Prostate cancer (PCa) is one of the most commonly diagnosed cancers in men and has the fifth highest mortality globally (Sung et al., 2021). Approximately 15%–30% of PCa patients may experience prostate-specific antigen (PSA) recurrence with radical treatment (Zumsteg et al., 2015; Cornford et al., 2021). Majority of these patients will receive androgen deprivation therapy (ADT) as initial treatment (Mohler and Antonarakis, 2019). However, long-term exposure to ADT eventually results in castration-resistant prostate cancer (CRPC), which contains metastatic (m) and nonmetastatic (nm) disease states (Karantanos et al., 2013; Mateo et al., 2019). The androgen receptor (AR) is overexpressed in such patients, which indicates that AR plays a central role in the pathogenesis of PCa. Studies have shown that direct inhibition of AR in addition to ADT may provide more complete blockade of androgen signaling than ADT alone (Clegg et al., 2012; Dai et al., 2017).

Apalutamide (Erleada^®), an oral selective AR inhibitor, binds directly to the ligand-binding domain of AR. It impeded AR-mediated gene transcription and impaired nuclear localization and DNA binding in PC cells. Apalutamide has been approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC) and metastatic castration-sensitive prostate cancer (mCSPC) in various countries (Al-Salama, 2019; Boukovala et al., 2020; Dror and Chi, 2020; Hoy, 2020). The recommended dose is 240 mg (four 60 mg tablets) administered orally once daily, and patients should also receive ADT. Meanwhile, the efficacy of apalutamide has been investigated recently. The large landmark randomized, double-blind, placebo-controlled clinical trials SPARTAN (NCT01946204) (Perez-Ruixo et al., 2020; Smith et al., 2021) and TITAN (NCT02489318) (Chi et al., 2019; Chi et al., 2021) confirmed that the addition of apalutamide to ADT prolongs metastasis-free survival and overall survival, maintained health-related quality of life, and the safety profile did not differ substantially from the placebo group. The most common AEs to apalutamide are fatigue, hypertension, rash, diarrhea, nausea, decreased weight, arthralgia, falls, hot flushes, decreased appetite, fracture, and peripheral edema.

Clinical trials are conducted under widely varying conditions, and AEs observed in the clinical trials of a drug may not reflect all AEs observed in practice. Thus, it is essential to evaluate the postmarketing safety profile of apalutamide in the real-world. The United States food and drug administration (FDA) adverse event reporting system (FAERS) is a well-known AE spontaneous reporting system (SRS), which can be employed to assess the potential association between drugs and AEs (Sakaeda et al., 2011; Michel et al., 2017). In this study, we aimed to explore the postmarketing safety profile of apalutamide based on AE reports from the FAERS database.

Apalutamide, a high-affinity AR inhibitor, binds directly to the ligand-binding domain of AR and inhibits nuclear localization and DNA binding within prostate cancer cells (Al-Salama, 2018; Rathkopf and Scher, 2018). Apalutamide is a well-tolerated drug for PCa patients and is associated with a favorable trend of improved overall survival. The recent guidelines were updated to recommend apalutamide in patients with nmCRPC and mCSPC with background ADT therapy (Mohler and Antonarakis, 2019; Cornford et al., 2021). Thus, there may be an increasing annual trend of prescriptions, as well as growing clinical experience with apalutamide. It is important to underline monitoring safety and postmarketing surveillance for apalutamide. The present study provides real-world data on the safety profile of apalutamide.

We systematically reviewed the literature to evaluate the safety profiles of apalutamide. Ten clinical trial studies for apalutamide in PCa were identified (Supplementary Table S2) (Rathkopf et al., 2013; Smith et al., 2016; Rathkopf et al., 2017; Chi et al., 2019; Tsuchiya et al., 2019; Perez-Ruixo et al., 2020; Chi et al., 2021; McKay et al., 2021; Saad et al., 2021; Smith et al., 2021). The addition of apalutamide to ADT resulted in a safety profile that showed no substantial difference from placebo plus ADT. The most frequently investigated AEs were skin rash, fatigue, fracture, hypertension, hot flush, diarrhea, seizures, arthralgia and so on. Our disproportionality analyses revealed that the most common and frequently reported PTs for apalutamide were rash, fatigue, hot flush, diarrhea, falls, decreased appetite, decreased weight, and dizziness. The results were mostly consistent with the manufacturer’s labeling and clinical trials. We also identified that rash was more frequently reported, while falls, hypothyroidism, and seizures occurred in only a few patients.

Otherwise, our findings raise some different safety concerns. First, we detected some rare AEs with a high ROR, such as increased blood testosterone, duodenal perforation, and right ventricular dysfunction. Second, we found some unexpected PTs with high ROR, included lichenoid keratosis, increased eosinophil count, bacterial pneumonia, pulmonary tuberculosis, hydronephrosis. Notably, clinicians and pharmacists should be aware of these rare, new and additional observed AEs. Furthermore, no signals were detected following disproportionality for several frequently reported AEs listed on the drug label, such as nausea, vomiting, fracture, hematuria. These discrepancies could be explained by the fact that AEs are fairly common for all drugs in the FAERS database. Signal scores can be suppressed by a large number of reports for an AE associated with multiple drugs. Disproportionality requires that an AE is reported more (or less) frequently for a specific drug. The absence of a signal does not imply the absence of relative AEs; it only indicates that there was no disproportion seen for these AEs.

Our disproportionality analyses identified that the most common and significant SOCs for apalutamide were “skin and subcutaneous tissue disorders”. Interestingly, majority PTs belongs to “skin and subcutaneous tissue disorders” were dermatological adverse events (dAEs) (e.g., rash, pruritus, heperhidrosis). The SPARTAN and TITAN trials reported that the incidence of skin rash was 23.8% and 27.1%, respectively (Uemura et al., 2020). However, most skin rashes were grade 1–3 and rarely caused dose reduction or discontinuation. The highest frequency of dAEs commonly occurs 1–4 months post apalutamide initiation for PCa. Interestingly, the other AR inhibitor enzalutamide, darolutamine, showed a low rash incidence in clinical trials. This difference may be due to the chemical structure of apalutamide, which has a more reactive 2-cyanopyridine moiety and more readily activates the immune system by increasing lymph node cellularity and T cell and B cell counts (Drago et al., 2021; Pan et al., 2022). A published study showed that high apalutamide exposure was significantly associated with skin rash; thus, dose reductions may help prevent dAE recurrence (Perez-Ruixo et al., 2020). Most dAEs were effectively managed with moderate to high-potency topical steroids and oral antihistamines.

Pain and fatigue are common symptoms in metastatic PCa, while fatigue is also a common and substantial AE of ADT (Holm et al., 2018). Data mining from the FAERs database for apalutamide shows that fatigue is a frequently reported AE (ROR = 3.17). The post hoc analysis for the TITAN study showed that pain and fatigue were improved or not worsened in patients with mCSPC treated with apalutamide compared with placebo (Agarwal et al., 2021). The analysis demonstrated that patients benefitted through delayed disease progression, and they also maintained HRQoL with no additional pain or fatigue burden.

Due to the presence of incomplete reports in the FAER database, we could not identify the grade of the AE reports. Hence, the serious outcomes of AEs reports were explored in this study. About 44.15% AE reports suffered specific serious outcomes, including hospitalization-initial or prolonged (24.57%) and death (16.17%). The risk factors (such as weight, age, dose) for serious AEs was explored, however there was no sufficient clinical information to certify these. Hence, we remind clinicians and pharmacists that the prescriber’s information should be followed for managing AE related dose interruptions and/or modifications. Besides, we found that in the death reports most were related to the cardiovascular and cerebrovascular disease (a grouped term that included various events), excepted the reports related to the disease progression of cancer. Patients with clinically significant cardiovascular and cerebrovascular disease who are prescribed apalutamide should be monitored for risk factors (Morgans et al., 2021).

The results of this study indicated that the median onset time was 62 days, and most AEs occurred within the first month (n = 530, 32.94%) after exposure to apalutamide. The majority of AEs were reported within half a year, but AEs might still have occurred after 1 year. Thus, a longer follow-up period is needed to observe the AEs of apalutamide in future clinical studies.

Several limitations of the present study need to be addressed. The FAERs database is a spontaneous reporting database, so the rates of occurrence of each AE for apalutamide could not be estimated. Besides, the existence of a report does not establish causation in the FAERS database, so the results in the present study merely showed the potential AEs that meant the clinicians and pharmacists to enhance their vigilance. Meanwhile, the estimates of exposure adjusted AEs was not possible owing to incomplete information extracted from the FAERs database. The ROR was used as the measure of disproportionality, which provided the highest number of signals, which only report information on a possible causal relationship between an adverse event and a drug. Further well-organized clinical trials were need to investigate the causal relationship. Lastly, we could not distinguish AE reports related to apalutamide and concomitant ADT therapy owing to incomplete information. Hence, the association between concomitant ADT therapy and some related AEs could not be examined. Despite these limitations, the FAERs is still very useful for post-marketing safety surveillance.

In conclusion, the present study scientifically and systematically quantified the safety profile of apalutamide by the FAERS database. The frequent AEs (e.g.,, rash, fatigue, diarrhea, hot flush, fall) and additional observed AEs (e.g., lichenoid keratosis, increased eosinophil count, bacterial pneumonia, pulmonary tuberculosis) need to be monitored. Moreover, we observed strong signals for dermatological adverse events associated with apalutamide. Overall AE profile detected in this study is consistent with the clinical trial experience reported in the past and the manufacturer’s drug label for apalutamide. We hope that further studies and clinical practice will provide valuable evidence for the safety profile of apalutamide.