Abstract
Background/Aim: Therapeutic strategies for prostate cancer are currently undergoing a paradigm shift due to the advent of next-generation androgen receptor inhibitors. Among these inhibitors, apalutamide is regarded as a key drug because of its effectiveness. However, risk factors for and the timing of the onset of apalutamide-related cutaneous adverse events remain unclear. Therefore, the present study investigated key risk factors for and timing of the onset of apalutamide-related cutaneous adverse events. Patients and Methods: Sixty-two Japanese patients with non-metastatic castration-resistant prostate cancer treated with 240 mg/day of apalutamide were enrolled in the present study. Results: Twenty-four patients (38.7%) developed cutaneous adverse events. Multivariable logistic regression analysis of age, height, and body weight identified body weight as a significant predictive factor for the incidence of cutaneous adverse events (p=0.019). When the mean body weight of patients (63.80 kg) was set as the cut-off value, the Kaplan–Meier analysis revealed that the risk of cutaneous adverse events was significantly increased in those with a body weight <63.8 kg (p=0.003, the log-rank test). The analysis also showed that cutaneous adverse events developed within the first 6 months regardless of body weight. Conclusion: A lower body weight is a significant risk factor for apalutamide-related cutaneous adverse events and their onset is within 6 months of initiation of therapy.
Therapeutic strategies for prostate cancer are currently undergoing a paradigm shift due to the advent of next-generation androgen receptor inhibitors. Among these inhibitors, apalutamide is regarded as a key drug because of its beneficial effectiveness. The SPARTAN study, a global phase III clinical trial on apalutamide for patients with non-metastatic castration-resistant prostate cancer (non-mCRPC), showed that metastasis-free survival and the time to symptomatic progression were significantly longer with apalutamide than with a placebo (1). The TITAN final analysis recently reported the long-term benefits of intensified androgen deprivation therapy (ADT) using apalutamide in the majority of patients with mCSPC (2).
Previous studies demonstrated the benefits of intensified ADT with additional treatments for patients with mCSPC. The CHAARTED (3), STAMPEDE (4, 5), and LATITUDE (6) studies reported improvements in the overall survival of patients with mCSPC based on long-term observations with docetaxel or abiraterone acetate added to ADT as the initial treatment. However, intensified ADT with docetaxel or abiraterone has not yet been widely applied because of the risk of adverse events associated with docetaxel and the long-term administration of corticosteroids in conjunction with abiraterone. Since the risk of severe adverse events following the administration of next-generation androgen receptor inhibitors, such as apalutamide, is lower, they may be the preferred treatment for mCSPC and non-mCRPC. Nevertheless, the safer usage of next-generation androgen receptor inhibitors is naturally desired.
Apalutamide is associated with some adverse events, including convulsions, ischemic heart disease, arrhythmia, interstitial lung disease, and cutaneous adverse events (7). Among these adverse events, cutaneous adverse events are reported to occur especially frequently (1). The package insert for apalutamide indicates that a dose reduction from 240 to 180 mg/day is warranted when a cutaneous adverse event is identified during the course of administration (7). A further dose reduction to 120 mg/day is recommended when the adverse event is not resolved at a dose of 180 mg/day (7). Despite this guidance, oncologists have expressed concerns regarding the follow-up of patients treated with apalutamide because the risk factors for and timing of the onset of cutaneous adverse events remain unclear. Therefore, the present study was performed to identify key risk factors and the timing of the onset of apalutamide-related cutaneous adverse events.
Patients and Methods
Ethical approval. The Ethics Committee of The Jikei University School of Medicine approved the study protocol (approval number: #32-125) and informed consent was obtained from patients in the form of opt-out.
Study population. We retrospectively recruited 62 Japanese patients who met the following inclusion criteria: i) Referral to The Jikei University School of Medicine-affiliated hospitals between June 2019 and September 2021 for non-mCRPC and ii) the selection of treatment with 240 mg/day of apalutamide by the patient (Table I). All patients concomitantly received ADT (a luteinizing hormone-releasing hormone agonist or antagonist). Patients visited our hospital every 4 weeks and clinical laboratory data, including serum prostate-specific antigen levels and adverse events, were carefully examined. A histopathological examination for cutaneous eruptions was performed for cases 45 and 61.
Data for each patient.
Apalutamide was continued until progression of prostate cancer-related symptoms or onset of severe adverse events (8). A dose reduction in or the discontinuation of apalutamide was performed according to the practical guide for the appropriate use of apalutamide (7). In case 47, apalutamide was re-administered after discontinuation due to a cutaneous adverse event according to the insert package (7). Adverse events were graded using the Common Terminology Criteria for Adverse Events of the National Cancer Institute, version 5.0 (9).
Statistical analysis. Statistical analyses were performed using SPSS version 22 software (IBM, Armonk, NY, USA). The log-rank test was used to compare data between patients using the mean body weight as a cut-off. A multivariable logistic regression analysis was conducted to identify parameters associated with the incidence of cutaneous adverse events. p-Values of less than 0.05 were considered to be significant.
Results
In all patients, the valves of average±standard deviation for age, height, body weight, and the body mass index were 78.66±8.33 years, 165.01±6.83 cm, 63.80±11.00 kg, and 23.33±3.20 kg/m2, respectively. Among patients overall, 24 (38.7%) developed cutaneous adverse events (Table I). The comparison between profiles of the patients with cutaneous adverse events and those without is shown in Table II. The severity of cutaneous adverse events was grade 1 in six patients, grade 2 in 12, and grade 3 in six according to the Common Terminology Criteria for Adverse Events version 5.0. The mean time from the initial administration of apalutamide to the onset of cutaneous adverse events was 65.5 days.
Comparison between profiles of patients with cutaneous adverse events and those without. Values are given as the mean±standard deviation.
Cutaneous adverse events appeared as small erythematous macules and patches, so-called maculopapular eruptions, on the trunk and gradually spread to the neck, head, and extremities. Images of two representative cases (cases 45 and 61) are shown in Figure 1. Their histopathological findings both included interface dermatitis. In case 47, with a grade 3 cutaneous adverse event, administration was discontinued according to the insert package. One month later, administration was restarted at 60 mg/day and no cutaneous adverse event has appeared after 1 year.
Representative images of apalutamide-related cutaneous adverse events. Case 45: Maculopapular eruptions are evident on the trunk and upper limbs. Vacuolar degeneration in the dermal-epidermal junction is visible (hematoxylin-eosin stain, ×400). Case 61: Maculopapular eruptions are evident on the trunk. Vacuolar degeneration in the dermal-epidermal junction and individual cell necrosis in epidermal cells can be seen (hematoxylin-eosin stain, ×400).
Multivariable logistic regression analysis of age, height, and body weight identified body weight as a significant predictive factor for the incidence of cutaneous adverse events (p=0.019) but not age or height (Table III). When the mean body weight of patients (63.80 kg) was set as the cut-off value, the Kaplan–Meier analysis revealed that the incidence of cutaneous adverse events significantly increased in patients with a body weight under 63.80 kg (log-rank p=0.003) (Figure 2). The analysis also showed that cutaneous adverse events appeared within the first 6 months regardless of body weight.
Results of multivariable logistic regression analysis.
Results of the Kaplan–Meier analysis. The vertical axis indicates the incidence of cutaneous adverse events. The horizontal axis shows the duration from the initial administration of apalutamide to the onset of cutaneous adverse events. Blue and red lines indicate the patient groups weighing less and more than the mean body weight, respectively.
Discussion
The present results on apalutamide-related cutaneous adverse events suggest that a lower body weight is a significant risk factor and the onset of such events is within 6 months of initiation of therapy.
With regard to the risk factors for apalutamide-related cutaneous adverse events, limited relevant information is available. In the SPARTAN study, in which a dose of 240 mg/day was administered regardless of the body weight of patients, cutaneous adverse events were detected in 19 out of 34 Japanese patients (55.9%) and 172 out of 769 non-Japanese patients (22.4%) (1, 10, 11). The median weight of Japanese patients was 61.9 kg, while that of all patients combined was 87.8 kg according to a previous study (11) and data on file at Janssen Pharmaceuticals (Beerse, Belgium).
With regard to the timing of the onset of apalutamide-related cutaneous adverse events, some relevant information is available. The plasma concentration of apalutamide gradually increases with repeated administration at 240 mg/day, leading to a steady-state plasma level in 4 weeks. The facts are supported by basic data which indicate a long half-life for apalutamide (130±36.9 h) and its slow catabolization (10). Moreover, 65% of the drug and its metabolites were excreted renally, while 24% were excreted in feces 71 days after single-dose administration of apalutamide at 240 mg to six healthy adult humans (10). A phase I study (PCR1008) showed that apalutamide-related cutaneous adverse events appeared at a mean of 68.9 days after the initiation of apalutamide administration (12). Similarly, the SPARTAN study showed that adverse events occurred at a mean of 87.1 days for 34 Japanese participants after the initiation of administration (12). Based on these results, cutaneous adverse events may occur when the concentration in the blood reaches a certain level after the initiation of administration.
A marked discrepancy was apparent between our results and the findings of the SPARTAN study in which no risk factors were associated with apalutamide-related cutaneous adverse events (1, 11). Uemura et al. reported that the body mass index did not correlate with the incidence of cutaneous adverse events when 25 kg/m2 was set as the cut-off value. In the present study, the mean body weight of 63.80 kg was set as the cut-off value, and the mean body mass index was 23.33 kg/m2 for the whole patient group (12). Our cut-off value for body weight appeared to be lower than that of Uemura et al. in reference to the mean body mass index in the present study. This may be one reason for the discrepancy observed in risk factors for cutaneous adverse events between the previous findings and present results.
Different findings in the lymphocyte transformation test, a test to detect lymphocyte activation by the causative drug, were reported in previous studies. Previous reports described two cases of toxic epidermal necrolysis, a potentially lethal drug-induced cutaneous eruption characterized by epidermal necrosis, and the cases had positive results in the lymphocyte transformation test (13, 14). Shima et al. reported three cases with apalutamide-related maculopapular rash including two cases with negative test results and one non-examined case (15). Therefore, the lymphocyte transformation test may be useful for distinguishing toxic epidermal necrolysis from other types of cutaneous adverse events.
Our histopathological examinations revealed interface dermatitis in the two cases examined (cases 45 and 61). A previous study detected three cases of maculopapular eruptions showing interface dermatitis histopathologically and two cases of toxic epidermal necrolysis, which histopathologically showed a severe interface change, among six cases with apalutamide-related cutaneous adverse events (16). Based on our results and these findings, apalutamide-related cutaneous adverse events may be characterized by interface damage at the dermal-epidermal junction.
Since apalutamide contributes to prolonging metastasis-free survival and overall survival in patients with non-mCRPC and mCSPC, respectively, the long-term administration of apalutamide is appropriate as long as its effectiveness continues in each patient, particularly those with mCSPC. Therefore, the timing of the onset of cutaneous adverse events in the long-term warrants further study. With regard to this, the present results indicated that cutaneous adverse events rarely occurred after 6 months from the initial administration. This evidence may reduce the strain on oncologists who follow-up patients treated with apalutamide in the long term.
A few limitations need to be considered. The present study was conducted as a retrospective analysis of a relatively small number of patients. A prospective study of a larger number of patients is needed to obtain higher-quality evidence. Furthermore, the present study lacked information on non-Japanese patients because data, including body size, for non-Japanese patients were unavailable for researchers not belonging to the company conducting the clinical trial. An analysis of data including non-Japanese patients will provide more universal evidence. Moreover, the patient group did not include patients with mCSPC. Since long-term administration of apalutamide is expected, particularly for patients with mCSPC, a study that includes patients with mCSPC is needed.
In conclusion, the present results on apalutamide-related cutaneous adverse events suggest that a lower body weight is a significant risk factor, and their onset is within 6 months of initiation of therapy. Oncologists need to carefully examine cutaneous symptoms in patients treated with apalutamide, particularly within 6 months of its initial administration.
Footnotes
Authors’ Contributions
MK, TK and YN were involved in study design and data interpretation. MK, TK, KT, MM, KH, TY, HO, TY, SS, YW and YN were involved in investigation and the data analysis. TK, YN, SE and AA reviewed the article. MK, YN and KT provided the interpretation of patients results and edited the article. All Authors critically revised the report, commented on drafts of the article, and approved the final report.
Conflicts of Interest
Shin Egawa is a paid consultant/advisor of Takeda, Astellas, AstraZeneca, Sanofi, Janssen, and Pfizer. Takahiro Kimura is a paid consultant/advisor of Astellas, Bayer, Janssen and Sanofi. The other Authors do not have any conflicts of interest to declare.
- Received January 6, 2022.
- Revision received February 26, 2022.
- Accepted March 3, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
