4.1 Patients With Prostate Cancer Are Commonly Treated for Various Comorbidities

Comorbidities that coexist in patients with prostate cancer over 65 years of age include hypertension, hypercholesterolemia, diabetes, cardiovascular diseases, chronic back pain, depression and anxiety, and others [43]. Therefore, patients with prostate cancer are commonly treated with drugs for a variety of other conditions and these need to be carefully managed together with medications aimed at treating their prostate cancer. Here, we describe potential DDIs between enzalutamide and other commonly prescribed drugs (Table 1) and frequently used supplements among patients with prostate cancer. We also propose strategies for preventing potentially problematic enzalutamide DDIs.

4.2 Oral Androgen Deprivation Therapy

Enzalutamide is prescribed in combination with androgen deprivation therapy (ADT) [26]. Commonly prescribed ADT drugs include the GnRH agonists leuprolide, goserelin, and triptorelin, and the GnRH antagonist degarelix [44]. These drugs are delivered via injection, are not metabolized via hepatic CYPs, and are not predicted to interact with enzalutamide [9]. Relugolix is an orally administered GnRH antagonist ADT that suppresses testosterone production in the treatment of prostate cancer [44]. Relugolix is a substrate of CYP3A, CYP2C8, and P-gp, and an inducer of CYP3A and CYP2B6 [45]. As enzalutamide is a mild P-gp inhibitor [35], it could increase the plasma concentration of P-gp substrates such as relugolix. However, enzalutamide is a strong inducer of CYP3A4, providing a mechanism through which it could potentially decrease the plasma concentration of relugolix. The HERO study demonstrated that relugolix suppresses testosterone in a manner superior to that of leuprolide in men with advanced prostate cancer [46]. In a subgroup and pharmacokinetic/pharmacodynamic analysis of the HERO study, George et al. demonstrated that treatment of patients with advanced prostate cancer with relugolix was associated with similar efficacy and safety outcomes with and without coadministration of enzalutamide [47]. Importantly, the results of this study suggest that any effects enzalutamide may have on relugolix metabolism do not have an overall impact on relugolix drug exposure or relugolix-mediated testosterone suppression [47]. Therefore, when enzalutamide is combined with relugolix, no dose adjustments are needed for either medication.

4.3 Enzalutamide and Agents Used to Treat Cardiovascular Diseases

Cardiovascular diseases are highly prevalent among patients with prostate cancer, especially those who are over 65 years of age [48]. Therefore, drugs used to treat and/or prevent cardiovascular disease will frequently need to be managed in patients over 65 years of age, including those with prostate cancer [49]. These include antithrombotic agents, statins, antihypertensive agents, antiarrhythmic agents, and drugs used to treat heart failure (HF).

4.3.1 Antithrombotic Agents

Anticoagulants and antiplatelet agents are critical for the prevention of thrombosis, which is the leading cause of all-cause death worldwide [50, 51]. However, a serious challenge posed by these drugs is the side effect of bleeding and this can be exacerbated by drug interactions.

4.3.1.1 Anticoagulants

Anticoagulant agents are primarily used for the treatment or prevention of venous or arterial thromboses [51]. They inhibit the coagulation cascade and thrombus formation by inhibiting factor Xa (FXa) or thrombin [51].

4.3.1.2 Direct Oral Anticoagulants

Direct oral anticoagulants (DOACs) are antithrombotic drugs that include apixaban, rivaroxaban, edoxaban, and dabigatran (Fig. 2). Apixaban, rivaroxaban, and edoxaban inhibit FXa, whereas dabigatran inhibits thrombin [51]. Apixaban and rivaroxaban are subject to potential DDIs by dual inhibitors and inducers of CYP3A4 and P-gp [52]. The effect of enzalutamide on the plasma concentration of these drugs is unclear because of opposing CYP3A4 and P-gp interactions. However, as enzalutamide is a strong CYP3A4 inducer and a mild P-gp inhibitor, its effects on CYP3A4 may be expected to be predominant resulting in a potential decrease in apixaban and rivaroxaban plasma concentrations, and therapy modification should be considered. Otsuka et al. [53] integrated in vitro and in vivo data into a physiologically based pharmacokinetic model to predict the extent to which enzalutamide and its active metabolite, N-desmethyl enzalutamide, impact apixaban and rivaroxaban plasma concentrations. The results predicted a 31% decrease in AUC and no change in Cmax for apixaban and a 45% decrease in AUC and a 25% decrease in Cmax for rivaroxaban following coadministration of the clinically relevant dose of 160 mg of enzalutamide [53]. Based on this study and current prescribing information, coadministration of these DOACs with enzalutamide should be carefully monitored with possible changes to dosing as necessary to ensure that drug efficacy and safety are maintained. Dabigatran and edoxaban are only minimally metabolized by CYPs and are only subject to DDIs by inhibitors and inducers of P-gp [52]. As enzalutamide was reported to be only a mild inhibitor of P-gp in human studies [35], any potential for DDIs with dabigatran and edoxaban may be less than for apixaban and rivaroxaban. However, concomitant use of P-gp inhibitors in renally impaired patients can increase the exposure of dabigatran, in which case the dabigatran dose should be reduced or coadministration should be avoided [54]. Dosing of dabigatran with enzalutamide should be based on the indication and level of renal dysfunction and we recommend that a pharmacist should be consulted to assist with the appropriate dose reduction of dabigatran or to determine if use of another DOAC is warranted.

Fig. 2

Enzalutamide with anticoagulants and antiplatelet agents

4.3.1.3 Warfarin

Warfarin is a vitamin K antagonist that blocks the coagulation cascade and thrombus formation by inhibiting thrombin [51]. Warfarin is a narrow therapeutic index medication that is a substrate of CYP2C9 and CYP3A4 [55]. As enzalutamide is a strong CYP3A4 inducer and moderate CYP2C9 inducer, it also has the potential to decrease the effect of warfarin (decrease international normalized ratio [INR]) by decreasing the exposure of warfarin. Coadministration of enzalutamide and warfarin should be avoided if possible or additional INR monitoring should be conducted if coadministration of these two drugs is unavoidable (Fig. 2).

4.3.1.4 Antiplatelet Agents

Antiplatelet agents primarily prevent arterial thrombus formation by disrupting the platelet cascade [51].

4.3.1.5 P2Y12 Inhibitors

Clopidogrel, prasugrel, and ticagrelor inhibit platelet activation by blocking platelet P2Y12 adenosine receptors [51]. These agents are commonly used to protect against strokes and heart attacks [56]. They also play an important role together with aspirin in dual antiplatelet therapy (DAPT) after coronary stent placement to prevent stent thrombosis/restenosis [57,58,59]. Although DAPT has proven to be successful in preventing stent thrombosis/restenosis, the benefits of prolonged DAPT must be carefully balanced against an increased bleeding risk [60]. Notably, it is important for patients to coordinate changes in DAPT with their cardiologist as switching between different P2Y12 inhibitors can be challenging because of their different potencies, half-lives, and the need for specific and appropriate loading doses [61]. If not done correctly, these changes can result in stent thrombosis, which can be fatal.

Clopidogrel and ticagrelor have known interactions with enzalutamide (Fig. 2). Clopidogrel is a prodrug that relies on CYP2C19 for conversion to its active metabolite [14] (Fig. 3). Clopidogrel is also converted to an inactive acyl-β-glucuronide metabolite that is a time-dependent inhibitor of CYP2C8 [62]. Clopidogrel interacts with enzalutamide via two distinct mechanisms (Fig. 3): (1) enzalutamide can induce CYP2C19 and therefore has the potential to increase serum exposure to the active metabolite of clopidogrel; (2) as CYP2C8 is the primary enzyme responsible for metabolizing enzalutamide, clopidogrel has the potential to increase enzalutamide exposure. Because the inactive metabolite of clopidogrel is a strong CYP2C8 inhibitor, the prescribing information for clopidogrel recommends a dose adjustment and appropriate monitoring of drugs that are primarily cleared by CYP2C8 [63]. The prescribing information for enzalutamide also states that it should not be coadministered with strong CYP2C8 inhibitors [6]. However, in gauging the real effect of CYP2C19 induction on the amount of active metabolite formed, it is important to note that only ~15% of clopidogrel is converted to its active metabolite [14], and dose adjustments are not provided for enzalutamide for use with moderate CYP2C8 inhibitors [6]. In summary, coadministration of clopidogrel and enzalutamide should be carefully considered and if both drugs are coadministered, patients should be carefully monitored for increased pharmacologic effects of both medications. Ticagrelor is primarily metabolized via CYP3A4 and its plasma concentration may be reduced upon coadministration with strong CYP3A4 inducers [64], such as enzalutamide. Coadministration of ticagrelor with strong CYP3A4 inducers, such as enzalutamide, may reduce the exposure and efficacy of ticagrelor and should be avoided [64]. In contrast to clopidogrel and ticagrelor, prasugrel is only a minor substrate of CYP3A4 and has no known interactions with enzalutamide [9] (Fig. 2).

Fig. 3

Complex interactions between enzalutamide and clopidogrel. CYP cytochrome P450

4.3.1.6 Aspirin

Aspirin (ASA) is an irreversible inhibitor of cyclo-oxygenase 1 that reduces the production of thromboxane within platelets, thereby inhibiting platelet aggregation and thrombus formation. Low-dose ASA (81 mg/day) can be effective at preventing heart attacks and strokes [65]. In addition to its role in DAPT, mentioned above, most clinicians consider ASA to be critical for secondary prevention of myocardial infarction (MI) and atherosclerotic cardiovascular disease [66]; many patients with prostate cancer will have already had either stroke, MI, or coronary artery disease (CAD), which warrant ASA treatment. Fortunately, ASA does not have known interactions with enzalutamide [9] (Fig. 2).

4.3.2 Statins

Statins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors used for the treatment of hypercholesterolemia, with high efficacy in reducing plasma low-density lipoprotein (LDL) and triglyceride levels [67]. Atorvastatin is a substrate of CYP3A4 and the transporters P-gp and BCRP [68], whereas simvastatin [69] and lovastatin [70] are primarily substrates of CYP3A4. Therefore, each of these drugs has potential for an interaction with enzalutamide [9]. Fluvastatin is primarily metabolized by CYP2C9 [71]. As enzalutamide is a moderate inducer of CYP2C9, it can also potentially interact with fluvastatin [9] with the potential to reduce fluvastatin exposure. Therefore, liver function and lipid levels should be monitored when statins are coadministered with enzalutamide to assess the safety and efficacy of statins. This should include checking a patient’s lipid panel at baseline before starting statin therapy or adjusting statin dosage levels during therapy and conducting additional monitoring every 6–8 weeks to assess the treatment response. If lipid control is satisfactory with no evidence of adverse events, subsequent lipid monitoring can be conducted every 4–6 months [72]. However, atorvastatin (revised 11/2021), simvastatin (revised 05/2022), and fluvastatin (revised 10/2012) product recommendations do not preclude coadministration or provide dose adjustment recommendations [68, 69, 71]. The BCRP substrates, pitavastatin, pravastatin, and rosuvastatin, are preferred statins for patients who take enzalutamide as these statins are minimally metabolized by CYPs [73] and either have a moderate or no known basis for interaction with enzalutamide [9]. Of these three statins, rosuvastatin should be emphasized in particular as it is also a high-intensity statin and was shown to reduce LDL levels to a greater extent than atorvastatin, simvastatin, and pravastatin [74]. At the highest dose of 40 mg, rosuvastatin reduced LDL levels by 55% compared with 51% for atorvastatin 80 mg and 46% pravastatin 80 mg [74].

4.3.3 Antihypertensive Agents

Calcium (Ca) channel blockers (e.g., amlodipine, diltiazem, verapamil, and others) are frequently prescribed to decrease blood pressure in patients with hypertension [75]. Most Ca channel blockers are metabolized by CYP3A4 [76]. As enzalutamide is a potent inducer of CYP3A4 [6, 33], there is a potential for a DDI where enzalutamide may decrease the plasma concentrations of many Ca channel blockers [6, 33]. Concomitant use of Ca channel blockers, such as amlodipine, with strong CYP3A4 inducers, such as enzalutamide, should be carefully considered [77]. If coadministration is necessary, the pharmacologic response of the Ca channel blocker should be monitored closely following the initiation or discontinuation of enzalutamide, and its dosage adjusted as necessary. If a patient requires treatment for hypertension, an angiotensin-converting enzyme (ACE) inhibitor, such as benazepril [78], which has no known interactions with enzalutamide [9], may be preferable to a Ca channel blocker. Beta-blockers, such as carvedilol, are also used to treat hypertension [79] and may also be preferable as they are not known to have interactions with enzalutamide [9].

4.3.4 Antiarrhythmic Agents

ADT has the potential to prolong the QT corrected for heart rate (QTc) interval and therefore the benefit–risk ratio of coadministration of enzalutamide with drugs known to prolong the QTc interval and/or induce Torsade de Pointes such as Class IA (e.g., disopyramide, quinidine, and procainamide) or Class III (e.g., amiodarone, dofetilide, and sotalol) antiarrhythmic agents [80] should be carefully considered [8]. However, in clinical practice, we only avoid prescribing enzalutamide if the patient has prolonged QTc or if the pharmacist raises a specific concern about a particular medication. In our opinion, potential risks of DDIs with enzalutamide and other drugs known to prolong the QTc interval can be safely overcome for most patients through multidisciplinary monitoring of serial electrocardiograms (EKGs) and ensuring that electrolytes are carefully managed. In this regard, we note that when the effects of enzalutamide 160 mg/day were evaluated in 796 men with CRPC, no large differences in the QTc interval caused by enzalutamide were observed [34]. Digoxin is a muscarinic M2 receptor activator Class IID antiarrhythmic drug [80] that is commonly prescribed for arrhythmia. As discussed above, digoxin is a P-gp substrate and coadministration of enzalutamide with digoxin increased digoxin exposure leading to the designation of enzalutamide as a mild P-gp inhibitor [35]. Poondru et al. concluded that dose modifications would most likely not be needed upon coadministration of enzalutamide and digoxin [35].

4.3.5 Other Heart Medications

Valsartan is an angiotensin type II receptor antagonist that blocks vasoconstriction [81]. Sacubitril is a prodrug that is activated to become a neprilysin inhibitor that reduces blood volume [82]. The combination of valsartan and sacubitril constitutes an important treatment for patients with heart failure [83]. These drugs do not have known interactions with enzalutamide [9]. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are effective antidiabetic therapies, as discussed below, but also have significant cardiovascular benefits via mechanisms independent of improved glycemic control that are being intensively investigated [