Apalutamide-associated rash combined with severe neutropenia and eosinophilia: a case report

Introduction

As a novel oral nonsteroidal androgen receptor (AR) competitive inhibitor, apalutamide can bind directly to the ligand-binding domain of the AR to prevent AR translocation and inhibit AR-mediated gene transcription (1). In the SPARTAN trial, the results demonstrated for the first time that apalutamide in combination with androgen-deprivation therapy (ADT) could significantly improve the metastasis-free survival and time to symptomatic progression in nonmetastatic castration-resistant prostate cancer (nmCRPC) patients compared to placebo (2). Moreover, the safety analysis of the SPARTAN trial showed that there was no significant difference in the rate of serious adverse events between the apalutamide and placebo groups (2). However, the incidence of rash was higher in patients receiving apalutamide than in the placebo group (23.8% vs. 5.5%). Of these, 5.2% developed a grade 3–4 rash (2). Similarly, in the TITAN trial, while overall survival and radiographic progression-free survival were significantly prolonged in metastatic hormone-sensitive prostate cancer (mHSPC) patients treated with apalutamide, the incidence of rash of any grade was more common than in patients treated with placebo (27.1% vs. 8.5%) (3). Among these patients, 6.3% experienced a grade 3 or higher rash (3).

Although apalutamide was generally well tolerated in both the SPARTAN and TITAN trials, treatment discontinuation due to apalutamide-associated rash occurred in 2.4% and 2.3% of patients, respectively (2,3). Furthermore, dose reductions resulting from rash were required in 2.7% and 5.3% of patients in the SPARTAN and TITAN trials, respectively (2,3). Severe cutaneous adverse drug reactions (SCARs) due to apalutamide therapy have been previously reported in several literatures, mainly focusing on Asian patients, but also including Caucasian patients (4-9). Some of these patients were drug reaction with eosinophilia and systemic symptoms (DRESS) (7), Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) (8), and acute generalized exanthematous pustulosis (AGEP) (9). Nevertheless, the occurrence of apalutamide-associated skin rash combined with apalutamide-induced neutropenia and eosinophilia in a single patient has not been reported previously. Here, we report a case of an mHSPC patient treated with apalutamide who experienced grade 3 rash combined with severe neutropenia and eosinophilia. We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-25-27/rc).

Case presentation

A 74-year-old male was diagnosed with prostate adenocarcinoma via transperineal prostate biopsy (12+/12 biopsy cores) with a highest Gleason score of 5+4=9. According to the multiparametric magnetic resonance imaging (mpMRI) of prostate and whole-body radionuclide bone scan, his clinical tumor-node-metastasis (TNM) classification was cT3bN1M1b. Approximately 1 month after the prostate biopsy, the patient started taking apalutamide at the dose of 240 mg once daily, combined with intramuscular injection of triptorelin pamoate at the dose of 15 mg every 3 months for ADT. And he had a previous history of good health and denied any history of drug allergies. His Eastern Cooperative Oncology Group (ECOG) performance status score was 0 and body mass index (BMI) was 24.34 kg/m² at the time of apalutamide initiation.

Forty-one days after receiving apalutamide, the patient developed a rash without obvious cause, primarily on his back (Figure 1). The skin temperature was mildly elevated, without itching or pain. That evening, the patient developed a fever with a maximum temperature of 39.2 ℃, accompanied by chills and shivering, but with no other symptoms. Subsequently, the patient presented to the emergency department of urology in our hospital. The results of routine blood test showed that the white blood cell (WBC) count was 2.1×10⁹/L and absolute neutrophil count (ANC) was 0.47×10⁹/L. Moreover, the coronavirus disease 2019 (COVID-19) antigen test was negative and the tests for nine respiratory pathogen immunoglobulin M (IgM) antibodies were negative. After consultation with the department of dermatology and infectious disease, he was initially diagnosed with an allergic rash combined with neutropenia. Therefore, the patient was instructed to discontinue apalutamide immediately and oral olopatadine hydrochloride tablets (5 mg per dose, twice daily) were prescribed for anti-allergic treatment. Additionally, subcutaneous injections of recombinant human granulocyte colony-stimulating factor (rhG-CSF) (75 µg per dose, once daily) were administered to elevate leukocyte levels. To prevent infection, the patient was given ertapenem (1 g per dose, once daily). During the initial week of treatment, the patient continued to have intermittent fever, with a maximum temperature of 38.1 ℃, and the systemic rash showed no significant improvement. On the 8^th day, a repeat routine blood test showed that the WBC count was 4.84×10⁹/L, ANC was 0.04×10⁹/L, and absolute eosinophil count was 0.98×10⁹/L. The tuberculosis infection T-cell spot test was negative, and both serum 1,3-β-D-glucan and galactomannan tests were negative. And the diagnosis was considered to be drug-induced rash combined with severe neutropenia and eosinophilia. Therefore, he was given the protective isolation and continued to receive subcutaneous injections of rhG-CSF (75 µg per dose, once a day) for severe neutropenia, ertapenem (1 g per dose, once a day) for infection prevention, combined with methylprednisolone sodium succinate (40 mg per dose, once a day). On the 11^th day, the patient underwent a bone marrow puncture. And the punch biopsy results showed that the bone marrow hyperplasia was active, the granulocyte proportion increased with nuclear left shift, and eosinophilia was observed. Whole-exome sequencing of the hematologic genome and whole-transcriptome sequencing of blood tumors showed there were no highly relevant disease-associated mutations. And the flow cytometry examination showed that the proportion of myeloid progenitor cells was not high, the granulocyte proportion was decreased without abnormal expression of CD13/CD16 and CD13/CD11b differentiation antigens, the proportion of eosinophils was increased, no erythroid cells were observed, and no abnormal phenotypes detected in monocytes and lymphocytes. From the 17^th day, the temperature of patient returned to normal. On the 23^rd day, a repeat routine blood test revealed the WBC count of 6.38×10⁹/L, ANC of 3.11×10⁹/L, absolute eosinophil count of 0.12×10⁹/L. Afterwards, the protective isolation, rhG-CSF, antibiotics, and glucocorticosteroid were discontinued, and the steroid cream was applied to the rash area. On the 32^nd day after discharge from the hospital, an outpatient follow-up showed that the rash of patient was in complete remission (Figure 1) and the repeat routine blood tests showed normal levels of WBC, neutrophils, and eosinophils (Figure 1). The patient is currently receiving an intramuscular injection of triptorelin pamoate (15 mg every 3 months), with his prostate-specific antigen (PSA) under effective control (Figure 1). The final diagnosis for this patient was drug-induced severe neutropenia, eosinophilia, drug-associated rash, and mHSPC (cT3bN1M1b).

Figure 1 Timeline of significant events before and after patient admission. ADT, androgen-deprivation therapy; PSA, prostate-specific antigen.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Based on the results of two phase 3, randomized, double-blind, placebo-controlled, multinational trials (TITAN and SPARTAN), apalutamide was approved by the US Food and Drug Administration for the treatment of mHSPC and nmCRPC patients. In addition to common side effects such as fatigue, rash of any type of grade 3 or higher were reported in 6.3% and 5.2% of patients treated with apalutamide, respectively (2,3). In a retrospective analysis based on the 119 Japanese patients, 46.2% developed skin adverse events of all grades. And the median time-to-first incidence of skin adverse events was 62 days (10). Similarly, in an integrated analysis based on the 68 Japanese patients, rash was observed in up to 51.5% of Japanese patients treated with apalutamide. And the results showed that the median time to the first occurrence of any grade rash was 66 days, and the time to the first incidence of grade 3 rash was 45 days (11). However, a real-world analysis on 100 patients at our center showed that only 32% of Chinese patients experienced rash after taking apalutamide. Among these, the median time to grade 1/2/3 rash was 73.5, 55.5, and 45.5 days, respectively (12). Thus, the results of the above two studies on Chinese and Japanese show that the median time to a grade 3 rash was about 45 days. In this case report, the patient experienced a systemic rash accompanied by fever 41 days after starting oral apalutamide. According to the Common Terminology Criteria for Adverse Events, he was diagnosed with a grade 3 rash. While drug-induced rash is a known adverse effect associated with various pharmacologic agents, the absence of any other drug exposure or allergy history in this previously healthy male suggested that the rash was attributable to apalutamide treatment. Given that skin rashes are among the most frequently reported adverse events associated with apalutamide, early recognition and grading of severity are essential. Moreover, common clinical management for rash includes topical or systemic corticosteroids, oral antihistamines, dose reduction or discontinuation of apalutamide (12-15). The choice of different treatment options often depends on the management approach at different medical centers or the grade of the rash. For grade 1 rash, apalutamide maintenance therapy, topical corticosteroids, and oral antihistamines are usually recommended. For grade 2 or symptomatic grade 1 rashes, the patients should discontinue apalutamide and be treated with the same therapy as for grade 1 rash. For grade 3 or higher rash, drug interruption and systemic corticosteroids are recommended (12-15). Additionally, there have also been several studies exploring ways to reduce the incidence of apalutamide-associated rash (16,17). In this patient, the grade 3 rash completely subsided after drug discontinuation, antihistamine, and systemic corticosteroid treatment.

Neutropenia is a syndrome characterized by an ANC in peripheral blood below 1.5×10⁹/L. An ANC below 0.5×10⁹/L, especially 0.2×10⁹/L or less, is referred to as severe neutropenia, also known as agranulocytosis (18). And the severity of neutropenia determines the functional consequences to a large extent. Excluding genetic or congenital diseases, drugs are one of the most common causes of acquired neutropenia, mainly comprising antineoplastic drugs, anti-inflammatory agents, antibiotics, antithyroid drugs, and antipsychotics (19). Furthermore, other factors that can also lead to neutropenia include infection, deficiencies in hematopoietic components or trace elements, bone marrow failure diseases, malignancy, autoimmune diseases, and hyperthyroidism (20). Eosinophilia is defined as an absolute eosinophil count in peripheral blood greater than 0.5×10⁹/L (500 cells/mm³) (21,22). Based on the level of eosinophil count, the degree of eosinophilia can be categorized as mild (500 to 1,500 cells/mm³), moderate (1,500 to 5,000 cells/mm³), or severe (>5,000 cells/mm³) (22). Factors such as parasitic diseases, drugs, malignancy, autoimmune disorders/immune dysregulation, atopic disorders, and allergic diseases are associated with the development of eosinophilia (22). In this patient, the routine blood tests were normal before treatment. However, 41 days after taking apalutamide, he developed a systemic rash accompanied by severe neutropenia and eosinophilia. Several publications have reported the cases of apalutamide-induced SCARs, including DRESS and SJS/TEN. DRESS, which is also known as drug hypersensitivity syndrome, is a multi-organ systemic drug reaction with the potential to be fatal (23). And the classic presentation of patients with DRESS syndrome includes fever, rash, lymphadenopathy, hematological abnormalities, and involvement of at least one organ system (23). Martin et al. reported a case of a 74-year-old male with DRESS syndrome caused by apalutamide (7). According to the Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) scoring system, the patient reported by the authors had a final score of 5 due to enlarged lymph nodes (one point), eosinophilia greater than 1,500 (two points), and skin rash suggesting DRESS with extent over 50% of the body surface area (two points) for a total of five points (7). However, in our clinical case, the patient exhibited no enlargement of lymph nodes, no vesicles, no pustules, and no facial or acral edema. Thus, the diagnosis of DRESS was not deemed applicable in this patient. Moreover, SJS and TEN form a spectrum of the same disease differentiated by the extent of epidermal necrosis and detachment, usually presenting with prodrome of flu-like symptoms, high fever, and malaise (23). And the major features of rash of SJS/TEN include erosive mucositis in two surfaces and palmoplantar tender erythema (19). In our case, the rash only appeared on his back without skin detachment and mucosal loss. Therefore, the diagnosis of SJS/TEN was not considered applicable in this patient.

After it was initially diagnosed as the underlying cause, apalutamide was immediately discontinued. And this patient was given protective isolation, rhG-CSF to increase neutrophil counts, and antibiotics to prevent infection. During the course of treatment, the patient completed the relevant examination including bone marrow examination, whole-exome sequencing of the hematologic genome, whole transcriptome sequencing of hematological malignancies, and flow cytometry detection, to rule out the bone marrow metastasis of prostate cancer, bone marrow failure disorders, and hematologic tumors. Further thyroid function tests, pathogen tests, and autoantibody tests were conducted to exclude hyperthyroidism, infections, and autoimmune diseases. The final diagnosis of this patient was severe neutropenia, eosinophilia, and drug-induced rash caused by apalutamide. After discontinuing apalutamide, providing protective isolation, preventing infection with antibiotics, stimulating neutrophil counts with rhG-CSF, and treating with methylprednisolone sodium succinate, the temperature of the patient and the counts of neutrophil and eosinophil returned to normal. Given the severity of the adverse reaction in this case, further use of structurally similar AR antagonists, such as enzalutamide or darolutamide, is not currently recommended. Although these agents share a common mechanism of action with apalutamide, they differ in molecular structure, metabolic pathways, and pharmacokinetic properties. To date, there is no conclusive evidence demonstrating cross-reactivity among these agents in terms of hypersensitivity reactions. The patient is currently managed with triptorelin pamoate monotherapy, which has maintained adequate PSA control. If PSA progression occurs in the future, treatment strategies will more likely involve agents with different mechanisms of action, such as abiraterone acetate plus prednisone or docetaxel chemotherapy, rather than another AR pathway inhibitor. Any reconsideration of AR-targeted agents would require individualized evaluation, close clinical monitoring, and a cautious risk-benefit assessment.

Conclusions

As a novel AR inhibitor, apalutamide combined with ADT has effectively improved the prognosis of patients with mHSPC and nmCRPC. However, some patients may develop a rash during apalutamide treatment, which not only reduces their quality of life but also affects their treatment adherence. Additionally, a small number of patients may develop neutropenia and eosinophilia during treatment, which can be life-threatening in severe cases. Therefore, a rash management guideline or booklet that outlines the skin care practices should be provided for patients before taking apalutamide. On this basis, clinical follow-up and management should be strengthened during apalutamide treatment. And we also recommend that routine blood tests should be performed when patients develop apalutamide-associated rash. By early identification of apalutamide-induced adverse events and timely intervention, drug dose reduction or treatment interruption could be effectively avoided, thereby maximizing the anti-tumor treatment effect and improving the quality of life for patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-25-27/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-25-27/prf

Funding: This work was supported by the National Natural Science Foundation of China (Nos. 81872078 and 82273262), the Natural Science Foundation of Tianjin (No. 21JCYBJC01430), the Key Program of Tianjin Municipal Education Commission (No. 2022ZD071), the Tianjin Health Research Project (No. TJWJ2023MS006), the Tianjin Institute of Urology Funding Program (No. MYSRC202315), the Tianjin Health Research Project (No. TJWJ2023XK008), and the Scientific Research Program of Tianjin Municipal Education Commission (No. 2023KJ022).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-25-27/coif). The authors have no 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. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

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. Ong TA, Saad M, Lim J, et al. Novel hormonal therapies in the management of advanced prostate cancer: extrapolating Asian findings to Southeast Asia. BMC Urol 2023;23:4. [Crossref] [PubMed]
2. 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]
3. 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]
4. Katayama H, Saeki H, Osada SI. Maculopapular Drug Eruption Caused by Apalutamide: Case Report and Review of the Literature. J Nippon Med Sch 2022;89:550-4. [Crossref] [PubMed]
5. Tohi Y, Kataoka K, Miyai Y, et al. Apalutamide-associated skin rash in patients with prostate cancer: Histological evaluation by skin biopsy. IJU Case Rep 2021;4:299-302. [Crossref] [PubMed]
6. Cremante M, Puglisi S, Gandini A, et al. Apalutamide-induced lichenoid reaction in a patient with non-metastatic castrate-resistant prostate cancer. J Oncol Pharm Pract 2023;29:1748-53. [Crossref] [PubMed]
7. Martin G, Lambert E, Wang GK. Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS) Syndrome Caused by Apalutamide: A Case Presentation. Cureus 2023;15:e41687. [Crossref] [PubMed]
8. Flynn CR, Liu SC, Byrne B, et al. Apalutamide-Induced Toxic Epidermal Necrolysis in a Caucasian Patient with Metastatic Castration-Sensitive Prostate Cancer: A Case Report and Review of the Literature. Case Rep Oncol 2023;16:652-61. [Crossref] [PubMed]
9. Honda T, Tohi Y, Kaku Y, et al. Acute generalized exanthematous pustulosis during apalutamide treatment in a patient with prostate cancer. IJU Case Rep 2022;5:497-500. [Crossref] [PubMed]
10. 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]
11. 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]
12. 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]
13. Marx G, Chowdhury S, Krieger L, et al. A practical guide for the use of apalutamide for non-metastatic castration-resistant prostate cancer in Australia. Asia Pac J Clin Oncol 2024;20:435-43. [Crossref] [PubMed]
14. Birtle AJ, Formisano L, Descamps V, et al. Early Identification and Management of Patients with Rash on Apalutamide. Oncol Ther 2024;12:609-20. [Crossref] [PubMed]
15. Pan A, Reingold RE, Zhao JL, et al. Dermatological Adverse Events in Prostate Cancer Patients Treated with the Androgen Receptor Inhibitor Apalutamide. J Urol 2022;207:1010-9. [Crossref] [PubMed]
16. Yang D, Chen W, Lai F, et al. Feasibility of apalutamide combined with androgen deprivation therapy and short-course low-dose prednisone in treating metastatic hormone-sensitive prostate cancer: a pilot randomized controlled trial. Front Oncol 2023;13:1110807. [Crossref] [PubMed]
17. Shore N, Hafron J, Saltzstein D, et al. Impact of a rash management guide in patients receiving apalutamide for high-risk localized prostate cancer in the Apa-RP study. Prostate Cancer Prostatic Dis 2024; Epub ahead of print. [Crossref]
18. Newburger PE, Dale DC. Evaluation and management of patients with isolated neutropenia. Semin Hematol 2013;50:198-206. [Crossref] [PubMed]
19. Gibson C, Berliner N. How we evaluate and treat neutropenia in adults. Blood 2014;124:1251-8; quiz 1378. [Crossref] [PubMed]
20. Palmblad J, Nilsson CC, Höglund P, et al. How we diagnose and treat neutropenia in adults. Expert Rev Hematol 2016;9:479-87. [Crossref] [PubMed]
21. Valent P, Gleich GJ, Reiter A, et al. Pathogenesis and classification of eosinophil disorders: a review of recent developments in the field. Expert Rev Hematol 2012;5:157-76. [Crossref] [PubMed]
22. Kuang FL. Approach to Patients with Eosinophilia. Med Clin North Am 2020;104:1-14. [Crossref] [PubMed]
23. Peter JG, Lehloenya R, Dlamini S, et al. Severe Delayed Cutaneous and Systemic Reactions to Drugs: A Global Perspective on the Science and Art of Current Practice. J Allergy Clin Immunol Pract 2017;5:547-63. [Crossref] [PubMed]