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ERLEADA®

(apalutamide)

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ERLEADA® (apalutamide)

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ERLEADA - Rash

Last Updated: 12/23/2024

Incidence of Rash in the SPARTAN Study

The SPARTAN study evaluated the efficacy and safety of ERLEADA in patients with nmCRPC (N=1207).1-3

All Grade Rash,

n (%)2-4

ERLEADA (n=803)

Placebo (n=398)

Cross over (n=76)

Primary

Analysisa

191 (23.8)

22 (5.5)

-

Final OS

Analysis

212 (26)

25 (6.3)

19 (25)
  • Rash led to treatment discontinuation in 19 (2.4%) patients in the ERLEADA group and in 0 patients in the placebo group.5 In the final OS analysis, maculo-papular rash led to treatment discontinuation in 0.7% of patients in the ERLEADA group.2

aThere were no grade 4 rash events and no events of DRESS, SJS, or TEN.5

Incidence of Rash in the TITAN Study

The TITAN study evaluated the efficacy and safety of ERLEADA in patients with mCSPC (N=1052).6-8

All Grade Rash,

n (%)6-8

ERLEADA (n=524)

Placebo (n=527)

Cross over (n=208)

Primary

Analysisa

142 (27.1)

45 (8.5)

-

Final OS

Analysis

153 (29.2)

49 (9.3)

45 (21.6)
  • Rash led to treatment discontinuation in 12 (2.3%) patients in the ERLEADA group and in 1 (0.2%) patient in the placebo group.10

aThere were no grade 4 rash events and no events of DRESS, SJS, or TEN.11

Management of Grade 1 Rash

Management of grade 1 rash (<10% of BSA) included the following4,9,12,13:

  • Continue ERLEADA at current dose and initiate dermatological treatmenta:
    • Topical steroid cream AND
    • Oral antihistamines
  • Monitor for change in severity.a
  • If there is blistering or mucosal involvement, stop ERLEADA dosing immediately.

aObtain bacterial/viral cultures if infection is suspected.

Management of Grade 2 (or Symptomatic Grade 1a) Rash

Management of grade 2 rash (10%-30% of BSA) included the following4,9,12,13:

  • At investigator discretion, hold ERLEADA for up to 28 days and initiate dermatological treatmentb:
    • Topical steroid cream AND
    • Oral antihistamines
  • Monitor for change in severity.b If rash or related symptoms improve, then reinitiate ERLEADA when rash is grade ≤1.
  • Consider 1 dose level reduction.
  • If there is blistering or mucosal involvement, stop ERLEADA dosing immediately.

aWhere patient presents with other rash-related symptoms, such as pruritus, stinging, or burning.
bObtain bacterial/viral cultures if infection is suspected.

Management of Grade ≥3 Rash

  • Management of grade ≥3 rash (>30% of BSA) included the following4,9,12,13:
  • Hold ERLEADA for up to 28 days and initiate dermatological treatmenta:
    • Topical steroid cream AND
    • Oral antihistamines AND
    • Short course of oral steroids can be considered
  • Reassess after 2 weeks.
    • If grade ≤1, reinitiate and consider dose reduction.
      • If dose <120 mg, discontinue.
    • If same or worsened, initiate oral steroids and refer to dermatologist.
      • If oral corticosteroids were previously started, continue for ≥1 week after resumption of reduced dose. If the proposed total oral steroid dose use exceeded 28 days, discontinue ERLEADA.
  • If not resolved to grade ≤1 after 28 days, consider discontinuation.
  • If there is blistering or mucosal involvement, stop ERLEADA dosing immediately.

aObtain bacterial/viral cultures if infection is suspected.

APA-RP Study Rash Management Guide

  • APA-RP was a phase 2, open-label, single-arm, multicenter study.14
  • This study evaluated the efficacy and safety of adjuvant treatment of ERLEADA and ADT in treatment-naïve patients with high-risk localized prostate cancer who had undergone radical prostatectomy (N=108).14
  • A prespecified rash management guide (see below) was implemented with the intent to reduce the onset and severity of rash events. Rash-related safety data were compared descriptively with those from North American patient population of the global SPARTAN and TITAN studies.14

APA-RP Rash
Management Guide

Please note that the information in the management of rash are not recommendations and pertain to the management of rash in the SPARTAN and TITAN studies. Interventions should be based on patient presentation and the clinical judgment of the treating healthcare professional.

Note: ADT, androgen deprivation therapy; AE, adverse event; A+P, anterior + posterior; BSA, body surface area; DRESS, drug reaction with eosinophilia and systemic symptoms; GnRH, gonadotropin-releasing hormone; mCSPC, metastatic castration-sensitive prostate cancer; NCI-CTCAE, National Cancer Institute - Common Terminology Criteria for Adverse Events; nmCRPC, non-metastatic castration-resistant prostate cancer; OS, overall survival; PO, orally; R, randomized; SJS, Stevens-Johnson Syndrome; TEN, toxic epidermal necrolysis.

Study Design

  • The phase 3 SPARTAN study evaluated the efficacy and safety of ERLEADA in patients with nmCRPC (N=1207).3

Patient Characteristics

  • Patient baseline demographics and disease characteristics were well balanced, with no significant differences between the 2 groups.4
  • The median treatment duration at the primary analysis was 16.9 months and 11.2 months in the ERLEADA and placebo groups, respectively.4
  • The final OS analysis was conducted after a median follow-up of 52 months (median treatment durations for the ERLEADA, placebo, and crossover groups were 32.9 months, 11.5 months, and 26.1 months, respectively).1
  • In the ERLEADA group, the rates of rash by grouped term (event rate/100 PY) did not change substantially after the first and second interim analyses.2
  • AEs were graded according to NCI-CTCAE v4.0.3

Incidence of Rash in the Phase 3 SPARTAN Study2-4

n (%)

ERLEADA Group (n=803)

Placebo Group (n=398)

Crossover Group (n=76)a

All Grades

Grade 3-4

All Grades

Grade 3-4

All Grades

Grade 3-4

Primary Analysisb,c

191 (23.8)

42 (5.2)

22 (5.5)

1 (0.3)

-

-

Final OS Analysis

212 (26)

42 (5.2)

25 (6.3)

1 (0.3)

19 (25)

2 (2.6)

Event (event rate/100 PY of exposure)d,e

394 (19)

49 (2.3)

39 (8.7)

1 (0.2)

28 (21)

3 (2.2)

aAfter study unblinding, patients in the placebo group were eligible for crossover into the ERLEADA group.
bIncludes rash, rash maculo-papular, rash generalized, urticaria, rash pruritic, rash macular, conjunctivitis, erythema multiforme, rash papular, skin exfoliation, genital rash, rash erythematous, stomatitis, drug eruption, mouth ulceration, rash pustular, blister, papule, pemphigoid, skin erosion, and rash vesicular.
cThere were no grade 4 rash events and no events of DRESS, SJS, or TEN.5
dTotal PY of exposure: ERLEADA group, 2117.9; placebo group, 446.0; and crossover group, 134.5.
eEvent rate exposure was calculated as 100×(number of distinct events)/total PY of exposure (total days of exposure/365.25) for the treatment group.
  • Rash associated with ERLEADA was most commonly described as macular or maculopapular.4
  • Treatment of rash included 1 or more of the following: topical corticosteroids, oral antihistamines, systemic corticosteroids, drug interruption, and dose reduction.5
  • Rash recurred in approximately half of the patients who were rechallenged with ERLEADA. Rechallenge did not result in anaphylactic or high-grade allergic reactions.4
  • Among the patients who were treated with ERLEADA and experienced a rash (n=191), 35% received antihistamines, 34% received topical corticosteroids, and 17% received systemic corticosteroids.4

Additional Analyses

  • Safety results, including rash, were also previously reported in the second interim OS analysis.15
  • Utilizing data from patients in the SPARTAN study, an exploratory exposure-response analysis using univariate and multivariate logistic models evaluating the relationship between ERLEADA and N-desmethyl-ERLEADA exposure and common TEAEs, including rash, was conducted.16
    • The univariate logistic regression analysis demonstrated that the probability of experiencing skin rash significantly increases as ERLEADA and N-desmethyl-ERLEADA AUC0-24h,ss increases (OR, 1.149×10 μg×h/mL; 95% CI, 1.113-1.185×10 μg×h/mL; P<0.001).
    • Additionally, in the multivariate regression analysis, the contribution of ERLEADA or N-desmethyl-ERLEADA AUC0-24h,ss was significant for the probability of experiencing skin rash.

Additional Information

Additional information regarding the SPARTAN study, including the clinical study report, protocol, and statistical analysis plan, can be found at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/Erleada_210951_toc.cfm (scroll to the “Sponsor Clinical Study Reports ARN-509-003 SPARTAN NCT # 01946204” section at the bottom of the web page).

Study Design

  • The phase 3 TITAN study evaluated the efficacy and safety of ERLEADA in patients with mCSPC (N=1052).6

Patient Characteristics

  • Patient baseline demographic and disease characteristics were well balanced, with no significant differences between the 2 groups.6
  • The median treatment duration at the primary analysis was 20.5 months and 18.3 months in the ERLEADA and placebo groups, respectively.6
  • The final OS analysis was conducted after a median follow-up of 44.0 months (median treatment durations for the ERLEADA, placebo, and crossover groups were 39.3 months, 20.2 months, and 15.4 months, respectively).7
  • Incidence of first any-grade skin rash event was higher in ERLEADA group than in the placebo group reaching a plateau after ~6 months.7
  • AEs were graded according to NCI-CTCAE v4.0.3.6

Incidence of Rash in the Phase 3 TITAN Study6-8

n (%)

ERLEADA Group (n=524)

Placebo Group (n=527)

Crossover Group (n=208)a

All Grades

Grade 3-4

All Grades

Grade 3-4

All Grades

Grade ≥3

Primary analysisb,c

142 (27.1)

33 (6.3)

45 (8.5)

3 (0.6)

-

-

Final OS analysisd

153 (29.2)

33 (6.3)

49 (9.3)

5 (0.9)

45 (21.6)

8 (3.8)

Event (event rate/100 PY of exposure)e,f

331 (24.4)

40 (2.9)

66 (8.3)

5 (0.6)

44 (18.1)

8 (3.3)

TEAE of rash

106 (20.2)

-

23 (4.4)

-

26 (12.5)

-

Treatment- related TEAE of rash

92 (17.6)

-

12 (2.3)

-

23 (11.1)

-

aAfter study unblinding, patients in the placebo group were eligible for crossover into the ERLEADA group.
bIncludes rash, butterfly rash, erythematous rash, exfoliative rash, follicular rash, generalized rash, macular rash, maculo-papular rash, papules, papular rash, pruritic rash, pustular rash, genital rash, blister, skin exfoliation, exfoliative dermatitis, skin reaction, systemic lupus erythematosus rash, toxic skin eruption, mouth ulceration, drug eruption, conjunctivitis, erythema multiforme, stomatitis, and urticaria.
cThere were no grade 4 rash events and no events of DRESS, SJS, or TEN.11
dSkin rash was a grouped term including rash, maculopapular rash, conjunctivitis, dermatitis, stomatitis, pruritic rash, urticaria, papular rash, skin exfoliation, blister, mouth ulceration, drug eruption, erythema multiforme, exfoliative rash, toxic skin eruption, papule, skin reaction, butterfly rash, generalized exfoliative dermatitis, genital rash, erythematous rash, macular rash, systemic lupus erythematosus rash, oral mucosal blistering, follicular rash, pustular rash, and vesicular rash.
eTotal PY of exposure: ERLEADA group, 1358.9; placebo group, 793.3; and crossover group, 243.6.
fEvent rate per 100 PY of exposure is calculated as 100×(number of distinct events with the group term)/total PY of exposure (total days of exposure/365.25) for the treatment group. AEs occurred from the time of the first dose of the study intervention through 30 days after the last dose. AEs were graded according to NCI-CTCAE v4.0.3. One patient who was assigned to the ERLEADA group withdrew consent before treatment.
  • Treatment of rash included 1 or more of the following: topical corticosteroids, oral antihistamines, systemic corticosteroids, dose interruption, and dose reduction.10
  • Among the patients who were treated with ERLEADA and experienced a rash (n=142), 38% received antihistamines, 43% received topical corticosteroids, and 20% received systemic corticosteroids.11
  • The following table summarizes the interventions that investigators in the SPARTAN and TITAN studies were instructed to perform in order to manage rash.9,12
    • These are not recommendations.
    • Interventions should be based on patient presentation and the clinical judgment of the treating physician.

Management of ERLEADA-Related Rasha in the SPARTAN and TITAN Studies4,9,13

Grade 1
<10% of BSA
  • Continue ERLEADA at the current dose and initiate the following dermatological treatmentb:
    • Topical steroid cream AND
    • Oral antihistamines
  • Monitor for change in severity.

Grade 2
(or symptomatic Grade 1c)
10%-30% of BSA
  • Per investigator discretion, hold ERLEADA for up to 28 days and initiate dermatological treatmentb:
    • Topical steroid cream AND
    • Oral antihistamine
  • Monitor for change in severity,b and if rash or related symptoms improve, reinitiate ERLEADA when rash is grade ≤1. Consider 1 dose level reduction.

Grade ≥3
>30% of BSA
  • Hold ERLEADA for up to 28 days and initiate dermatological treatmentb:
    • Topical steroid cream AND
    • Oral antihistamines AND
    • Short course of oral steroids can be considered.
  • Reassess after 2 weeks.
    • If reduction to grade ≤1, reinitiate ERLEADA and consider dose reduction.d
    • If same or worsened, initiate oral steroids (if not already done)e and refer to dermatologist.
  • If after 28 days the rash has not resolved to grade ≤1 after 28 days, consider discontinuation of ERLEADA.

If there is blistering or mucosal involvement, stop ERLEADA dosing immediately.

aRash may be graded differently according to the type of rash and associated symptoms. For example, maculo-papular rash is graded by the BSA covered and not the severity of the rash. Please consult NCI-CTCAE v4.03 for specific grading criteria for other types of rash.20
bObtain bacterial/viral cultures if infection is suspected.
cPatient presents with other rash-related symptoms, such as pruritus, stinging, or burning.
dIf the dose reduction would have led to a dose <120 mg, then the investigators were instructed to discontinue ERLEADA.
eIf a patient previously started oral corticosteroids, continue for ≥1 week after resumption of reduced dose of ERLEADA. If the proposed total oral steroid dose use exceeded 28 days, the investigators were instructed to discontinue ERLEADA.
  • Early skin care measures were recommended to help prevent the onset of rash. During visits and phone calls with the care team, patients were educated on gentle skin care.
    Recommendation included14:
    • Consider: light emollients (lotion) daily after any other prescribed topical steroid lotion had dried; antiseptic-containing soap substitute or mild pH-neutral soap; sunblock (SPF 50) when outdoors. Additionally, intensify usual skin care routine for patients with pre-existing eczema.
    • Avoid: harsh soaps; strong sun and weather extremes; long, hot baths, showers, and saunas (use of tepid water for bathing); alcohol-based and fragranced skin care products.
  • In patients receiving ERLEADA who presented with rash, the Rule of Nines for adults (age >14 years) was used to assess severity of rash. The following table summarizes the interventions that the investigators in the APA-RP study were instructed to perform in order to manage rash.14

Management of ERLEADA-Related Rasha in the APA-RP Study14

Grade 1
Macules/papules covering <10% of BSA ± symptoms (eg, pruritus, burning, tightness)
  • Continue ERLEADA at the same dose AND initiate:
    • High potency topical steroid lotion (eg, fluocinonide 0.05%, clobetasol 0.05%, or betamethasone 0.05%) AND
    • Oral antihistamine hydroxyzine (grade 1, 10 mg BID; grade 2, 25 mg BID)
  • Monitor for change in severity AND contact patient at a minimum of every 2 weeks.
    • If rash is stable or improves, continue current management and monitoring until it resolves.
    • If rash worsens, follow guidance for grade 3.

Grade 2
Macules/papules covering 10-30% of BSA ± symptoms; limiting instrumental ADL; rash covering >30% of BSA ± mild symptoms

Grade ≥3
Macules/papules covering >30% BSA with moderate or severe symptoms; limiting self-care ADL
  • Pause ERLEADA until rash is grade ≤1 AND initiate:
    • Prednisone 0.5-1 mg/kg/day for 20 days or equivalent with maximum dose of 100 mg/day AND
    • High potency topical steroid lotion or solution BID (eg, fluocinonide 0.05%, clobetasol 0.05%, or betamethasone 0.05%)
  • Monitor for 2 weeks:
    • If rash is the same or has worsened, continue to pause ERLEADA and refer to a dermatologist.
    • If rash improves to grade 2, continue to pause ERLEADA and continue current management; monitor for 1 week.
      • If the rash is the same or has worsened after 1 week of monitoring, continue to pause ERLEADA and refer to a dermatologist.
      • If the rash improves to grade ≤1 after 1 week of monitoring, see the next sub-bullet.
    • If rash improves to grade ≤1:
      • Reinitiate ERLEADA at half dose (120 mg) for 2 weeks
      • Continue oral antihistamines for 2 weeks
      • Start tapering oral steroids
      • Continue topical treatment until rash resolves
      • Return to full dose ERLEADA after 2 weeks of half dose if rash remains grade ≤1

aRash is a grouped term that includes MedDRA Preferred Terms related to the general term ‘rash’.

Rash Grading

  • Rash may be graded differently according to the type of rash and associated symptoms.18
    • For example, maculopapular rash is graded by the BSA covered, presence of symptoms, and limitation on ADL, and not the severity of the rash.
  • Please consult NCI-CTCAE v5.0 for specific grading criteria for various types of rash.18

BSA Calculation

  • The SPARTAN and TITAN studies do not specify tools for calculating BSA.3,6,9,12
  • BSA calculators and resources are available in the public domain, including The Rule of Nines (also known as the Wallace Rule of Nines), for estimating BSA involvement in burn patients.19,20
  • The Rule of Nines estimation of BSA involvement is based on assigning percentages to different body areas as shown below.19-21
  • In the literature, the palm of the hand with fingers has also been used for estimating the BSA of an affected area and is considered approximately 1% of total BSA (not shown below).20,22

The Rule of Nines Estimate of BSA21

Etiology of Rash

  • The etiology of rash with ERLEADA remains unclear.23
  • Preclinical data that evaluated the in vitro chemical reactivity and hypersensitivity potential of ERLEADA and enzalutamide in a mouse drug allergy model have also been reported.24

Other Studies and Analyses

  • Additional studies/analyses were conducted to evaluate:
    • Pharmacokinetics and relationship between ERLEADA exposure and selected clinical efficacy and safety observations, including skin rash, in the TITAN study.25
    • Incidence and management of skin rash, and the association of rash with clinical outcomes in Asian and non-Asian patients from the SPARTAN and TITAN studies.26
    • Incidence, clinical risk factors, and correlation of rash with plasma exposure in Japanese patients from SPARTAN, TITAN, and a phase 1 study in patients with mCRPC.27
    • Identification, incidence, and/or management of rash/dermatologic AEs in patients with prostate cancer treated with ERLEADA.28-31
    • Effects of dose reduction32,33 and dose titration34 on skin-related AEs as well as low body weight as a risk factor and timing of onset for cutaneous AEs in patients treated with ERLEADA.35

Postmarketing Safety and Case Reports

Rash:

  • Rash safety data from the FAERS database and case reports were identified in the literature.36-42
  • A relevant review article was identified in the literature describing the author’s experience with 1 patient who had a rash while receiving treatment with ERLEADA and the subsequent interventions performed.43

SCARs

  • Rare postmarketing cases of SCARs, including DRESS and SJS/TEN, which can be life threatening or may lead to death, have been reported with ERLEADA. Discontinue ERLEADA immediately if signs or symptoms of a SCAR develop.44 Please refer to local labeling for additional considerations and data.
  • There were no events of DRESS, SJS, or TEN reported with ERLEADA in the phase 3, randomized, placebo-controlled, registrational TITAN (N=1052) and SPARTAN (N=1207) studies in patients with mCSPC and nmCRPC, respectively.11,45,46
  • SCARs safety data from retrospective studies, the FAERS database, and published case reports in patients receiving ERLEADA were identified in the literature.39,47-61
A+P Anterior + posterior MedDRA Medical Dictionary for Regulatory Activities
ADL Activities of daily living NCI-CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events
ADT Androgen deprivation therapy nmCRPC Non-metastatic castration- resistant prostate cancer
AE Adverse event OR Odds ratio
AUC Area under the curve OS Overall survival
AUC0-24h,ss Area under the curve after 24 hours, steady state PO Orally
BID Twice daily PY Patient-years
BSA Body surface area R Randomized
CI Confidence interval SCARs Severe cutaneous adverse reactions
DRESS Drug reaction with eosinophilia and systemic symptoms SJS Stevens-Johnson Syndrome
FAERS United States Food and Drug Administration Adverse Event Reporting System SPF Sun protection factor
GnRH Gonadotropin-releasing hormone TEAE Treatment-emergent adverse event
mCRPC Metastatic castration-resistant prostate cancer TEN Toxic epidermal necrolysis
mCSPC Metastatic castration-sensitive prostate cancer
  1. Smith MR, Saad F, Chowdhury S, et al. Apalutamide and overall survival in prostate cancer. Eur Urol. 2021;79(1): 150-158.
  2. Smith MR, Saad F, Chowdhury S, et al. Supplement to: Apalutamide and overall survival in prostate cancer. Eur Urol. 2021;79(1):150-158.
  3. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378:1408-1418.
  4. J&J PRD. Clinical Study Report: A multicenter, randomized, double-blind, placebo-controlled, phase III study of ARN- 509 in men with non-metastatic (M0) castration-resistant prostate cancer selective prostate AR targeting with ARN-509 (SPARTAN) protocol ARN-509-003; Phase 3 JNJ-56021927 (apalutamide); 2017. Updated March 29, 2018. Accessed September 19, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/rev_210951_arn-509-003_CSR_ Redacted.pdf.
  5. Smith MR, Saad F, Chowdhury S, et al. Supplement to: Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418.
  6. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381:13-24.
  7. Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021;39(20):2294-2303.
  8. Chi KN, Chowdhury S, Bjartell A, et al. Supplement to: Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021;39(20):2294-2303.
  9. Chi KN, Agarwal N, Bjartell A, et al. Protocol for: Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381:13-24.
  10. Chi KN, Agarwal N, Bjartell A, et al. Supplement to: Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381:13-24.
  11. Data on File. Apalutamide. TITAN Clinical Study Report. Janssen Research & Development, LLC. EDMS-ERI-174221283; 2019.
  12. Smith MR, Saad F, Chowdhury S, et al. Protocol for: Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418.
  13. Data on File. Apalutamide. Investigator's Brochure: Edition 18. Janssen Research and Development, LLC. EDMS-ERI-71748133; 2024.
  14. 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. [published online ahead of print July 05, 2024]. Prostate Cancer Prostatic Dis. doi:10.1038/s41391-024-00858-4.
  15. Small EJ, Saad F, Chowdhury M, et al. Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer. Ann Oncol. 2019;30(11):1813-1820.
  16. Perez-Ruixo C, Ackaert O, Ouellet D, et al. Efficacy and safety exposure-response relationships of apalutamide in patients with nonmetastatic castration-resistant prostate cancer. Clin Cancer Res. 2020;26(17):4460-4467.
  17. National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0. National Institute of Health. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf. Accessed December 08, 2022.
  18. National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.03. National Institute of Health. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Accessed December 08, 2022.
  19. Wallace AB, McGill MSc, Edin MB. The exposure treatment of burns. Lancet. 1951:1(6653):501-504.
  20. Lund CC, Browder NC. Davis L. Surgery: Gynecology and Obstetrics. Boston, MA: The Surgical Publishing Company of Chicago; 1944:352-358.
  1. Moore RA, Waheed A, Burns B. Rule of nines. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. 2000- [cited 2020 December 9]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK513287/.
  2. Agarwal P, Sahu S. Determination of hand and palm area as a ratio of body surface area in Indian population. Indian J Plast Surg. 2010;43(1):49-53.
  3. Data on File. Apalutamide. Investigator's Brochure: Edition 10. Janssen Research and Development, LLC. EDMS- ERI-71748133; 2017.
  4. Ji C, Guha M, Zhu X, et al. Enzalutamide and apalutamide: in vitro chemical reactivity studies and activity in a mouse drug allergy model. Chem Res Toxicol. 2020;33(1):211-222.
  5. 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(5):629-641.
  6. Azad AA, Chua MLK, Smith MR, et al. Exploratory analyses of incidence of skin rash and efficacy with apalutamide treatment of patients with advanced prostate cancer in SPARTAN and TITAN studies. Poster presented at: 13th European Multidisciplinary Congress on Urological Cancers (EMUC21); November 25-28, 2021; Athens, Greece.
  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(1):139.
  8. Pan A, Reingold RE, Zhao JL, et al. Dermatologic adverse events in prostate cancer patients treated with the androgen receptor inhibitor apalutamide. J Urol. 2022;207(5):1010-1019.
  9. Munoz Calahorro C, Rivero Belenchón I, Moliner Malaxechevarría J, et al. Rash in patients treated with apalutamide in different prostate cancer settings. A real world study [abstract]. Eur Urol Open Sci. 2022;45(Suppl. 2):S161. Abstract P085.
  10. Birtle AJ, Formisano L, Descamps V, et al. Early identification and management of patients with rash on apalutamide. Oncol Ther. 2024;12(3):609-620.
  11. 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(1):171.
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