Practical guidance was developed by a group of oncologists, urologists and dermatologists to bring together their joint experience in treating cancer and managing skin reactions. The aim is to identify apalutamide-related rash at the earliest opportunity in order to minimise its impact on cancer treatment. In principle, this includes: (1) patient education to increase awareness and facilitate early recognition and presentation in the event of a rash developing; (2) advising patients to adopt gentle skin care from the start of treatment; and (3) recommendations for the management of rash according to its severity. Patients starting treatment with apalutamide should be educated on what to look for, encouraged to proactively care for their skin (see Fig. 1) and be closely monitored for any changes. The importance of skin care and rash reporting should be highlighted at every appointment. Importantly, patients should contact their cancer care team at the first sign of a rash or skin changes so that the team can intervene early when the rash is at grade 1 or 2, thereby enabling apalutamide treatment to be continued, even if a temporary dose reduction is needed. It is imperative to inform patients about the risk of rash development and explain what to look for by showing pictures of the typical apalutamide-related rash. In clinical trials as well as in current practice, the cutaneous manifestation is often described as macular or maculo-papular, characterised by itchy macules (flat) and papules (elevated) that spread centripetally from the upper trunk (see Fig. 2).

Practical guidance on managing skin rash in patients treated with apalutamide

Maculo-papular rash in two patients treated with apalutamide. ADT Androgen deprivation therapy, mHSPC metastatic hormone-sensitive prostate cancer

While maculo-papular rash is the most common type of presentation, clinicians should be aware that other possible manifestations can occur with apalutamide, including exfoliative rash, and that rash can affect various areas of the body, including the mouth, eyes and genitals. Oral or eye mucosal involvement should always trigger urgent dermatology referral. It is important to explain to the patient that although the rash can look unpleasant, it is rarely dangerous and usually resolves with appropriate interventions. Patients should be made aware of the warning signs of a serious AE, such as mucosal or eye involvement, and advised to stop apalutamide and seek immediate medical attention if this happens. Any systemic symptoms, such as a high temperature, pain or blistering, or a rash that covers > 30% of the body would be signs that the patient should be urgently reviewed the dermatologist. The rash may also be a manifestation of a more severe systemic syndrome, such as DRESS with organ involvement, especially of the liver. A simple total blood count to check for abnormal leukocyte count (atypical lymphocytes and/or eosinophilia) is recommended for making or excluding a diagnosis of DRESS, which is not limited to the severity of the rash but linked to visceral manifestations, in particular, liver involvement. It is also important to educate the patient’s caregiver in this process so they can support them and help with skin care and monitoring.

At the start of treatment, clinicians should ask the patient about pre-existing skin problems and examine their skin, including the soles of the feet. At each follow-up appointment—including in-person, online and phone consultations—the patient should be asked proactively if they have noticed any skin rash or changes. If the patient reports a rash or other skin changes, they should be assessed in person as soon as possible to establish whether the rash is related to apalutamide or has another cause, such as an inflammatory skin disorder, drug interaction, infection, allergy or insect bite. Clinicians should ask about concomitant medications, especially antibiotics, as well as the patient’s travel history or if anything has changed in their environment (see Table 1). Clinicians should consider the criteria for DRESS, such as fever, facial oedema, lymph node enlargement and abnormal leukocyte count, and those for SJS/TEN, such as mucous membrane involvement or blistering. If the precise cause of the rash is unclear, clinicians should consider referring the patient to dermatology for consultation. Skin biopsies could be useful in establishing the cause of the rash but should only be needed for grade 2 or 3 or if the patient has an abnormal leukocyte count. It should be noted that, in contrast to other drug reactions, there can be a significant delay in the development of the rash and that this delay does not rule out a drug reaction, especially for DRESS when a delay of several weeks is possible. If the rash is considered to be not related to apalutamide, the patient should be evaluated and treated according to the aetiology and symptoms. A diagnosis of adverse drug reaction (ADR) can be made when other possible causes have been ruled out, and its severity graded in accordance with the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0, as shown in Table 2 [8].

Grade 1 and 2 toxicities can usually be managed by the cancer care team but consideration should be given to referring the patient for a dermatological consultation if the skin toxicity is worsening despite intervention after a week of treatment, if > 30% of the skin’s surface is involved or if there is any sign of swelling or pain. All patients who experience skin toxicity ≥ 3 should be referred for dermatological consultation. For all grades, clinicians should ensure that the patient understands the need for good skin care with regular emollients/moisturisers containing ingredients such as urea ≤ 5% and/or glycerine (which should have been started prior to the initiation of apalutamide treatment). For topical treatments, some patients prefer ointments as they adhere to the skin, but runnier lotions may be preferable for covering large surface areas. Interventions could include topical steroids to control inflammation, oral antihistamines every 12 h, using non-sedating during the day and a sedating one at night when the itch can be more troublesome, and oral steroids for more severe reactions (see Fig. 1). If corticosteroids are needed, the patient should receive education on their appropriate use, as some patients may have concerns, as well as an explanation of how much to use: for example, one phalanx of a digit is enough to cover one hand.

If the rash does not improve after 5–7 days of treatment and other symptoms, including pain, blistering erythroderma, facial swelling or other signs of DRESS, appear, a complete blood count with blood smear and liver test is necessary to look for atypical lymphocytes, eosinophilia and hepatitis, and the patient should be referred for dermatological consultation and apalutamide treatment paused. In very severe cases, admitting the patient to hospital should be considered. Once the rash has improved to at least grade 1, corticosteroids can be gradually discontinued to avoid the rash flaring up, and treatment with apalutamide can be restarted at the same or a reduced dose (180 mg or 120 mg) if warranted. Apalutamide must not be restarted in patients who have experienced DRESS or SJS/TEN, and an alternative treatment should be considered.

For detailed guidance of the management of rash by grade, see Fig. 1.