apalutamide-induced rash. For such patients, dose reduction, when clinically indicated, may help lower the incidence of adverse events. Furthermore, as our analysis demonstrated that reduced RDI was not an independent predictor of disease progression, careful patient monitoring with timely dose modification or interruption appears to be a safe and effective management approach.

Acknowledgments

The authors thank Textcheck, Inc. for performing English language editing of this manuscript. The authors also thank all members of the Department of Urology, The Jikei University School of Medicine, particularly those from the four university hospitals—Jikei University Hospital, Jikei Kashiwa Hospital, Jikei the 3rd Hospital, and Jikei Katsushika Medical Center—as well as the urologists from the 15 affiliated general hospitals: JR General Hospital, Atsugi City Hospital, Machida Municipal Hospital, Fuji City General Hospital, Tokyo Metropolitan Hiroo Hospital, Yamato Tokushukai Hospital, Tokyo-Kita Medical Center, Nerima Hikarigaoka Hospital, Saitama Hokubu Hospital, Tokyu Hospital, Ohori International Hospital, Makita General Hospital, Ota General Hospital, Kameda General Hospital, and Saitama Jikei Hospital. The authors sincerely appreciate their valuable contributions and collaboration.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-635/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-635/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-635/prf

Funding: This study was supported by a research grant from Nippon Shinyaku Co., Ltd.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-635/coif). All authors declare that this study was supported by a research grant from Nippon Shinyaku Co., Ltd. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Institutional Review Board of The Jikei University School of Medicine (approval No. 33-260[10878]). Given the retrospective nature of the study, the requirement for individual informed consent was waived by the Institutional Review Board.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Westaby D, Fenor de La Maza MLD, Paschalis A, et al. A New Old Target: Androgen Receptor Signaling and Advanced Prostate Cancer. Annu Rev Pharmacol Toxicol 2022;62:131-53. [Crossref] [PubMed]
2. Hoeh B, Garcia CC, Wenzel M, et al. Triplet or Doublet Therapy in Metastatic Hormone-sensitive Prostate Cancer: Updated Network Meta-analysis Stratified by Disease Volume. Eur Urol Focus 2023;9:838-42. [Crossref] [PubMed]
3. Mandel P, Hoeh B, Wenzel M, et al. Triplet or Doublet Therapy in Metastatic Hormone-sensitive Prostate Cancer Patients: A Systematic Review and Network Meta-analysis. Eur Urol Focus 2023;9:96-105. [Crossref] [PubMed]
4. Hussain M, Tombal B, Saad F, et al. Darolutamide Plus Androgen-Deprivation Therapy and Docetaxel in Metastatic Hormone-Sensitive Prostate Cancer by Disease Volume and Risk Subgroups in the Phase III ARASENS Trial. J Clin Oncol 2023;41:3595-607. [Crossref] [PubMed]
5. Tilki D, van den Bergh RCN, Briers E, et al. EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer. Part II-2024 Update: Treatment of Relapsing and Metastatic Prostate Cancer. Eur Urol 2024;86:164-82. [Crossref] [PubMed]
6. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 2019;381:13-24. [Crossref] [PubMed]
7. Uemura H, Koroki Y, Iwaki Y, et al. 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. BMC Urol 2020;20:139. [Crossref] [PubMed]
8. 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. [Crossref] [PubMed]
9. Uemura H, Satoh T, Tsumura H, et al. 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. Prostate Int 2020;8:190-7. [Crossref] [PubMed]
10. Katsuta M, Kimura T, Tashiro K, et al. Low Body Weight as a Risk Factor for Apalutamide-related Cutaneous Adverse Events. Anticancer Res 2022;42:2023-8. [Crossref] [PubMed]
11. Urabe F, Muramoto K, Yanagisawa T, et al. Changes in the treatment landscape of metastatic hormone-sensitive prostate cancer following approval of upfront androgen receptor signaling inhibitors: A multicenter study. Int J Urol 2024;31:1248-55. [Crossref] [PubMed]
12. Urabe F, Tashiro K, Muramoto K, et al. Locations of metastases in and oncological outcomes of patients with metastatic castration-sensitive prostate cancer: Real-world data from a multicenter study. Urol Oncol 2025;43:336.e1-336.e11. [Crossref] [PubMed]
13. Urabe F, Imai Y, Goto Y, et al. Real-world evidence of triplet therapy efficacy in patients with metastatic castration-sensitive prostate cancer: a Japanese multicenter study. Jpn J Clin Oncol 2024;54:1208-13. [Crossref] [PubMed]
14. Urabe F, Kagawa H, Yanagisawa T, et al. Comparative adverse event profiles of triplet therapy versus docetaxel-based therapy in patients with metastatic prostate cancer: a multicenter retrospective study. Prostate Int 2025;13:41-8. [Crossref] [PubMed]
15. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med 2015;373:737-46. [Crossref] [PubMed]
16. Scher HI, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol 2016;34:1402-18. [Crossref] [PubMed]
17. Tohi Y, Kato T, Fukuhara H, et al. Real-world analysis of apalutamide-associated skin adverse events in Japanese patients with advanced prostate cancer: a multi-institutional study in the Chu-shikoku Japan Urological Consortium. Int J Clin Oncol 2022;27:1348-55. [Crossref] [PubMed]
18. Yang Z, Shao Y, Huang H, et al. Real-world analysis of apalutamide-associated skin rash in Chinese patients with prostate cancer. World J Urol 2024;42:171. [Crossref] [PubMed]
19. Sasaki D, Hatakeyama S, Tanaka T, et al. Impact of body size on skin-related adverse events in advanced prostate cancer treated with apalutamide: A multicenter retrospective study. Int J Urol 2022;29:772-3. [Crossref] [PubMed]
20. Suzuki K, Shiraishi Y, Okamura Y, et al. Dose Per Body Weight Predicts Incidence and Severity of Apalutamide-Related Skin Rash in Metastatic Castration-Sensitive Prostate Cancer. Clin Genitourin Cancer 2025;23:102250. [Crossref] [PubMed]
21. Akagi N, Obayashi R, Yamamoto A, et al. Skin rash induced by apalutamide correlated with age and relative dose intensity adjusted by body surface area in Japanese patients with prostate cancer. Jpn J Clin Oncol 2025;55:963-9. [Crossref] [PubMed]
22. Hashimoto K, Shindo T, Nishida S, et al. Management of apalutamide-induced rash with focus on early peaks. Int J Urol 2025;32:113-5. [Crossref] [PubMed]
23. T'jollyn H, Ackaert O, Chien C, et al. Efficacy and safety exposure-response relationships of apalutamide in patients with metastatic castration-sensitive prostate cancer: results from the phase 3 TITAN study. Cancer Chemother Pharmacol 2022;89:629-41. [Crossref] [PubMed]
24. Oishi T, Hatakeyama S, Tabata R, et al. Effects of apalutamide dose reduction on skin-related adverse events in patients with advanced prostate cancer: A multicenter retrospective study. Prostate 2023;83:198-203. [Crossref] [PubMed]
25. Bromley HL, Varughese M, Gilbert DC, et al. Comparison of standard-dose and reduced-dose treatment of metastatic prostate cancer with enzalutamide, apalutamide or darolutamide: a rapid review. BMJ Oncol 2024;3:e000198. [Crossref] [PubMed]