patient care perspectives

Avoiding Drug-Drug Interactions in Patients With Nonmetastatic Castration-Resistant Prostate Cancer

by Michael J. Morris, MD


Men with nonmetastatic castration-resistant prostate cancer (nmCRPC) often have age-associated comorbidities requiring medications that may lead to drug-drug interactions (DDIs). The risk for DDIs may be a consideration when initiating treatment for nmCRPC with an androgen receptor (AR) inhibitor.

Expert Commentary

Michael J. Morris, MD

Prostate Cancer Section Head, Division of Solid Tumor Oncology
Memorial Sloan Kettering Cancer Center
New York, NY

"Like many men with prostate cancer, patients with nmCRPC are generally older and take multiple medications for comorbid conditions, including diabetes, hypertension, coronary artery disease, Parkinson’s disease, depression, and dementia. While beta blockers, antipsychotics, anticoagulants, antiplatelets, and oral hypoglycemics treat these comorbidities, they may interact with newer AR-targeted therapies.

Michael J. Morris, MD

Many men with nmCRPC may be older and take multiple medications for comorbid conditions, including diabetes, hypertension, coronary artery disease, Parkinson’s disease, depression, and dementia. While beta blockers, antipsychotics, anticoagulants, antiplatelets, and oral hypoglycemics treat these comorbidities, they may interact with newer AR-targeted therapies. Therefore, clinicians must inform their patients of these potential DDIs before initiating treatment.

Also, patients with pulmonary emboli or atrial fibrillation who are receiving antiplatelet drugs or anticoagulants should be carefully monitored for potential DDIs. Although there are reported interactions that can occur with abiraterone, the effect is more pronounced with enzalutamide and apalutamide due to significant CYP3A4 metabolism. For certain medications, dose titrations may help to maintain serum concentrations within the therapeutic range while minimizing adverse reactions. It is essential to recognize that the other medications that patients are taking are also critical to managing their comorbidities. Therefore, finding alternative treatments without DDIs may be necessary in some cases. 

There may also be unanticipated DDIs when prostate cancer treatments are combined or sequenced, as was seen in the ERA 223 study. This study tested the hypothesis that combining androgen deprivation therapy and abiraterone with or without radium-223 would be more effective than administering these treatments as sequential therapy. However, findings from this study indicated that combining androgen deprivation therapy, abiraterone, and radium-223 increased the rate of nonmetastatic-related fractures. By combining these agents, patients are at an increased risk for osteoporosis and bone fragility. However, adding bone protection with either denosumab or zoledronic acid can mitigate this adverse effect. Based on this study, we need to be mindful that standard therapies that are known to prolong survival with sequential use can produce adverse effects when used as combination therapy.

Another factor to consider is that the lack of a central medical record can be an impediment to a full understanding of what medications a patient has been prescribed. We also cannot rely on pharmacies to flag DDIs because patients may fill prescriptions at multiple pharmacies. Therefore, it is important to remind patients to update their medication lists with each of their doctors (or, even better, to bring the bottles of all medicines and supplements that they are taking to each medical appointment). Online patient portals can be helpful tools to maintain an updated medication list, but these tools do require patients or family members to have access to a computing device, comfort with these systems, and the ability to enter information accurately.   


Benoist GE, van Oort IM, Smeenk S, et al. Drug-drug interaction potential in men treated with enzalutamide: mind the gap. Br J Clin Pharmacol. 2018;84(1):122‐129. doi:10.1111/bcp.13425

Del Re M, Fogli S, Derosa L, et al. The role of drug-drug interactions in prostate cancer treatment: focus on abiraterone acetate/prednisone and enzalutamide. Cancer Treat Rev. 2017;55:71-82. doi:10.1016/j.ctrv.2017.03.001

Kelsey R. Prostate cancer: enzalutamide-cabazitaxel interactions. Nat Rev Urol. 2018;15(2):69. doi:10.1038/nrurol.2017.212

Shatzel JJ, Daughety MM, Olson SR, Beer TM, DeLoughery TG. Management of anticoagulation in patients with prostate cancer receiving enzalutamide. J Oncol Pract. 2017;13(11):720‐727. doi:10.1200/JOP.2017.022004

Shore N, Zurth C, Fricke R, et al. Evaluation of clinically relevant drug–drug interactions and population pharmacokinetics of darolutamide in patients with nonmetastatic castration‑resistant prostate cancer: results of pre‑specified and post hoc analyses of the phase III ARAMIS trial. Target Oncol. 2019;14(5):527-539. doi:10.1007/s11523-019-00674-0

Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in Lancet Oncol. 2019;20(10):e559]. Lancet Oncol. 2019;20(3):408-419. doi:10.1016/S1470-2045(18)30860-X

Tombal BF, Loriot Y, Saad F, et al. Decreased fracture rate by mandating bone-protecting agents in the EORTC 1333/PEACE III trial comparing enzalutamide and Ra223 versus enzalutamide alone: an interim safety analysis. J Clin Oncol. 2019;37(15 suppl):5007. doi:10.1200/JCO.2019.37.15_suppl.5007

Zurth C, Koskinen M, Fricke R, et al. Drug-drug interaction potential of darolutamide: in vitro and clinical studies. Eur J Drug Metab Pharmacokinet. 2019;44(6):747-759. doi:10.1007/s13318-019-00577-5

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