Elicit: Safety and Interactions of Enzalutamide

Safety and drug–drug interaction considerations for enzalutamide

Enzalutamide has a favorable benefit-risk profile but necessitates careful drug interaction management due to its strong CYP3A4 induction affecting up to 93% of patients, requiring dose adjustments with CYP2C8 inhibitors and systematic screening for interactions with commonly used medications including opioids, chemotherapy agents, and narrow therapeutic index drugs.

Abstract

Enzalutamide demonstrates a favorable benefit-risk profile in metastatic castration-resistant prostate cancer, with improved overall survival (HR 0.67, 95% CI 0.52-0.86, p=0.002), though it carries notable safety concerns. The most common adverse events include fatigue (70% of patients, with 14% experiencing grade 3/4), with additional risks of seizures (1% incidence), cardiovascular events (HR 1.31), and falls in elderly patients. The safety profile remains consistent over extended treatment periods exceeding 4 years. Enzalutamide functions as a strong inducer of CYP3A4 and moderate inducer of CYP2C19 and CYP2C9, resulting in widespread drug interactions affecting 32-93% of patients depending on screening methodology. Clinically significant interactions include 44.7% reduction in oxycodone exposure, 22% reduction in cabazitaxel exposure, and substantial decreases in exposure to midazolam (86%), omeprazole (70%), and warfarin (56%).

Clinical management requires dose reduction to 80 mg daily when coadministered with strong CYP2C8 inhibitors, avoidance of narrow therapeutic index drugs metabolized by CYP2C9, CYP2C19, or CYP3A4, and careful monitoring for inadequate pain control with opioids and for overdose risk upon enzalutamide discontinuation. Given that the majority of patients take five or more concomitant medications, systematic screening for drug interactions is essential before initiating therapy. Special consideration is needed for elderly patients (mean age 77 years), who face elevated risks from polypharmacy, falls, and cognitive effects when enzalutamide is combined with CNS depressants used by 63% of patients. Treatment modifications were necessary in 9.2% of patients, and 9.8% experienced adverse events directly attributable to drug interactions.

Methods

We analyzed 10 sources from an initial pool of 200, using 8 screening criteria. Each paper was reviewed for 6 key aspects that mattered most to the research question.

Records from Elicit search

n = 200

Papers screened using: Human Participants with Enzalutamide, Safety or Drug Interaction Outcomes, Appropriate Study Design, Separable Enzalutamide Data, Beyond Efficacy Only, Human Data Available, Sufficient Publication Detail, Enzalutamide Specificity

n = 200

Papers screened out

n = 190

Papers included for extraction

n = 10

Paper search

We performed a semantic search across over 138 million academic papers from the Elicit search engine, which includes all of Semantic Scholar and OpenAlex.

We ran this query: "Safety and drug–drug interaction considerations for enzalutamide"

The search returned 200 total results from Elicit.

We retrieved 200 papers most relevant to the query for screening.

Screening

We screened in sources based on their abstracts that met these criteria:

Data extraction

We asked a large language model to extract each data column below from each paper.

Adverse Events

Extract all adverse events and safety concerns specifically related to enzalutamide, including:

Drug Interactions

Extract all drug-drug interaction data involving enzalutamide, including:

Population Considerations

Extract safety and drug interaction considerations specific to different patient populations receiving enzalutamide, including:

Dosing Safety

Extract dosing information related to safety and drug interactions for enzalutamide, including:

Study Population

Extract characteristics of the study population relevant to interpreting safety and drug interaction data, including:

Key Findings

Extract the main conclusions and clinical recommendations regarding enzalutamide safety and drug interactions, including:

Results

Characteristics of Included Studies

Study Full text retrieved? Study type Patient population Sample size Follow-up duration
S. D. O. Detert Oude Weme et al., 2023 Yes Drug interaction study Men with prostate cancer 26 patients Up to 8 hours
I. Davis et al., 2019 Yes Randomized controlled trial Advanced prostate cancer, mCRPC 5,202 patients (2,736 abiraterone, 2,466 enzalutamide) Indexed to 6 months after ADT initiation
A. Merseburger et al., 2022 No Randomized phase 3b trial mCRPC, progressed on ADT 271 patients (136 enzalutamide, 135 placebo) Data cutoff April 30, 2020
G. E. Benoist et al., 2018 Yes Retrospective review mCRPC 105 patients November 2013 to July 2016
J. Gibbons et al., 2015 Yes Phase I drug interaction studies Healthy males and mCRPC patients 41 healthy subjects + 14 mCRPC patients Not specified
Juan Vicente-Valor et al., 2021 No Cross-sectional study mCRPC 173 patients August 2016 to July 2020
S. Appukkuttan et al., 2021 No Claims database analysis nmCRPC, mean age 77 years 149 Apa, 319 Enza patients January 2017 to March 2020
B. Belderbos et al., 2017 Yes Pharmacokinetic crossover study mCRPC, progressed after docetaxel 14 evaluable patients Three consecutive cabazitaxel cycles
Y. Ning et al., 2013 No FDA drug approval summary mCRPC, previously received docetaxel 1,199 patients (800 enzalutamide, 399 placebo) Not specified
C. Higano et al., 2015 No Phase 1-2 long-term follow-up study CRPC with and without prior chemotherapy 140 patients More than 4 years

The included studies comprised a mix of randomized controlled trials, drug interaction studies, retrospective analyses, and regulatory summaries. Study populations ranged from healthy volunteers to patients with metastatic castration-resistant prostate cancer (mCRPC), with sample sizes ranging from 14 to over 5,000 patients. Most studies focused on mCRPC patients who had received prior treatments including androgen deprivation therapy and chemotherapy.

Adverse Events and Safety Profile

Common Adverse Events

The most frequently reported adverse events with enzalutamide included fatigue (70% of patients), asthenia, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, and upper respiratory infection. Fatigue emerged as the predominant dose-dependent adverse event, with 14% of patients experiencing grade 3/4 fatigue. The safety profile remained consistent over extended treatment periods, with minimal changes in adverse event rates even after up to 4 years of treatment.

In the PRESIDE trial, the most common grade 3 adverse events were neutropenia (13%) and asthenia (7%). Grade 4 neutropenia occurred in 17% of patients in the enzalutamide group compared to 21% in the placebo group. Treatment discontinuations due to adverse events were more frequent with enzalutamide (33 events) compared to standard care (14 events).

Serious Adverse Events

Seizures represented a notable safety concern, occurring in 1% of patients in the enzalutamide group compared to none in placebo groups. In one drug interaction study, a generalized tonic-clonic seizure led to treatment discontinuation. The risk of seizures increased when enzalutamide was coadministered with strong CYP2C8 inhibitors, particularly at doses above 240 mg.

Cardiovascular events also emerged as a concern. The ENZAMET trial demonstrated an increased risk of major cardiovascular events with enzalutamide (HR 1.31, 95% CI 1.08-1.59). The number needed to harm for a major cardiovascular event was 88. Serious treatment-emergent adverse events were reported in 49% of patients in the enzalutamide group versus 39% in the placebo group.

Special Safety Considerations

Enzalutamide treatment was associated with an increased risk of falls in elderly patients, which is particularly relevant given that patients treated with enzalutamide were typically older (mean age 77 years) with multiple comorbidities. Long-term androgen deprivation therapy increased the risk of fractures and neurocognitive effects. When combined with CNS depressants—used by 63% of patients in one cohort—enzalutamide may increase the risk of cognitive side effects.

Gastrointestinal bleeding risk increased when enzalutamide was used with proton pump inhibitors (PPIs), which were taken by 56% of patients in one study. This interaction resulted from decreased plasma concentrations of PPIs due to enzalutamide’s enzyme-inducing properties.

Drug-Drug Interactions

Mechanisms of Interaction

Enzalutamide functions as a strong inducer of CYP3A4 and a moderate inducer of CYP2C19 and CYP2C9. This enzyme induction capacity leads to decreased exposure to drugs metabolized by these pathways. Specifically, enzalutamide reduced exposure to midazolam by 86%, omeprazole by 70%, and S-warfarin by 56%. Conversely, enzalutamide exposure increased when coadministered with strong CYP2C8 inhibitors (gemfibrozil) by 2.2-fold and with strong CYP3A4 inhibitors (itraconazole) by 1.3-fold.

Specific Drug Interactions

Opioid Analgesics: Enzalutamide significantly reduced oxycodone exposure, decreasing mean AUC₀₋₈ₕ by 44.7% (p<0.001) and Cₘₐₓ by 35.5% (p=0.004). The active metabolite oxymorphone showed even greater reductions, with AUC₀₋₈ₕ decreased by 74.2% (p<0.001) and Cₘₐₓ by 56.0% (p=0.001). This interaction posed risks of inadequate pain control when starting enzalutamide and potential overdose upon enzalutamide discontinuation.

Chemotherapy Agents: When combined with cabazitaxel, enzalutamide reduced cabazitaxel exposure by 22% (95% CI 9-34%, p=0.005). The geometric mean AUC₀₋₂₄ₕ of cabazitaxel decreased from 234 ng·h/mL to 181 ng·h/mL. This reduction was attributed to CYP3A4 induction and raised concerns about subtherapeutic cabazitaxel concentrations, particularly when lower cabazitaxel doses were used.

Common Concomitant Medications: Enzalutamide interacted with multiple medication classes commonly prescribed to prostate cancer patients. Medications flagged for potential interactions included fentanyl, carbamazepine, nifedipine, ticagrelor, and various CNS depressants. Polypharmacy was prevalent, with 75.9-79.8% of patients taking five or more medications, substantially increasing the risk of clinically significant interactions.

Prevalence of Drug Interactions

The prevalence of potential drug-drug interactions (pDDIs) varied considerably depending on the screening tool used. Using Lexicomp, 85% of patients had at least one pDDI, compared to 54% with Micromedex and 32% with the Dutch drug database. In another study, 93.0% of enzalutamide-treated patients had at least one pDDI. The median number of interactions per patient ranged from 0-2 (Dutch database) to 4 (Lexicomp). Notably, 85% of identified interactions were classified as major, and 6.3% carried X-risk ratings indicating contraindication due to high probability of adverse events.

Population-Specific Considerations

Elderly Patients

Enzalutamide is primarily used in older men (mean age 77 years), a population at increased risk for drug interactions due to polypharmacy and age-related physiologic changes. Elderly patients (65-75 years) faced elevated risks due to multiple comorbidities and use of multiple potent drugs with narrow therapeutic windows. Higher comorbidity scores were associated with increased risk of adverse events. The combination of advanced age and CNS depressant use increased the risk of cognitive side effects and falls.

Organ Impairment

Studies excluded patients with significant hepatic impairment (Child-Pugh classification B or C) and renal impairment (eGFR <60 mL/min/1.73 m²). Patients were required to have adequate liver function, defined by specific bilirubin and liver enzyme thresholds. Hepatic disorders that could affect drug metabolism were identified as particular concerns.

Concomitant Therapy Considerations

For patients receiving chemotherapy, enzalutamide showed both benefits and risks. The PRESIDE trial demonstrated that continuing enzalutamide with docetaxel plus androgen deprivation therapy delayed time to progression. However, the combination increased toxicity, with serious adverse events occurring more frequently. Patients with a history of seizures or predisposition to seizures were excluded from combination therapy studies.

All patients were required to continue androgen deprivation therapy while receiving enzalutamide. Medications that could interact with enzalutamide via CYP3A4, CYP2C8, CYP2C9, or CYP2C19 pathways were prohibited in controlled studies.

Dosing and Safety Management

Standard Dosing

The standard recommended dose of enzalutamide is 160 mg administered orally once daily. This dose was established as the phase 3 dose following dose-finding studies that evaluated ranges from 30-600 mg/day.

Dose Modifications for Drug Interactions

When coadministered with strong CYP2C8 inhibitors such as gemfibrozil, the enzalutamide dose should be reduced to 80 mg once daily. This reduction is necessary because strong CYP2C8 inhibition increases enzalutamide exposure by 2.2-fold, raising the risk of dose-dependent adverse events, particularly seizures. Conversely, concomitant use with strong CYP3A4 inhibitors like itraconazole, which increases exposure by only 1.3-fold, does not require dose adjustment.

Medications Requiring Avoidance or Monitoring

Concomitant use of enzalutamide with narrow therapeutic index drugs metabolized by CYP2C9, CYP2C19, or CYP3A4 should be avoided. Specific medications in this category include phenytoin, warfarin, alfentanil, ergotamine, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. If avoidance is not possible, intensive monitoring is required for patients with major potential drug interactions.

For chemotherapy combinations, dose modifications may be necessary to maintain therapeutic drug levels. With cabazitaxel, the 22% reduction in exposure raised concerns about maintaining efficacy, particularly since recent data support using a lower standard cabazitaxel dose of 20 mg/m².

Maximum Tolerated Dose and Safety Monitoring

The maximum tolerated dose was identified as 240 mg/day. Doses above this threshold increased the risk of seizures. During long-term dosing studies, patients were initially switched to the maximum tolerated dose before transitioning to the phase 3 dose of 160 mg/day.

Therapeutic drug monitoring should focus on drugs metabolized by CYP2C9, CYP2C19, and CYP3A4, particularly during the first month of enzalutamide treatment when enzyme induction effects are establishing. Treatment modifications were implemented in 9.2% of patients to manage drug interactions, and 9.8% of patients experienced adverse events directly attributable to drug-drug interactions.

Clinical Practice Recommendations

Benefit-Risk Assessment

Enzalutamide demonstrated a favorable benefit-risk profile for treating metastatic castration-resistant prostate cancer, with FDA confirmation of this assessment. The drug significantly improved overall survival (HR 0.67, 95% CI 0.52-0.86, p=0.002) and progression-free survival (HR 0.39, p<0.001). However, the benefits must be weighed against the increased incidence of seizures, cardiovascular events, and the high prevalence of drug interactions.

Comparative safety profiles suggest that enzalutamide may be preferred over abiraterone for patients at higher risk of metabolic and cardiovascular events, as it carries a lower risk of these complications (though still elevated compared to placebo). Conversely, patients with cognitive impairment or those using multiple CNS depressants may experience fewer side effects with abiraterone.

Drug Interaction Management

The high prevalence of drug interactions necessitates systematic screening before initiating enzalutamide. Healthcare providers should be aware of enzalutamide’s enzyme-inducing properties and their potential to reduce exposure to concomitant medications. Specific recommendations include:

Given the substantial variability in drug interaction screening tools (32-85% of patients flagged depending on the database used), standardized guidance on managing interactions is needed.

Safety Monitoring

Team-based care involving primary care providers is recommended to manage adverse events and maintain quality of life. Specific monitoring should include:

Strict monitoring is indicated when initiating enzalutamide in patients with polypharmacy, which characterized the majority of treated patients. Patient selection should consider individual risk profiles, with careful evaluation of potential drug interactions, comorbidities, and baseline cardiovascular and neurological status.