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

Introduction Apalutamide‐associated skin rash is a more common adverse event in the Japanese population than in the global population. However, its mechanism remains elusive, and limited histopathological information hampers further understanding. Case presentation Case 1: a 71‐year‐old man with metastatic castration‐sensitive prostate cancer developed a skin rash after 70 days of apalutamide treatment. Case 2: a 71‐year‐old man with non‐metastatic castration‐resistant prostate cancer developed a skin rash after 71 days of apalutamide treatment. In both cases, the skin rash presented as a slightly exudative erythema. The histology showed spongiosis of the epidermis and perivascular and interstitial infiltration of lymphocytes and eosinophils in the upper dermis without necrotic keratinocytes. Conclusion Apalutamide‐induced skin rashes can involve an eczematous reaction clinically and histologically.


Introduction
Apalutamide is a next-generation antiandrogen for the treatment of nmCRPC and mCSPC. 1,2 Apalutamide treatment demonstrated the prolonged metastatic-free survival and overall survival in phase III studies, and is one of the first-line drugs for nmCRPC and mCSPC. 1,2 A skin rash is a more common adverse event in Japanese patients (51.5%) than in the global population (SPARTAN study, 23.8%; TITAN study, 27.1%). [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.

Case presentation Case 1
A 71-year-old man with mCSPC had no allergies, was not taking any medications, and had no comorbidities. Apalutamide was administered orally (240 mg/day) with a gonadotropinreleasing hormone agonist as first-line of treatment. Seventy days after initiating apalutamide, the patient developed slightly exudative erythema with pruritus on both forearms, both legs, and chest. The patient did not have high fever, no erosions on mucosa, no sterile pustules, and no Nikolsky's sign. The erythema was slightly raised, covering 30% of the body's area, and was classified as grade 2 according to the CTCAE, version 5.0. Laboratory data showed no eosinophilia. No other drugs were changed or added except for apalutamide. The patient scored a 9 on the Naranjo scale; therefore, a causal relationship between the skin rash and apalutamide was strongly suspected. 5 Apalutamide was discontinued for 3 weeks and restarted at 180 mg/day. Thirty-five days after re-administration, the patient developed grade 2 erythema (Fig. 1a-c). A skin biopsy of the forearm revealed spongiosis of the epidermis without necrotic keratinocytes, as well as perivascular and interstitial infiltration of lymphocytes and a few eosinophils in the upper dermis. Vacuolar changes in the dermo-epidermal interface were not prominent. (Fig. 1d,e). Histological evaluation eliminated SAEs.
Apalutamide was discontinued once again, and topical corticosteroids and oral antihistamines were administered to reduce the eruption. Three weeks after the second discontinuation, apalutamide was restarted at 120 mg/day in combination with an oral antihistamine. Six weeks after the third administration, the patient developed grade 1 erythema. The skin eruption was controlled to within tolerable levels for 8 weeks without the need for apalutamide discontinuation ( Fig. 2a; Table 1).

Case 2
A 71-year-old man with nmCRPC had no allergies, was taking three medications, and had comorbidities such as cerebral   infarction and atrial fibrillation developed a skin rash 71 days after apalutamide treatment. The patient did not have high fever. The skin rash presented as a slightly exudative erythema on the extremities and the body relatively symmetrically without erosions on mucosa and sterile pustules, and were classified as grade 3 according to CTCAE (Fig. 1f,g). There was no Nikolsky's sign. No other drugs were changed or added, except for apalutamide. A skin biopsy of the chest revealed spongiosis of the epidermis without necrotic keratinocytes, as well as perivascular and interstitial infiltration of lymphocytes and a few eosinophils in the upper dermis. Vacuolar changes in the dermo-epidermal interface were not prominent. (Fig. 1h,i). A histological evaluation eliminated SAEs, which support continuation of apalutamide. Thereafter, the skin rash improved with discontinuation of apalutamide; however, 49 days after re-administration with the two dose reductions, the patient developed grade 1 erythema. The skin eruption was controlled to within tolerable levels for 8 months without apalutamide discontinuation in combination with an oral antihistamine. The medication was switched to darolutamide as requested by the patient due to apalutamideassociated skin rash ( Fig. 2b; Table 1).

Discussion
In our two cases, the clinical features of skin rash induced by apalutamide presented slightly exudative erythema, and the histological features revealed spongiosis without necrotic keratinocytes. These findings were in line with the histological features of a previous report on a skin rash biopsy. 6 However, in case 2, maculopapular exanthema cannot be ruled out, because erythematous maculopapulous eruption was distributed symmetrically on the body. 7 Severe adverse cutaneous drug reactions, such as SJS, TEN, and DRESS, were excluded from the differential diagnosis despite a previous fatal case. 8 Other common adverse cutaneous drug reactions, such as acute generalized exanthematous pustulosis, and fixed drug eruption, were also excluded clinically and histologically. 7,9 Therefore, previous 6 studies and our cases suggest that atypical eczematous rash may be a unique adverse reaction to apalutamide whereas further studies are required to categorize the phenotypes of the drug eruptions.
The mechanism of apalutamide-associated skin rash is poorly understood. 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.
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 Switch to darolutamide as requested by the patient 85 kg). 1,11 The initial dose of 240 mg of apalutamide may be too high for Japanese patients. Therefore, one possible approach is to start with an adjusted dose to avoid skin rash; however, there is currently no evidence for this approach and further study is needed.
In conclusion, our cases support the idea that eczematous eruption is one of the representative types of apalutamideinduced skin rash. Clinical and histological features of our cases provide useful information for the management of this common adverse events and enhance the mechanistic understanding in future studies.