Review of drug-drug interactions in patients with prostate cancer

Abstract

Objective

The objective of this review is to provide an overview of common drug-drug interactions (DDIs) associated with prostate cancer treatments and outline recommendations for managing polypharmacy.

Data sources

A literature search of PubMed, Embase, and CINAHL was carried out to identify pharmacokinetic and pharmacodynamic changes caused by DDIs that are relevant for prostate cancer patients, DDIs between prostate cancer therapies and co-administered medications (both prescription and over-the-counter), and measures to prevent DDIs. Medication package inserts were used to identify the impact of DDI on the prostate cancer therapy and suggested interventions.

Data summary

No DDIs are expected for the LHRH agonists leuprolide acetate, histrelin, goserelin, or leuprolide mesylate. However, DDIs have been reported for GnRH antagonists, anti-androgens, PARP inhibitors, and taxanes. Although there are no confirmed DDIs for sipuleucel-T to date, it is not generally recommended to use sipuleucel-T concurrently with immunosuppressive medications. Interventions to prevent DDIs include the use of software that can detect clinically significant DDIs, up-to-date medication reconciliation, the inclusion of dedicated clinical pharmacists in cancer treatment teams, and patient/caregiver education.

Conclusions

Prostate cancer patients have a high risk of potential DDIs due to numerous new anti-cancer therapies, the increased use of treatment combinations, and the likelihood of comorbid conditions also requiring drug therapy. Drug-drug interaction screening software, up-to-date medication reconciliation, inclusion of oncology pharmacists on healthcare teams, and patient/caregiver education will aid the development of treatment plans that focus on achieving an optimal risk-benefit profile whilst reducing the risk of DDIs.

Introduction

The prostate cancer (PCa) treatment landscape has expanded significantly over the past ten years and continues to evolve, with the approval of many new agents to treat this disease. Medications used to treat PCa include antineoplastic chemotherapies, hormonal therapies, poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, radiopharmaceuticals, cellular immunotherapy, and immune checkpoint inhibitors. These treatment options have greatly reduced mortality rates for PCa patients.^1,2 Of the systemic PCa treatments, hormonal agents and PARP inhibitors can be taken orally. Although this route of administration may afford patients greater convenience and improved quality of life compared to intravenous administration, these oral anticancer treatments are associated with the risk of nonadherence and many possible drug-drug interactions (DDIs).

Prostate cancer patients are at a high risk of DDIs due to the use of multiple new and existing therapies, including treatment combinations, comorbidities that require additional medication management, and increasing age. First, treatment combinations (vs. monotherapy) to achieve improved efficacy are now standard of care,^3,4 which can result in more DDIs. Comorbidities requiring additional medications are common in PCa patients, ⁵ adding another layer of complexity to treatment management. Increasing age is another factor that increases DDI risk, as age-related physiological changes can alter drug pharmacokinetics (PK). For example, moderately or severely decreased kidney function is strongly associated with increasing age, ⁶ with decreased glomerular filtration rates impacting the excretion of some drugs. A study of drug combinations that are commonly problematic in older adults (≥65 years) listed 66 interactions deemed to be moderate (moderate injury requiring intervention), major (major injury requiring intervention), or catastrophic (leading to death, multiple permanent injuries, or irreversible health effects). ⁷ Most DDIs on this list concern antithrombotic agents, cardiovascular system drugs, central nervous system drugs, and drugs with a narrow therapeutic index (e.g., digoxin). However, their negative consequences can be avoided by treatment modification or monitoring. ⁷

The high likelihood of PCa patients experiencing DDIs is a significant clinical concern because unwanted effects may occur (e.g., loss of efficacy and/or increased adverse events). The objective of this review is to provide an overview of common DDIs associated with PCa treatments and outline recommendations for managing polypharmacy.

Patient vignettes of serious drug-drug interactions with prostate cancer therapies: introduction of cases

Four hypothetical cases of potential DDIs in PCa patients are presented in this review. These cases are introduced below and resolved at the end of the manuscript.

Case 1: A 75-year-old man with a history of myocardial infarction, psoriasis, and a recent diagnosis of metastatic castration-resistant PCa (mCRPC) is treated with atorvastatin, cyclosporine, enzalutamide, and relugolix.

Case 2: A 79-year-old man with CRPC and concurrent Type-2 diabetes is prescribed leuprolide acetate, abiraterone, prednisone, and repaglinide.

Case 3: A 77-year-old man with atrial fibrillation, who is on warfarin (for anticoagulation) and diltiazem (for rate control), is prescribed olaparib at 300 mg by mouth twice daily in combination with goserelin for mCRPC showing Ataxia-Telangiectasia Mutated (ATM) mutation.

Case 4: A 79-year-old man with non-metastatic CRPC (nmCRPC) and a history of venous thromboembolism necessitating long-term use of the anticoagulant apixaban is prescribed apalutamide and triptorelin.

Mechanisms of possible drug-drug interactions in patients with prostate cancer

Pharmacokinetics

Drug-drug interactions occur when the PK of one drug is modified by the administration of another. The four main PK parameters are absorption, distribution, metabolism, and excretion (ADME).

Causes for absorption-related DDIs include the inhibition or induction of drug transporters responsible for absorption within the enterocyte and changes in gastrointestinal (GI) bioavailability. Transporters linked to DDIs include P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion-transporting polypeptide 1B1 (OATP1B1). ⁸ Found in the liver, pancreas, kidneys, and GI tract, P-gp regulates intestinal drug absorption, promotes drug excretion, and limits drug tissue distribution. BCRP is expressed in many tissues, including the intestines and liver, and limits the intestinal absorption of some drugs. Organic anion-transporting polypeptide 1B1 is highly expressed in the sinusoidal membrane of hepatocytes and mediates the uptake of drugs from many classes. ⁸ Additionally, drug-induced changes in gastric pH or GI motility can alter GI drug absorption.^9,10 Although not strictly DDIs, food-related changes in drug absorption are important, for example, grapefruit juice can alter the plasma concentration of many drugs ¹¹ and food should not be consumed for at least two hours before and one hour after taking non-micronized abiraterone to avoid increased exposure (up to 10-fold). ¹² This is further complicated by the requirement for taking prednisone concomitantly with abiraterone, ¹² as steroids should be taken with food to reduce GI upset. Absorption of micronized abiraterone is unaffected by food. ¹³ Clinicians should ensure patients are aware of these types of issues and counsel them on how to safely incorporate the medications into a routine.

Distribution-related DDIs may occur when one drug is displaced by another with a stronger affinity for the same binding site. ¹⁰ Drugs are generally distributed via binding to plasma and tissue proteins, and as only free drug can be delivered to extravascular or tissue sites, the concentration of unbound drug is most relevant for efficacy. Important plasma proteins that bind drugs include albumin, α₁-acid glycoprotein, and lipoproteins. ¹⁰ Acidic drugs tend to bind more extensively to albumin and basic drugs to α₁-acid glycoprotein, lipoproteins, or both. ¹⁰ Highly protein-bound drugs, such as anticonvulsants, are very prone to DDIs mediated by effects on distribution. ¹⁴ To the best of our knowledge, there are no distribution-related DDIs for prostate cancer drugs. However, although not a DDI itself, drug-induced hepatotoxicity may indirectly lead to distribution-related DDIs by, for instance, causing hypoalbuminemia that would impact the binding of concomitant therapy.^15,16 Hepatotoxicity due to chemotherapy drugs (e.g., docetaxel, cabazitaxel) occurs frequently in an unpredictable fashion, and pre-existing liver disease increases this risk; hence, clinicians should closely monitor patients receiving chemotherapy. ¹⁵

Drugs that impact the activity of cytochrome P450 (CYP450), the class of enzymes that plays a role in metabolizing 90% of drugs, ¹⁷ can alter the metabolism of concurrently administered drugs, leading to DDIs. ¹⁸ Drugs that impact CYP450 activity can be inhibitors, inducers, substrates, or both inhibitors/inducers and substrates for a specific enzymatic pathway.^18–20 The most significant CYP450 enzymes involved in DDIs are 3A4 and 2D6. ¹⁷ A common cause of severe DDIs is the inhibition of CYP450 enzymes by the co-administered drug. ²¹ When competing for the same enzyme, the elimination of one of the co-administered drugs will be reduced, leading to its accumulation. Enzyme induction, or an increase of activity through increased enzyme synthesis, ¹⁷ can also result in DDIs. With the increase in enzyme expression levels, drug exposure and consequently efficacy will decrease in a time-dependent manner. ¹⁰ Substrates are drugs that bind to an enzyme and are transformed into metabolites. ¹⁹ The strength of binding is measured as “binding affinity,” and substrate affinities can be classified as being weak, intermediate, or strong. ¹⁹ Drug-drug interactions can lead to changes in the binding affinity of a substrate, thus affecting its metabolism. ¹⁹ Not all CYP-mediated DDIs have clinically important consequences, but those impacting drugs with narrow therapeutic windows are more likely to be clinically significant. For example, concomitant use of enzalutamide (a strong 3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer) with narrow therapeutic index drugs metabolized by CYP3A4 (e.g., cyclosporine), CYP2C9 (e.g., warfarin), and CYP2C19 (e.g., S-mephenytoin) should be avoided as exposure of the narrow therapeutic index drugs may decrease, ²² which could potentially reduce efficacy with unwanted clinical consequences. Additionally, strong inhibitors (e.g., clarithromycin) or inducers (e.g., rifampin) of CYP enzymes have a greater impact on exposure to the concomitant drug than moderate or weak inhibitors or inducers, so DDIs involving strong inhibitors/inducers are more clinically relevant.

Changes in drug excretion, which impact plasma drug concentration, can also cause DDIs. Renal drug excretion, the most common route, is primarily mediated by drug transporters within renal tubular cells. Potential mechanisms for such interactions include competition at a tubular reabsorption site leading to an increase in drug excretion, change in urinary pH and/or flow that can increase or decrease drug excretion, and inhibition of drug metabolism within the kidney. ²³ Biliary excretion through the liver is another important route for drug elimination, ²⁴ and drug-induced changes (e.g., through inhibition of efflux transporters) may change the PK of a concomitant drug, resulting in a DDI. ²⁵

In conclusion, only absorption- and metabolism-related clinically significant DDIs for PCa drugs have been reported. However, clinicians should be mindful of DDIs related to all four PK parameters as not all possible DDIs have been reported, and DDIs may still occur with non-cancer drugs that patients with PCa are prescribed.

Pharmacodynamics

In addition to the PK interactions discussed above that alter a drug's pharmacological effect by changing absorption, distribution, metabolism, and/or excretion, pharmacodynamic (PD) interactions also require monitoring. A clinically important example is QT prolongation, which is when two or more drugs that prolong QT interval are co-prescribed, resulting in an additive or potentiating effect. ²⁶ Androgen deprivation therapy (ADT), including luteinizing hormone-releasing hormone (LHRH) agonists and gonadotropin-releasing hormone (GnRH) antagonists, has been associated with significant prolongation of QT interval, ²⁷ and PCa patients may be prescribed many concomitant therapies that can compound QT prolongation while receiving ADT. For example, some antidepressants (e.g., citalopram) are associated with QT prolongation. ²⁸ Significant QT prolongation carries a risk of sudden cardiac death due to polymorphic tachycardia, also known as Torsades de Pointes. ²⁹ The risk-benefit profile of using drugs that prolong QT should be considered on an individualized basis, taking into account the medical history, baseline electrocardiogram, and blood tests. ²⁹ Labelling for ADT drugs recommends periodic monitoring of electrolytes and electrocardiograms to identify increases in the QT interval.^30–32 Monitoring levels of potassium, magnesium, and calcium is particularly important if there are additional clinical reasons for concern, e.g., GI disturbances.^30–32 It is vital that pharmacists and clinicians review all patients’ treatment plans to avoid DDIs that may increase cardiovascular risk.

Drug-drug interactions with common concomitant therapies in patients with PCa by drug class

As men with PCa frequently have comorbidities that require medications in addition to their cancer treatments, clinicians should be vigilant about potential DDIs when creating or adjusting treatment plans. Although DDI precautions are often described in the prescribing information,^33–35 clinicians may not always know where to find specific information or be aware of these precautions, and the DDIs listed may not be all-inclusive. A comprehensive list of DDIs for PCa therapies can be found in Table 1.

Table 1.

Drug-drug interactions of prostate cancer therapies.

a. LHRH Agonists

Drug Class	LHRH Agonists
Therapy	Leuprolide Acetate (IM:LUPRON DEPOT®) [1989] (SQ: ELIGARD®) [2002]	Triptorelin Pamoate (TRELSTAR®) [2000]	Goserelin Acetate (ZOLADEX®) [1989]	Histrelin Acetate (VANTAS®) [2004]	Leuprolide Mesylate (CAMCEVI™) [2021]
Avoid	None listed30,31	None listed 36	None listed 37	None listed 38	None listed 39
Impact on Exposure of PCa Therapy or Co-Administered Drug	N/A	N/A	N/A	N/A	N/A
Examples	N/A	N/A	N/A	N/A	N/A
Suggested Intervention	N/A	N/A	N/A	N/A	N/A

b.

LHRH Antagonist, and Combination PARP Inhibitor and Androgen Synthesis Inhibitor

Drug Class	LHRH Antagonist		Combination PARP Inhibitor and Androgen Synthesis Inhibitor
Therapy	Relugolix (ORGOVYX™)[2020]		Niraparib and Abiraterone Acetate (AKEEGA™)[2023]
Avoid	P-gp inhibitors 32	Combined P-gp and strong CYP3A inducers 32	Strong CYP3A4 inducers 40	Sensitive CYP2D6 or 2C8 substrates 40
Impact on Exposure of PCa Therapy or Co-Administered Drug	Increased exposure of PCa therapy 32	Decreased exposure of PCa therapy 32	3A4 inducers: decreased exposure of abiraterone component of treatment 40	2D6/2C8 substrates: increased exposure to these substrates 40
Examples	Antibiotics: erythromycin, cyclosporine Antifungals: clotrimazole, ketoconazole Antihypertensives: amlodipine, verapamil, reserpine, nifedipine, nicardipine, diltiazem Anti-neoplastic agents: daunorubicin Corticosteroids: dexamethasone	Anti-androgens: apalutamide, enzalutamide Antibiotics: rifampicin Antifungals: clotrimazole Corticosteroids: rimexolone, dexamethasone Herbal anti-depressants: St John's wort	Antibiotics: rifampicin Anticonvulsants: Phenytoin, carbamazepine	Antidepressants: desipramine Antidiabetics: repaglinide Antihypertensives: nebivolol Antitussives: dextromethorphan
Suggested Intervention	> Avoid P-gp inhibitors if possible. If concurrent therapy is necessary, take relugolix first, separate dosing by at least 6 h and monitor patients closely for toxicity > Interrupting relugolix for up to 2 weeks may be appropriate for short courses of certain P-gp inhibitors 32 > Consider a switch to an injectable LHRH agonist (e.g., leuprolide acetate, goserelin acetate) or antagonist (degarelix)	> Avoid co-administration if possible. If unavoidable, increase the relugolix dose to 240 mg once daily > After discontinuation of the combined P-gp and strong CYP3A inducer, resume the recommended relugolix dose of 120 mg once daily 32 > Consider a switch to an injectable LHRH agonist (e.g., leuprolide acetate, goserelin acetate) or antagonist (degarelix)	> Avoid strong CYP3A4 inducers with this medication > There is no dose modification recommendation available 40	> Monitor for toxicity from CYP2D6 or 2C8 substrates > Consider dose reduction of these substrates if there is a narrow therapeutic index 40

c.

Anti-androgens (1 of 2)

Drug Class	Anti-androgens (1 of 2)
Therapy	Abiraterone (ZYTIGA®, YONSA®)[2011]			Enzalutamide (XTANDI®)[2012]
Avoid	CYP2D6 substrates	Strong CYP3A4 inducers	Strong CYP3A4 inhibitors	Strong CYP2C8 inhibitors	Moderate CYP3A4 or CYP2C8 inducers	CYP3A4, CYP2C9, and CYP2C19 substrates
Impact on Exposure of PCa Therapy or Co-Administered Drug	Increased exposure of co-administered drug(s) 12	Strong CYP3A4 inducers reduce the AUC∞ by approximately half 13	Strong CYP3A4 inhibitors seem to have no meaningful pharmacokinetic effect on abiraterone 13	Increased exposure of PCa therapy 22	Decreased exposure of PCa therapy 22	Decreased exposure of co-administered drug(s) 22
Examples	Antihypertensives: metoprolol, flecainide, carvedilol Opioid analgesics: tramadol, codeine, oxycodone, methadone Psychotropics: duloxetine, haloperidol, dextromethorphan, paroxetine, risperidone, clomipramine, amitriptyline, aripiprazole, fluoxetine, nortriptyline	Anticonvulsants: phenytoin, carbamazepine Antibiotics: rifampin, rifabutin, rifapentine Sedative: phenobarbital	Antiinfectives: ritonavir, erythromycin, ketoconazole, itraconazole, clarithromycin, atazanavir, saquinavir, telithromycin, indinavir, nelfinavir, voriconazole Antidepressant: nefazodone Calcium channel blocker: verapamil	Antihypertensive: felodipine Lipid-regulator: gemfibrozil Antiplatelet: clopidogrel Antifungals: clotrimazole, ketoconazole Anti-asthmatics: salmeterol, fluticasone	Cardiovascular modifying agents: bosentan, irbesartan, nicardipine, diltiazem, amlodipine, lovastatin Antibiotic: nafcillin Corticosteroids: dexamethasone Antifungals: ketoconazole, clotrimazole	Erectile dysfunction treatments: tadalafil, vardenafil Antihypertensives: lovastatin, diltiazem, amlodipine, atorvastatin, felodipine, nifedipine, losartan Oral anticoagulants: warfarin, apixaban Lipid-regulator: fluvastatin Antidiabetics: rosiglitazone, glyburide, chlorpropamide, gliclazide Nonsteroidal anti-inflammatory (NSAID): celecoxib, diclofenac, ibuprofen, naproxen Antihistamine: chlorpheniramine
Suggested Intervention	Monitor for increased toxicity of CYP2D6 substrates 12	>If a strong CYP3A4 inducer must be given concurrently, increase the frequency of abiraterone to twice a day >Resume once daily frequency upon stopping the strong CYP3A4 inducer >There is no recommended change to the milligram dose; only frequency >Ex. Increase abiraterone 1000 mg once daily to 1000 mg twice a day 13	Monitor for abiraterone toxicity 12	Reduce the dose of enzalutamide to 80 mg once daily during treatment with strong CYP2C8 inhibitors 22	Increase the dose of enzalutamide to 240 mg once daily during treatment with strong CYP3A4 inducers 22	Monitor for decreased efficacy of CYP3A4, CYP2C9, and CYP2C19 substrates 22

c.

Anti-androgens (2 of 2)

Drug Class	Anti-androgens (2 of 2)
Therapy	Apalutamide (ERLEADA®)[2018]		Darolutamide (NUBEQA™)[2019]
Avoid	Strong CYP2C8 or CYP3A4 inhibitors	CYP3A4, CYP2C19, CYP2C9, UGT, P-gp, BCRP, or OATP1B1 substrates	Combined P-gp and strong or moderate CYP3A inducers	Combined P-gp and strong CYP3A inhibitors	BCRP substrates
Impact on Exposure of PCa Therapy or Co-Administered Drug	Increased exposure of PCa therapy 41	Decreased exposure of co-administered drug(s) 41	Decreased exposure of PCa therapy 42	Increased exposure of PCa therapy 42	Increased exposure of co-administered drug(s) 42
Examples	Antihypertensive: felodipine Lipid-regulator: gemfibrozil Antiplatelet: clopidogrel Antiasthmatics: salmeterol, fluticasone Antiinfectives: ketoconazole, clotrimazole itraconazole, ritonavir, saquinavir, atazanavir, indinavir, nelfinavir, voriconazole, clarithromycin Antidepressant: nefazodone	Erectile dysfunction treatments: tadalafil, vardenafil Antihypertensives: amlodipine, diltiazem, losartan, olmesartan Oral anticoagulant: warfarin Lipid-regulators: lovastatin, fluvastatin, simvastatin Nonsteroidal anti-inflammatory (NSAID): ibuprofen Corticosteroid: dexamethasone Antifungal: ketoconazole Analgesic: acetaminophen	Antibiotic: rifampicin Corticosteroids: dexamethasone, rimexolone Antifungal: clotrimazole Herbal supplement: St John's wort	Antibiotics: clarithromycin, troleandomycin, Antifungals: ketoconazole, itraconazole	Antihypertensive: prazosin Lipid-regulator: pravastatin Antidiabetic: glyburide
Suggested Intervention	>No initial dose changes to apalutamide are recommended >Monitor and reduce the dose based on tolerability 41	Monitor for decreased efficacy of CYP3A4, CYP2C19, CYP2C9, UGT, P-gp, BCRP, or OATP1B1 substrates 41	>Avoid co-administration of these agents with darolutamide. >There is no dose modification recommendation available 42	>Monitor for darolutamide toxicity more frequently. >No dose adjustment recommended initially 42	Monitor patients more frequently for adverse reactions, and consider dose reduction of the BCRP substrate drug 42

d.

PARP Inhibitors

Drug Class	PARP Inhibitors
Therapy	Olaparib (LYNPARZA®)[2020]			Rucaparib (RUBRACA®) [2020]	Talazoparib (TALZENNA®)[2023]
Avoid	Strong or moderate CYP3A inducers 43	Strong or moderate CYP3A inhibitors 43	CYP2C9, 1A2, and/or 3A4 substrates 43	Sensitive CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates 44	P-gp inhibitors 2	BCRP inhibitors 2
Impact on Exposure of PCa Therapy or Co-Administered Drug	Decreased exposure of PCa therapy 43	Increased exposure of PCa therapy 43	Increased exposure of co-administered drug(s)	Increased exposure of co-administered drug(s) 44	Increased exposure of PCa therapy 2	Increased exposure of PCa therapy 2
Examples	Antibiotics: rifampicin, nafcillin Anticonvulsants: phenytoin, carbamazepine Endothelin receptor antagonists: bosentan Herbal supplement: St John's Wort HIV antivirals: efavirenz, etravirine Stimulants: modafinil	Antibiotics: telithromycin, clarithromycin, ciprofloxacin, erythromycin Antidepressants: nefazodone Antiemetics: aprepitant Antifungals: itraconazole, ketoconazole, voriconazole, posaconazole, fluconazole Antihypertensives: diltiazem, imatinib, verapamil Chemotherapies: crizotinib HIV antivirals: amprenavir, atazanavir, darunavir/ritonavir, fosamprenavir	Anticoagulants: Warfarin	Antiarrhythmic and blood pressure support: digoxin Oral anticoagulant: warfarin Proton-pump inhibitors: omeprazole Sedatives: midazolam	Specific P-gp inhibitors requiring talazoparib dose adjustment for example: Antiarrhythmics: amiodarone Antibiotics: clarithromycin Antifungals: itraconazole Antihypertensives: verapamil, carvedilol	Antifungals: ketoconazole HIV antivirals: nelfinavir
Suggested Intervention	> Avoid strong or moderate inducers. There is no available recommended dose adjustment for olaparib 43	> Avoid strong or moderate inhibitors when possible. > If unavoidable, reduce olaparib dose to 100 mg twice daily with a strong inhibitor or 150 mg twice daily with a moderate inhibitor. > After the inhibitor is discontinued for 3–5 half-lives, resume original olaparib dose 43	> Monitor for increased toxicity of CYP2C9, 1A2, and/or 3A4 substrates	> Monitor for increased toxicity of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates. > Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated 44	> Avoid listed P-gp inhibitors when possible. If unavoidable, reduce the dose of talazoparib to 0.75 mg once daily. > When the P-gp inhibitor is discontinued for 3 to 5 half-lives, resume the original talazoparib dose 2	> Monitor for increased talazoparib toxicity 2

e.

Autologous Cellular Immunotherapy and Herbal Supplements

Drug Class	Autologous Cellular Immunotherapy	Herbal Supplements
Therapy	Sipuleucel-T (PROVENGE®)[2010]	Saw Palmetto			Black Cohosh
Avoid	None listed 45	CYP3A4 substrates 46	CYP2D6 substrates 46	CYP2C9 substrates 46	CYP2D6 substrates 47
Impact on Exposure of PCa Therapy or Co-Administered Drug	N/A	Increased exposure of co-administered drug(s)	Increased exposure of co-administered drug(s)	Increased exposure of co-administered drug(s)	Increased exposure of co-administered drug(s)
Examples	N/A	Anticoagulants: rivaroxaban	Anticoagulants: Warfarin Antihypertensives: metoprolol, flecainide, carvedilol Opioid analgesics: tramadol, codeine, oxycodone, methadone Psychotropics: duloxetine, haloperidol, dextromethorphan, paroxetine, risperidone, clomipramine, amitriptyline, aripiprazole, fluoxetine, nortriptyline	Anticoagulants: warfarin Antidiabetics: tolbutamide Antidepressants: fluoxetine Antiepileptics: phenytoin Antihypertensives: losartan Diuretics: torsemide	Anticoagulants: Warfarin Antidepressants: Desipramine Antihypertensives: metoprolol, flecainide, carvedilol Opioid analgesics: tramadol, codeine, oxycodone, methadone Psychotropics: duloxetine, haloperidol, dextromethorphan, paroxetine, risperidone, clomipramine, amitriptyline, aripiprazole, fluoxetine, nortriptyline
Suggested Intervention	N/A	N/A	N/A	N/A

f.

Taxane Chemotherapies

Drug Class	Taxane Chemotherapies
Therapy	Doxetaxel (TAXOTERE®) [2004]	Cabazitaxel (JEVTANA®) [2010]	Paclitaxel (ABRAXANE®)[2005]
Avoid	Strong CYP3A inhibitors 48	Strong CYP3A inhibitors 49	CYP3A4 inhibitors 50	CYP3A4 substrates 50	CYP2C8 inhibitors 50	CYP2C8 substrates 50
Impact on Exposure of PCa Therapy or Co-Administered Drug	Increased exposure of PCa therapy 48	Increased exposure of PCa therapy 49	Increased exposure of PCa therapy 50	Increased exposure of co-administered drug(s) 50	Increased exposure of PCa therapy 50	Increased exposure of co-administered drug(s) 50
Examples	Antibiotics: clarithromycin, telithromycin Antidepressants: nefazodone Antifungals: ketoconazole, itraconazole, voriconazole HIV antiviral: ritonavir, saquinavir, atazanavir, indinavir, nelfinavir	Antibiotics: clarithromycin, telithromycin Antidepressants: nefazodone Antifungals: ketoconazole, itraconazole, voriconazole Herbal supplements: St John's wort HIV antivirals: ritonavir, saquinavir, atazanavir, indinavir, nelfinavir	Antibiotics: clarithromycin, telithromycin Antidepressants: nefazodone Antifungals: ketoconazole, itraconazole, voriconazole HIV antivirals: ritonavir, saquinavir, atazanavir, indinavir, nelfinavir	Antibiotics: cyclosporin, erythromycin Sedatives: diazepam	Anti-asthmatics: salmeterol, fluticasone Antifungals: clotrimazole, ketoconazole Antihypertensive: felodipine Antiplatelet: clopidogrel Lipid-regulator: gemfibrozil	Antidiabetics: repaglinide Antidepressants: desipramine Antihypertensives: nebivolol Antitussives: dextromethorphan Antivirals: dasabuvir
Suggested Intervention	> Monitor for increased side effects of docetaxel. > Consider 50% dose reduction of docetaxel 48	> Monitor for increased side effects of cabazitaxel > Consider 25% dose reduction of cabazitaxel 49	N/A	N/A	N/A	N/A

Luteinizing hormone-releasing hormone agonists and gonadotropin-releasing hormone antagonists

Luteinizing hormone-releasing hormone agonists (e.g., leuprolide acetate, triptorelin pamoate, goserelin acetate, histrelin acetate, leuprolide mesylate) and GnRH antagonists (e.g., relugolix, degarelix) are options for ADT, the foundational systemic therapy for men with advanced PCa. Although no PK DDI studies have been conducted with leuprolide acetate, DDIs are not expected as it is a peptide that is primarily degraded by peptidase, not CYP450 enzymes as noted in specific studies, and is not highly protein-bound.^30,31,51 Similar to leuprolide acetate, no potential DDIs or precautions are listed for histrelin, ³⁸ goserelin, ³⁷ or leuprolide mesylate.^37–39 The triptorelin label recommends that it should not be used concomitantly with hyperprolactinemic drugs because hyperprolactinemia reduces the number of pituitary GnRH receptors, although no DDI studies have been conducted. ³⁶ However, DDIs have been noted for GnRH antagonists. Relugolix should not be co-administered with P-gp inhibitors ³² or combined P-gp and strong CYP3A inducers. ³² Co-administration of relugolix with P-gp inhibitors leads to increased relugolix exposure, which may increase the risk of adverse reactions. ³² If co-administration is unavoidable, relugolix should be taken first, dosing should be separated by at least six hours, and patients should be monitored frequently for adverse reactions. ³² Co-administration of relugolix with combined P-gp and strong CYP3A inducers should be avoided because the DDI leads to decreased relugolix exposure, which may decrease efficacy. ³² However, if co-administration is unavoidable, the relugolix dose should be increased to 240 mg once daily. Although not included in the label, a 2022 review recommended that relugolix should not be administered concomitantly with many androgen-receptor-axis targeted therapies (e.g., abiraterone, apalutamide), cabazitaxel, or lutetium Lu 177 vipivotide tetraxetan as the safety of these combinations have not been established. ⁵² The National Comprehensive Cancer Network (NCCN) guidelines for the treatment of PCa have similar recommendations on combining novel hormonal therapies with relugolix and note that further studies are needed to evaluate the safety of these combinations. ⁵³ The degarelix label states that clinically significant CYP450 interactions are unlikely, but a study found that its combination with enzalutamide resulted in significant QT prolongation compared to degarelix monotherapy. ⁵⁴ Hence, clinicians should be aware that clinically significant DDIs are possible when prescribing GnRH antagonists concurrently with other frequently used drugs. This is a relevant factor to be considered when selecting the most appropriate drug for ADT.

Anti-androgens

First-generation anti-androgens (bicalutamide, flutamide, nilutamide) are androgen receptor inhibitors used in combination with ADT. Co-administration of bicalutamide, a CYP3A4 inhibitor, with a CYP3A4 substrate such as midazolam increased mean substrate concentrations 1.5-fold, potentially increasing risk of adverse events. ⁵⁵ Bicalutamide can also displace anticoagulants from binding sites, causing loss of efficacy; there have been post-marketing reports of serious bleeding in patients taking both bicalutamide and an anticoagulant e.g., warfarin. ⁵⁵ Flutamide prescribing information also warns that when administered concomitantly with warfarin, close monitoring and anticoagulant dose adjustment may be necessary. ⁵⁶ Nilutamide inhibits the activity of CYP450 isoenzymes and may reduce the metabolism of drugs requiring these systems, especially those with a low therapeutic margin (e.g., vitamin K, phenytoin), causing delayed elimination and increased half-life leading to toxicity. ⁴¹ Dose reduction of the co-administered drug may need to be required. ⁴¹

Second generation anti-androgens (e.g., enzalutamide, apalutamide, darolutamide, abiraterone), which inhibit binding of androgen-to-androgen receptors, are hormone therapies that are administered concurrently with ADT. Enzalutamide is indicated for metastatic castration-sensitive PCa (mCSPC), non-metastatic castration-sensitive PCa (nmCSPC), and CRPC ²² ; apalutamide is indicated for mCSPC and nmCRPC ⁴² ; darolutamide is indicated for mCSPC (with docetaxel) and nmCRPC ⁵⁷ ; and abiraterone is indicated (with prednisone) for mCSPC and mCRPC. ¹² Co-administration of enzalutamide with the CYP inhibitors gemfibrozil and itraconazole has been shown to increase the composite area under the curve of enzalutamide by 220% and 130%, respectively. ⁵⁸ Similarly, co-administration of a single dose of apalutamide with the CYP inhibitor gemfibrozil increases systemic exposure of apalutamide by 68%. ⁴² These increases in exposure of enzalutamide and apalutamide may increase the risk of toxicity. Conversely, strong CYP3A4 inducers like rifampin, which is also a CYP2C8 inducer, have been shown to decrease plasma concentrations of enzalutamide. ²² Although rifampin, a strong CYP3A4 and CYP2C8 inducer, decreases apalutamide active moieties, these changes are not significant enough to require dose modification. ⁵⁹ A phase 1 study evaluating co-administration of a P-gp and CYP3A4 inducer with darolutamide in healthy volunteers demonstrated a 72% decrease in darolutamide exposure, potentially decreasing efficacy. ⁶⁰ Additionally, preclinical data indicated that darolutamide may inhibit substrates of BCRP, OATP1B1, OAT3, and OATP1B3. ⁶⁰ Abiraterone should not be co-administered with strong CYP3A4 inducers or CYP2D6 substrates. ¹² A DDI between abiraterone and a strong CYP3A4 inducer (e.g., rifampin) results in decreased abiraterone exposure, which could decrease drug efficacy and negatively impact clinical outcomes. ¹² If co-administration is unavoidable, clinicians should increase abiraterone dosing frequency. ¹² Additionally, co-administration of abiraterone and CYP2D6 substrates with a narrow therapeutic index (e.g., thioridazine) leads to a DDI that increases the exposure of the substrate. ¹² If an alternative treatment cannot be used, clinicians should exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate. ¹²

Given that many patients with PCa are at high risk of cardiovascular adverse events, ⁶¹ DDIs with direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, and apixaban, are important to consider. For example, co-administration of the strong CYP3A4 inducer enzalutamide with apixaban, which is metabolized by CYP3A4, reduces apixaban exposure, potentially decreasing efficacy for treatment and prevention of blood clots. ⁴³ Thus, DDIs with these second-generation anti-androgens are very likely, particularly as they are often administered as part of combination treatments in PCa management and with other drugs for concurrent illness.

PARP inhibitors

PARP inhibitors (olaparib, talazoparib, rucaparib, niraparib), which are indicated for mCRPC, are at high risk for DDIs. First, clinicians must consider DDIs with PARP inhibitors themselves. Olaparib should not be co-administered with strong or moderate CYP3A inhibitors or inducers. ⁴⁴ If talazoparib is co-administered with some P-gp inhibitors (itraconazole, amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil), the talazoparib dose should be reduced to 0.75 mg once daily and patients should be monitored for increased adverse reactions. ² Patients taking both talazoparib and BCRP inhibitors should also be monitored for potential increased toxicity. ² Concomitant administration of rucaparib with some CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates can increase the systemic exposure of these substrates, potentially increasing the frequency or severity of adverse effects. ⁴⁰ More recently, PARP inhibitors can be administered in combination with other PCa therapies (for example, olaparib with abiraterone, prednisone or prednisolone, ⁴⁴ and ADT; talazoparib with enzalutamide and ADT ² ; rucaparib with ADT), ⁴⁰ so DDIs with these other therapies must be considered as well. The tablet combining niraparib and abiraterone acetate should not be administered with strong CYP3A4 inducers, or CYP2D6 or 2C8 substrates. ⁴⁵ Currently, there are more PARP inhibitor combination therapies under clinical investigation and undergoing FDA review. Therefore, new DDIs may emerge, requiring increased vigilance in PCa DDIs.

Sipuleucel-T

Sipuleucel-T is an immunotherapy derived from patients’ own cells approved only for treatment of mCRPC that is asymptomatic or minimally symptomatic. ⁶² To date, there are no confirmed DDIs that influence PK or PD of sipuleucel-T. ⁶² However, based on the presumed effect that immunosuppressive medications, such as chemotherapy or corticosteroids, may diminish patients’ immune response to sipuleucel-T or impede the harvesting of cells during leukapheresis, it is not generally recommended to use these treatments concurrently. ⁶² Of note, patients on immunosuppressive medications were excluded from clinical trials. ⁶² Patients who are receiving steroids as part of their treatment with docetaxel and/or abiraterone, for example, need to be appropriately counseled to also stop the steroid when they discontinue docetaxel/abiraterone in anticipation of receiving sipuleucel-T.

Taxane chemotherapy

Taxanes (docetaxel, paclitaxel, and cabazitaxel) have historically been used in metastatic castration-resistant disease upon failure of other therapies, but earlier use in the course of disease may become more frequent given the demonstrated survival benefit in combination with ADT, ⁶³ or, more recently, as part of triplet therapy in combination with abiraterone or darolutamide and ADT.^48,64 Clinically significant DDIs may occur with this class of drugs, as well as overlap when used in combination with anti-androgens due to commonalities in CYP450 enzymes. For example, the metabolism of docetaxel may be altered if it is co-administered with CYP450 3A4 inducers, inhibitors, or substrates. ⁴⁹ A 50% dose reduction of docetaxel should be considered if co-administration with a strong CYP3A4 inhibitor is unavoidable. ⁴⁹ If co-administered with a strong CYP3A inhibitor, cabazitaxel exposure may increase, thereby increasing the risk of adverse effects. ⁵⁰ Additionally, co-administration of cabazitaxel with a CYP3A inducer is expected to decrease cabazitaxel exposure, potentially decreasing efficacy. ⁵⁰ Therefore, co-administration of cabazitaxel with strong CYP3A inhibitors and inducers should be avoided. ⁵⁰ Cabazitaxel prescribing information also advises that patients should refrain from taking St John's wort. ⁵⁰ Paclitaxel prescribing information warns that caution should also be exercised when administering paclitaxel concomitantly with CYP3A4 and CTP2C8 substrates or inhibitors, ⁶⁵ but does not list suggested interventions if co-administration is unavoidable.

Strong patient/provider partnerships reduce risk of drug-drug interactions

In addition to healthcare providers working together in inter-disciplinary teams (e.g., primary care physicians [PCP], oncologists, urologists, pharmacists) to identify and prevent potential DDIs, a member of the healthcare team should proactively engage patients early in the treatment process to establish a strong patient/provider partnership. Patients who feel that they have a strong relationship with members of their healthcare team may, for instance, be more likely to fully disclose all over-the-counter and herbal supplements they take, which when administered with prescription medicines can have serious clinical consequences due to DDIs.^66,67 Effective medication reconciliation is crucial to ensure medication safety and appropriate, informed clinical decision-making. ⁶⁸

Drug-drug interactions may occur with herbal supplements commonly taken by PCa patients, including saw palmetto and black cohosh. Saw palmetto is an over-the-counter product some patients may use to treat symptoms of benign prostatic hyperplasia.^69,70 There is evidence that saw palmetto may decrease the level of testosterone in the body, ⁷¹ inhibit an enzyme that converts testosterone to DHT (5α-reductase), ⁷² and have an anti-inflammatory effect on the prostate. ⁴⁶ An in vitro study found potent inhibition of CYP3A4, 2D6 and 2C9 by saw palmetto, and the authors concluded that there is potential for strong adverse DDIs. ⁷³ A separate publication suggested that inhibition of CYP2C9 by saw palmetto may account for interactions between the supplement and warfarin. ⁷⁴ It also may reduce the number of estrogen and androgen receptors and thus have hormone-like effects. ⁴⁶ Additionally, a potential DDI with the anticoagulant rivaroxaban, in which saw palmetto may have contributed to hemopericardium by increasing rivaroxaban activity, has been reported. ⁷⁵ Although not a direct DDI, a laboratory study found that saw palmetto can increase the sensitivity of normal prostate cells to radiation. ⁷⁶ As this can increase the risk of complications, patients with PCa should consult their physician before using saw palmetto supplements during radiation therapy. ⁷⁶ Black cohosh root is commonly taken by PCa patients on hormonal therapy to reduce hot flashes. ⁴⁷ Drug-drug interactions may occur between black cohosh and CYP2D6 substrates (e.g., desipramine), ⁷⁷ which could decrease the efficacy of the co-administered drug or increase the risk of adverse effects.

In addition to non-prescription medications that may be selected by the patient or a caregiver without informing their healthcare team, use of medications like a testosterone replacement therapy, which could negate the impact of ADT, may not be disclosed to the healthcare team if the patient does not understand what medications they are using and why. Thus, a good partnership between the provider and patient and/or caregiver, in which the patient fully discloses their medication regimen and the provider educates the patient on each medication, is an important element in preventing adverse DDIs.

Patient vignettes of serious drug-drug interactions with prostate cancer therapies continued: resolution of cases

The following are the continuation of the four illustrative patient case reports: this section presents how the potential DDIs could be prevented to avoid negative clinical consequences.

Case 1: Two potential clinically significant DDIs were flagged by DDI screening software: enzalutamide and atorvastatin, ²² and relugolix and cyclosporine. ³² Clinicians amended the treatment plan by replacing atorvastatin with rosuvastatin and instructed the patient to take relugolix at least six hours before cyclosporine. If these DDIs had not been flagged by the software or a pharmacist, the patient may have suffered hypercholesterolemia, potentially recurrent myocardial infarctions due to decreased atorvastatin exposure, and/or adverse reactions associated with relugolix.

Case 2: A potential clinically significant DDI between abiraterone and repaglinide was flagged by DDI screening software, allowing clinicians to amend the treatment plan. If this DDI had not been identified by the software or a pharmacist, inhibition of CYP2C8 by abiraterone could have led to increased repaglinide exposure, ¹² causing the patient to suffer hypoglycemic episodes with blood glucose levels less than 30 mg/dL and possibly require hospitalization.

Case 3: Two potential clinically significant DDIs were flagged by DDI screening software and the treating clinician consulted the clinical pharmacist for input. The first DDI was between olaparib and warfarin. The clinical pharmacist recommended replacing warfarin with a direct oral anticoagulant to avoid increased serum concentration of warfarin and consequent increased risk of warfarin-associated adverse events. The second DDI was between olaparib and diltiazem. Diltiazem is a known CYP3A4 inhibitor and is categorized as “moderate.” ⁷⁸ The FDA-approved prescribing information for olaparib recommends against concurrent treatment with moderate or strong CYP3A4 inhibitors. ⁴⁴ However, the prescribing information also suggests the dose of olaparib can be reduced to 150 mg twice daily if moderate inhibitors must be used concurrently. ⁴⁴ If this DDI had not been identified, inhibition of CY3PA4 by diltiazem could have led to increased olaparib exposure, ⁴⁴ thus increasing the risk for adverse reactions.

Case 4: A potential clinically significant DDI between apalutamide and apixaban was flagged by a clinical pharmacist and the treatment plan was discussed. Apalutamide is a known “strong” inducer of CYP3A4 as well as an inducer of P-glycoprotein (P-gp)/ABCB1. Both apixaban ⁷⁹ and rivaroxaban ⁸⁰ are not recommended to be used concurrently with any strong inducer of both CYP3A4 and P-gp. Among direct oral anticoagulants, edoxaban is still potentially sensitive to P-gp induction-mediated decreased efficacy based on data when used with strong CYP3A4 inducer and P-gp inducer rifampin ⁸¹ but, from a risk-benefit standpoint, represents the least amount of overall interaction potential. Given the lack of efficacy monitoring for DOACs ⁸² and adherence concerns with enoxaparin, ⁸³ in discussion with the patient and treating physician the decision was made to switch to edoxaban. If this DDI had not been identified, decreased apixaban exposure caused by the strong CYP3A4 inducer apalutamide could have reduced apixaban efficacy and increased risk of recurrent venous thromboembolism.

Discussion of measures to prevent drug-drug interactions

In addition to vigilance by clinicians and pharmacists when formulating treatment plans and developing strong patient-provider partnerships, further measures are important to prevent DDIs. These interventions include the use of software that can detect clinically significant DDIs, up-to-date medication reconciliation, the inclusion of dedicated clinical pharmacists in cancer treatment teams, and patient/caregiver education.

As clinicians may not have the resources to identify and manage drug toxicities, DDI screening software can help reduce the risk of preventable harm. An analysis of data from 775,186 patients across 572 pharmacies found that computerized prescription entry and drug interaction screening reduced the dispensing of prescriptions with potentially severe interactions by 63%. ⁸⁴ There are various options for DDI screening software. A random-sampling-based statistical algorithm aimed at identifying DDIs based on MEDLINE records was found to have high accuracy, based on case studies of four commonly prescribed drugs (warfarin, ibuprofen, furosemide, and sertraline). A separate study comparing five common DDI programs (Lexi-Interact, Micromedex Drug Interactions, iFacts, Medscape, and Epocrates) found that Lexi-Interact identified DDIs with the greatest accuracy and comprehensiveness. ⁸⁵ Although such programs cannot replace clinician evaluation of medical histories, monitoring, and evidence-based judgement, they represent powerful support tools.

However, it should be noted that DDI screening software and pharmacists can only identify potential DDIs if patients’ electronic medical records are accurate. Given that elderly PCa patients are likely to receive medicines prescribed by multiple specialists (e.g., urologists, cardiologists, oncologists, endocrinologists, PCP, etc.), accurate and up-to-date medication reconciliation may be a challenge. A study reporting an increased risk of potentially inappropriate drug combinations with greater numbers of treating physicians concluded that a single PCP and single dispensing pharmacy may be protective factors against DDIs. Healthcare providers across disciplines should work together to ensure that patient records are accurate and up-to-date to help in the prevention of DDIs. If a PCa patient does not have a PCP, the treating urologist or oncologist should ensure that the patient has one before starting advanced care and maintain open communication with the PCP. The PCP can manage the patient's non-oncology-related issues, manage relevant DDIs, care for the “whole” patient, and oversee all potential DDIs, allowing the oncologist or urologist to focus on treating the cancer.

Oncology pharmacy is a field that combines the expertise of pharmacy practice with a focus on hematology and oncology, ⁸⁶ and the inclusion of oncology pharmacists in cancer treatment teams can help prevent DDIs. A position statement from the International Society of Oncology Pharmacy Practitioners states that the primary role of an oncology pharmacist is to ensure safe and appropriate medication use for individuals with cancer. ⁸⁶ This includes assessing medication safety, adjusting drug dose and verifying that prescriptions are accurate. ⁸⁶ An analysis of clinical interventions by an oncology pharmacist found that, out of 346 total interventions, one was classified as potentially lethal, 114 as serious and 140 as significant, ⁸⁷ indicating that the presence of an oncologist pharmacist on inter-disciplinary teams is highly likely to improve patient safety.

Educating patients and caregivers on how to identify and prevent DDIs may also be beneficial and should increase feelings of empowerment. The Food and Drug Administration has published a guide to help patients avoid DDIs, which includes how to read drug labels and what questions to ask their doctor or pharmacist such as “Can I take it with other drugs? Should I avoid certain foods, beverages, or other products? What are possible drug interaction signs I should know about?” ⁸⁸ A member of the healthcare team could direct patients and/or caregivers to this guide before starting new medications and answer any questions their patients may have. There is some evidence of a gap between the amount of information about DDIs that patients would like to receive from pharmacists and what they actually receive, ⁸⁹ indicating a need to improve patient-centered communication in pharmacies. To the best of our knowledge, the impact of patient and/or caregiver education on reducing DDI's has not been assessed in a trial.

Conclusions

In general, prevention of DDIs has become an increasingly important consideration in the development of treatment plans, particularly for an aging population with associated comorbidities and polypharmacy. Patients with PCa have a high risk of potential DDIs due to numerous new anti-cancer therapies, the increased use of treatment combinations, and the likelihood of comorbid conditions also requiring drug therapy. Drug-drug interactions can result in adverse PK or PD effects that can impact efficacy, toxicity, and/or pharmacological activity of one or more of the medicines being taken. Although most DDIs are listed on drug labels, these listings are not comprehensive, and clinicians may not always be aware of appropriate precautions. An especially important PD DDI to consider for PCa patients is QT prolongation, which can increase the risk of arrhythmia and cardiac arrest. Drug-drug interaction screening software, up-to-date medication reconciliation, inclusion of oncology pharmacists on healthcare teams, patient/caregiver education, and strong patient/provider partnerships will assist development of treatment plans that focus on achieving an optimal risk-benefit profile whilst reducing the risk of DDIs.