Abstract
Background
Skin rash is a common adverse event in patients with metastatic hormone-sensitive prostate cancer (mHSPC) treated with apalutamide. This study aims to investigate the incidence rate of skin rash and the predictive value of inflammation markers for skin rash in real-world Korean patients.
Materials and Methods
We conducted a retrospective analysis of patients with prostate cancer (PCa) who received apalutamide across 18 institutions in Korea, with a follow-up period of at least three months. A total of 218 patients were evaluated.
Results
Among the 214 patients analyzed, 78 (36.4%) developed a skin rash. The severity of the rash was classified as grade 1 (G1) in 27 patients (12.6%), grade 2 (G2) in 29 patients (13.5%), and grade 3 (G3) in 22 patients (10.3%). The median time to onset of any skin rash was 65.5 days (interquartile range, IQR 31.0-88.0). The monocyte-to-lymphocyte ratio (MLR) and systemic immune-inflammation response index (SIRI) were significantly higher in the G2 plus G3 group compared to the no rash plus G1 group (p=0.006, p=0.013, respectively) before apalutamide treatment. After 3 months, platelet-to-lymphocyte ratio (PLR) and SIRI were significantly higher in the G2 plus G3 group compared to the no rash plus G1 group (p=0.010, p=0.025, respectively)
Conclusions
In a real-world cohort of Korean patients, skin rash occurred in 36.4% of cases, with a median time to onset of 65.5 days. Grade 3 skin rash developed in 10.3% of cases. While MLR and SIRI were significantly higher in the G2 plus G3 group, these markers cannot be considered reliable predictors due to a low area under the curve (AUC < 0.7) before apalutamide treatment. However, increased levels of PLR, SII, and SIRI could potentially be useful for monitoring for the risk of severe rash development in these patients.
Keywords: Apalutamide, Prostatic neoplasms, Neoplasm metastasis
1. Introduction
Prostate cancer (PCa) is the most commonly diagnosed cancer among men in the United States, with an estimated 288,300 new cases and 34,700 deaths are anticipated in 2023.1 The incidence of PCa diagnosed with distant metastasis (metastatic hormone-sensitive PCa, mHSPC) was approximately 8% in the United States from 2015 to 2019. The 5-year survival rate for patients with mHSPC from 2012 to 2018 was about 32%.1
Traditionally, androgen deprivation therapy (ADT) was the standard treatment for mHSPC until 2015.2 Since then, the combination of ADT with abiraterone, enzalutamide, or apalutamide has become the mainstay of treatment for mHSPC.3,4 These combinations have also been associated with improved oncological outcomes in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) in a real-world setting, regardless of tumor aggressiveness.5
Apalutamide is a novel, nonsteroidal, competitive inhibitor of the androgen receptor (AR) that works by binding directly to the ligand-binding domain of AR. This prevents AR translocation from the cytoplasm to the nucleus and inhibits AR-dependent gene transcription.6 In patients with metastatic castration-resistant prostate cancer (mCRPC), apalutamide combined with ADT was effective in extending progression-free survival (PFS) and overall survival (OS) compared to placebo plus ADT.7 The combination of ADT with apalutamide has demonstrated significant oncological benefits in patients with mHSPC, with rapid and profound PSA responses serving as potential predictors of improved oncological and survival outcomes.8 In the SPARTAN and TITAN trials, the incidence of rash was reported as 23.8% and 27.1%, respectively.9,10 Moreover, real-world data revealed higher incidences of skin rash, with rates of 46.2% in Japan and 32% in China, compared to the SPARTAN and TITAN trials.11,12
Inflammatory markers, such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), have been employed to predict the presence and severity of various cancers and dermatologic conditions.13, 14, 15, 16, 17, 18, 19 Increased neutrophil and platelet counts relative to lymphocyte counts are particularly indicative of acute inflammation. NLR has been associated with numerous inflammatory dermatologic diseases, including urticaria, vitiligo, rosacea, erythema nodosum, dermatomyositis, psoriasis, systemic lupus erythematosus, acne vulgaris, and atopic eczema.13, 14, 15, 16, 17 However, no studies have yet investigated the association between skin rash and inflammatory markers in patients with prostate cancer (PCa) undergoing treatment with apalutamide. This study aims to assess the incidence of skin rash and evaluate the predictive value of inflammatory markers in forecasting skin rash in real-world Korean patients.
2. Materials and methods
2.1. Patients
Apalutamide has been approved for the treatment of mHSPC in Korea since April 2023. We conducted a retrospective analysis of patients with PCa who received apalutamide at 18 institutions, with a minimum follow-up period of three months. A total of 218 patients were evaluated. The study protocol was approved by the Ethics Committee of Chungbuk National University Hospital (IRB approval number: 2024-07-033-001). The Institutional Review Board of Chungbuk National University Hospital approved the sample collection and analysis procedures.
2.2. Study variables
We retrospectively collected patient characteristics, including age, medical history (diabetes, hypertension, rheumatic disease, allergy, infectious disease), prostate size, Gleason score at initial diagnosis, metastasis (LN, bone, lung, liver), prostate-specific antigen (PSA) levels, complete blood count (CBC), and chemistry before and after apalutamide treatment, apalutamide treatment date, last follow-up date, apalutamide-associated skin rash onset date, and clinical characteristics of the skin rash from medical records.
The following parameters were evaluated: incidence and severity of skin rash, time to onset of skin rash, changes in PSA levels before and after apalutamide treatment, inflammation markers before and after apalutamide treatment, and changes in CBC profiles before and after apalutamide treatment.
Inflammation markers were calculated from CBC data using the following formulas:
| Neutrophil-to-lymphocyte ratio (NLR) = absolute neutrophil count (ANC) / absolute lymphocyte count (ALC) |
| Platelet-to-lymphocyte ratio (PLR) = absolute platelet count (APC) / ALC |
| Monocyte-to-lymphocyte ratio (MLR) = absolute monocyte count (AMC) / ALC |
| Neutrophil-to-monocyte-plus-lymphocyte ratio (NMLR) = ANC / (AMC + ALC) |
| Derived neutrophil-to-lymphocyte ratio (d_NLR) = ANC / (white blood cell count (WBC) – ANC) |
| Systemic immune-inflammation index (SII) = (ANC x APC) / ALC |
| Systemic inflammatory response index (SIRI) = (ANC x AMC) / ALC |
2.3. Statistical analysis
Quantitative variables are presented as means with standard deviation (SD) or medians with interquartile range (IQR). Data were compared between groups using the chi-square or Fisher's exact test for categorical variables and the Student's t-test or Mann–Whitney U test for continuous variables. Statistical significance was set at P < 0.05. All statistical analyses were performed using SPSS for Windows version 27.0 (IBM Corp., Armonk, NY, USA) and Python with Google Colaboratory (Google, San Francisco, CA, USA).
3. Results
3.1. Baseline characteristics and skin rash
Out of 214 patients, 78 (36.4%) developed a skin rash. The severity of the rash was classified as grade 1 (G1) in 27 patients (12.6%), grade 2 (G2) in 29 patients (13.5%), and grade 3 (G3) in 22 patients (10.3%). The median time to onset of any skin rash was 65.5 days (IQR 31.0-88.0), with G1 at 77.0 days (interquartile range, IQR 28.0-86.0), G2 at 84 days (IQR 43.0-94.5), and G3 at 58.5 days (IQR 28.0-82.5). Patient baseline characteristics are shown in Table 1.
Table 1.
Baseline characteristics
| No skin rash group (N = 136) | Skin rash group (N = 78) | P | |
|---|---|---|---|
| Age (mean) | 71.21 ± 8.929 | 74.87 ± 8.635 | 0.004 |
| Prostate size, g (mean) | 54.71 ± 42.81 | 60.87 ± 46.10 | 0.352 |
| Diabetes history, n (%) | 0.063 | ||
| No | 90 (59.6) | 61 (40.4) | |
| Yes | 46 (73.0) | 17 (27.0) | |
| Hypertension history, n (%) | 0.878 | ||
| No | 66 (64.1) | 37 (35.9) | |
| Yes | 70 (63.1) | 41 (36.9) | |
| Rheumatic dis. history, n (%) | 0.189 | ||
| No | 133 (63.3) | 77 (36.7) | |
| Yes | 3 (100.0) | 0 (0.0) | |
| Missing | 0 (0.0) | 1 (100.0) | |
| Allergy history, n (%) | 0.307 | ||
| No | 131 (63.0) | 77 (37.0) | |
| Yes | 5 (83.3) | 1 (16.7) | |
| Infection dis. history, n (%) | 0.867 | ||
| No | 133 (63.6) | 76 (36.4) | |
| Yes | 3 (60.0) | 2 (40.0) | |
| GS at initial diagnosis | 0.471 | ||
| 6 | 0 (0.0) | 1 (100.0) | |
| 7 | 14 (60.9) | 9 (39.1) | |
| 8 | 49 (60.5) | 32 (39.5) | |
| 9 | 59 (69.4) | 26 (30.6) | |
| 10 | 7 (58.3) | 5 (41.7) | |
| Missing | 7 (58.3) | 5 (41.7) | |
| LN metastasis | 0.500 | ||
| No | 48 (66.7) | 24 (33.3) | |
| Yes | 88 (62.0) | 54 (38.0) | |
| Bone metastasis | 0.962 | ||
| No | 31 (63.3) | 18 (36.7) | |
| Yes | 105 (63.6) | 60 (36.4) | |
| Lung metastasis | 0.835 | ||
| No | 108 (63.9) | 61 (36.1) | |
| Yes | 28 (62.2) | 17 (37.8) | |
| Liver metastasis | 0.867 | ||
| No | 133 (63.6) | 76 (36.4) | |
| Yes | 3 (60.0) | 2 (40.0) |
GS, Gleason score.
3.2. Changes in PSA levels before and after apalutamide treatment
In the no skin rash group, the mean PSA levels pre-apalutamide, after 1 month, 2 months, and 3 months were 272.0 ± 583.7, 12.6 ± 28.3, 6.4 ± 15.4, and 3.7 ± 10.9 ng/dL, respectively. In the skin rash group, the mean PSA levels pre-apalutamide, after 1 month, 2 months, and 3 months were 521.1 ± 1114.2, 41.0 ± 119.8, 9.4 ± 19.0, and 4.3 ± 10.0 ng/dL, respectively (Table 2).
Table 2.
Change of PSA levels before and after apalutamide treatment (excluded pre-apalutamide PSA less than 10 ng/dL)
| Pre-apalutamide |
After 1 mo |
After 2 mo |
After 3 mo |
|||||
|---|---|---|---|---|---|---|---|---|
| PSA | P | PSA | P | PSA | P | PSA | P | |
| Skin rash | 0.066 | 0.048 | 0.389 | 0.764 | ||||
| No | 272.0 ± 583.7 (n = 97) | 12.6 ± 28.3 (n = 76) | 6.4 ± 15.4 (n = 54) | 3.7 ± 10.9 (n = 76) | ||||
| Yes | 521.1 ± 1114.2 (n = 64) | 41.0 ± 119.8 (n = 56) | 9.4 ± 19.0 (n = 42) | 4.3 ± 10.0 (n = 58) | ||||
PSA, prostate specific antigen.
3.3. Inflammation markers before apalutamide treatment
No significant differences in inflammation markers were observed between the no skin rash group and the skin rash group before apalutamide treatment (Table 3). However, MLR and SIRI were significantly higher in the G2 plus G3 group compared to the no rash plus G1 group (P = 0.006, P = 0.013, respectively) (Table 4).
Table 3.
Pre-apalutamide results of inflammation markers between no skin rash group and skin rash group
| No skin rash group (N = 123) | Skin rash group (N = 73) | P | |
|---|---|---|---|
| NLR | 2.806 ± 2.409 | 2.914 ± 2.071 | 0.749 |
| PLR | 146.320 ± 64.813 | 140.564 ± 63.474 | 0.545 |
| MLR | 0.337 ± 0.153 | 0.358 ± 0.182 | 0.402 |
| NMLR | 2.007 ± 1.229 | 2.073 ± 1.240 | 0.717 |
| dNLR | 1.856 ± 1.143 | 1.934 ± 1.221 | 0.650 |
| SII | 684.573 ± 865.136 | 642.566 ± 541.249 | 0.709 |
| SIRI | 21.681 ± 13.276 | 23.221 ± 14.718 | 0.452 |
dNLR, derivate Neutrophil-to-Lymphocyte Ratio; MLR, Monocyte-to-Lymphocyte Ratio; NLR, Neutrophil-to-Lymphocyte Ratio; NMLR, Neutrophil-to-Monocyte-plus-Lymphocyte Ratio; PLR, Platelet-to-Lymphocyte Ratio; SII, Systemic immune-inflammation index; SIRI, Systemic inflammatory response index.
Table 4.
Pre-apalutamide results of inflammation markers between no-skin rash plus grade 1 and grade 2 plus 3 skin rash in patients with apalutamide (no + G1 vs. G2+G3)
| No rash + G1 group (N = 147) | G2 + G3 group (N = 49) | P | |
|---|---|---|---|
| NLR | 2.750 ± 2.330 | 3.135 ± 2.137 | 0.308 |
| PLR | 142.729 ± 62.596 | 148.517 ± 69.340 | 0.586 |
| MLR | 0.326 ± 0.147 | 0.400 ± 0.199 | 0.006 |
| NMLR | 1.993 ± 1.266 | 2.147 ± 1.122 | 0.449 |
| dNLR | 1.847 ± 1.197 | 1.999 ± 1.089 | 0.434 |
| SII | 655.380 ± 804.053 | 709.570 ± 612.175 | 0.666 |
| SIRI | 20.843 ± 12.633 | 26.488 ± 16.288 | 0.013 |
dNLR, derivate Neutrophil-to-Lymphocyte Ratio; G1, grade 1; G2, grade 2; MLR, Monocyte-to-Lymphocyte Ratio; NLR, Neutrophil-to-Lymphocyte Ratio; NMLR, Neutrophil-to-Monocyte-plus-Lymphocyte Ratio; PLR, Platelet-to-Lymphocyte Ratio; SII, Systemic immune-inflammation index; SIRI, Systemic inflammatory response index.
3.4. Changes in neutrophil, lymphocyte, monocyte, and eosinophil counts before and after apalutamide treatment between no rash plus grade 1 groups and grade 2 plus grade 3 groups
Before apalutamide treatment, there were no significant differences in neutrophil, lymphocyte, monocyte, and eosinophil counts between the two groups. After apalutamide treatment, there were no significant differences in neutrophil counts between the two groups. However, lymphocyte counts were significantly lower in the G2 plus G3 group compared to the no rash plus G1 group (after 1 month, P < 0.001; after 2 months, P < 0.005; after 3 months, P = 0.002). Monocyte counts were higher in the G2 plus G3 group after 3 months (P < 0.001). Eosinophil counts were higher in the G2 plus G3 group after 2 and 3 months (P = 0.011, P < 0.001, respectively) (Table 5) (Fig. 1).
Table 5.
Change of neutrophil, lymphocyte, monocyte, and eosinophil before and after apalutamide treatment (no + G1 vs. G2+G3).
| Pre-apalutamide (N = 147 vs 49) | P | After 1 mo (N = 126 vs 45) | P | After 2 mo (N = 85 vs 36) | P | After 3 mo (N = 132 vs 47) | P | |
|---|---|---|---|---|---|---|---|---|
| Neutrophil | 0.841 | 0.435 | 0.267 | 0.082 | ||||
| No + G1 | 4423.8 ± 2643.2 | 3358.0 ± 1525.0 | 3154.5 ± 1322.5 | 3112.9 ± 1049.0 | ||||
| G2 + G3 | 4506.5 ± 2007.1 | 3151.8 ± 1487.2 | 3446.1 ± 1293.5 | 3505.1 ± 1885.3 | ||||
| Lymphocyte | 0.100 | <0.001 | 0.005 | 0.002 | ||||
| No + G1 | 1807.9 ± 616.0 | 1701.7 ± 572.0 | 1608.4 ± 654.4 | 1646.4 ± 724.6 | ||||
| G2 + G3 | 1641.4 ± 593.4 | 1336.3 ± 566.4 | 1275.7 ± 395.6 | 1287.1 ± 542.5 | ||||
| Monocyte | 0.303 | 0.947 | 0.052 | <0.001 | ||||
| No + G1 | 551.2 ± 218.4 | 541.3 ± 172.3 | 546.3 ± 187.3 | 522.8 ± 184.7 | ||||
| G2 + G3 | 587.7 ± 200.4 | 543.4 ± 203.8 | 622.6 ± 214.4 | 657.4 ± 276.3 | ||||
| Eosinophil | 0.566 | 0.951 | 0.011 | <0.001 | ||||
| No + G1 | 165.4 ± 146.7 | 251.8 ± 226.6 | 228.8 ± 190.0 | 276.9 ± 425.1 | ||||
| G2 + G3 | 151.7 ± 137.1 | 255.2 ± 493.3 | 620.7 ± 1373.2 | 669.8 ± 931.5 |
G1, grade 1; G2, grade 2; G3, grade 3.
Fig. 1.
Changes in neutrophil, lymphocyte, monocyte, and eosinophil counts before and after apalutamide treatment between no rash plus grade 1 groups and grade 2 plus grade 3 groups.
3.5. Changes in inflammation markers before and after apalutamide treatment between no rash plus grade 1 groups and grade 2 plus grade 3 groups
After 1 month, MLR and SIRI were significantly higher in the G2 plus G3 group compared to the no rash plus G1 group (P = 0.011, P = 0.010, respectively), consistent with the results before apalutamide treatment. At 2 months, PLR and SII were significantly higher in the G2 plus G3 group compared to the no rash plus G1 group (P = 0.007, P = 0.002, respectively). After 3 months, PLR and SIRI were significantly higher in the G2 plus G3 group compared to the no rash plus G1 group (P = 0.010, P = 0.025, respectively) (Fig. 2).
Fig. 2.
Changes in inflammation markers before and after apalutamide treatment between no rash plus grade 1 groups and grade 2 plus grade 3 groups.
4. Discussion
This study examined the clinical characteristics and efficacy of inflammation markers for predicting apalutamide-associated skin rash in Korean patients from multiple institutions. Skin rash was observed in 36.4% of patients, with a median time to onset of 65.5 days. Grade 2 rash was observed in 13.5%, and grade 3 rash in 10.3%. The incidence of skin rash in this study was higher than in the SPARTAN and TITAN clinical trials (23.8% and 27.1%, respectively) and the real-world Chinese population (32%).9,10,12 However, the incidence was lower than in the Japanese cohort in the SPARTAN and TITAN trials (51.5%) and the real-world Japanese population (46.2%).11,20 This study is the first to investigate apalutamide-associated skin rash in real-world Korean patients and to examine inflammation markers for predicting skin rash.
Skin rash is the most common adverse event associated with apalutamide. Pan et al. reported that 23.4% of patients treated with apalutamide experienced all-grade adverse events, with a median onset of 77 days postexposure.21 Cremante et al. reported a lichenoid reaction in a 57-year-old patient with m0CRPC treated with apalutamide.22 Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous drug-related adverse event. Honda et al. reported the first case of skin rash with clinical features of AGEP during apalutamide treatment.23 Flynn et al. reported Stevens-Johnson syndrome or toxic epidermal necrolysis (TEN) in an 83-year-old Caucasian male.24
Histopathological examination of apalutamide-associated skin rash from skin biopsy demonstrated spongiosis of the epidermis, along with perivascular and interstitial infiltration of lymphocytes and eosinophils in the upper dermis, without evidence of necrotic keratinocytes.25 Consequently, we explored the role of inflammatory markers in patients treated with apalutamide. Inflammatory markers have been widely used to predict the severity of various diseases.26, 27, 28, 29 We hypothesized that changes in complete blood count (CBC) profiles and inflammatory markers would occur before and after apalutamide treatment, and that significant differences might exist between patients with and without skin rash. However, no significant differences were observed in inflammatory markers between the no rash and skin rash groups prior to apalutamide treatment.
To further investigate, we divided patients into two groups: no rash plus G1, and G2 plus G3, as G1 rashes were considered mild and likely not significantly different from the no rash group. Our findings revealed that MLR and SIRI were significantly higher in the G2 plus G3 group compared to the no rash plus G1 group. However, no significant differences in CBC profiles, including neutrophils, lymphocytes, monocytes, and eosinophils, were detected prior to apalutamide treatment.
Monocytes and macrophages are key innate immune cells that play a critical role in the inflammatory response.30 Monocytes originate from a well-defined differentiation pathway of monocyte progenitors in the bone marrow (BM), and are traditionally considered precursors to tissue-resident macrophages (TRMs).31 During inflammation, circulating monocytes from the BM infiltrate inflamed tissues and differentiate into macrophages.32 Therefore, an increase in monocyte levels may contribute to heightened inflammatory responses, such as skin rash, potentially exacerbating inflammation.
Post-apalutamide treatment, lymphocyte counts were consistently lower in the G2 plus G3 group compared to the no rash plus G1 group (at 1, 2, and 3 months), while monocyte and eosinophil counts were higher in the G2 plus G3 group after 3 months. Eosinophils are known to play pivotal roles in the pathogenesis of allergic and inflammatory disorders.33 Additionally, rare cases of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome have been reported following apalutamide treatment, suggesting that eosinophils may contribute to dermatologic adverse reactions induced by the drug.34 Histopathological examination of apalutamide-associated skin rashes revealed interstitial infiltration of lymphocytes in the upper dermis,25 which may explain the decreased circulating lymphocyte levels in patients with severe skin rash. However, the precise mechanisms underlying increased circulating eosinophils and decreased lymphocytes require further elucidation.
Despite these findings, the area under the curve (AUC) for MLR and SIRI was less than 0.7, indicating that they may not be reliable predictors of severe skin rash. Additionally, our results suggest that PLR, SII, and SIRI were significantly elevated in the G2 plus G3 group following apalutamide treatment. Therefore, increased levels of PLR, SII, and SIRI could potentially be useful for monitoring for the risk of severe rash development in these patients.
This multi-institutional study has several limitations. First, some institutions have upper limits for PSA values, such as 1,000, 5,000, or 1,460 ng/dL. Among the patients, nine had values of 1,000, one had 5,000, and one had >1,460, so the actual PSA levels before apalutamide treatment could be higher. Second, this is a retrospective study. As a result, PSA and CBC profiles after 1, 2, and 3 months could not be collected for all patients, as the protocol for PSA and CBC testing differed by institution. Therefore, the missing data could introduce potential biases that may influence the results of this study.
5. Conclusions
In a real-world cohort of Korean patients, skin rash occurred in 36.4% of cases, with a median time to onset of 65.5 days. Grade 3 skin rash developed in 10.3% of cases. While MLR and SIRI were significantly higher in the G2 plus G3 group, these markers cannot be considered reliable predictors due to a low area under the curve (AUC <0.7) before apalutamide treatment. However, increased levels of PLR, SII, and SIRI could potentially be useful for monitoring for the risk of severe rash development in these patients.
Declaration of Generative AI and AI-assisted technologies in the writing process
AI tools were used to improve the readability and language of the manuscript.
Funding
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2020R1I1A3062508); the NRF Regional Innovation Strategy funded by the Ministry of Education (grant 2021RIS-001); and the NRF BK21 FOUR program funded by the Ministry of Education (grant 5199990614277).
Conflicts of interest
The authors declare no competing interests.
Acknowledgment
None.
Contributor Information
Sung Kyu Hong, Email: skhong@snubh.org.
Jae Young Joung, Email: urojy@ncc.re.kr.
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