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Drug-drug interaction (DDI) is an important consideration for clinical decision making in prostate cancer treatment. The objective of this study was to evaluate the effect of enzalutamide, an oral androgen receptor inhibitor, on the pharmacokinetics (PK) of digoxin (P-glycoprotein [P-gp] probe substrate) and rosuvastatin (breast cancer resistance protein [BCRP] probe substrate) in men with metastatic castration-resistant prostate cancer (mCRPC). This was a phase I, open-label, fixed-sequence, crossover study (NCT04094519). Eligible men with mCRPC received a single dose of transporter probe cocktail containing 0.25 mg digoxin and 10 mg rosuvastatin plus enzalutamide placebo-to-match on day 1. On day 8, patients started 160 mg enzalutamide once daily through day 71. On day 64, patients also received a single dose of the cocktail. The primary end points were digoxin and rosuvastatin plasma maximum concentration (C max ), area under the concentration-time curve from the time of dosing to the last measurable concentration (AUC last ), and AUC from the time of dosing extrapolated to time infinity (AUC inf ). Secondary end points were enzalutamide and N-desmethyl enzalutamide (metabolite) plasma C max , AUC during a dosing interval, where tau is the length of the dosing interval (AUC tau ), and concentration immediately prior to dosing at multiple dosing (C trough ). When administered with enzalutamide, there was a 17% increase in C max , 29% increase in AUC last , and 33% increase in AUC inf of plasma digoxin compared to digoxin alone, indicating that enzalutamide is a "mild" inhibitor of P-gp. No PK interaction was observed between enzalutamide and rosuvastatin (BCRP probe substrate). The PK of enzalutamide and N-desmethyl enzalutamide were in agreement with previously reported data.The potential for transporter-mediated DDI between enzalutamide and digoxin and rosuvastatin is low in men with prostate cancer. Therefore, concomitant How to cite this article: Poondru S, Ghicavii V, Khosravan R, et al. Effect of enzalutamide on PK of P-gp and BCRP substrates in cancer patients: CYP450 induction may not always predict overall effect on transporters.

303 Background: Enzalutamide (ENZA), an androgen receptor (AR) inhibitor that blocks multiple steps in the AR signaling pathway, is approved for patients (pts) with metastatic castration-resistant prostate cancer. This Phase 2, open-label, extension study (NCT01534052) evaluated long-term safety of continued ENZA administration. Methods: Prostate cancer pts previously treated with ENZA in Phase I studies (NCT01902251; NCT01911728; NCT02225093) continued to receive ENZA 160 mg/day until the investigator considered it no longer beneficial or consent was withdrawn. The primary end point was safety. Baseline data from the parent studies were used. Results: 52 pts were enrolled and received ENZA treatment (median age, 67 years [range, 54–88]). Median treatment duration was 443 days (range, 63–2010) since first administration and 392 days (range, 3–1926) in the extension study. In the extension, 43 pts (82.7%) experienced ≥1 any grade treatment-emergent adverse event (TEAE) with the most common (≥10% of pts) being fatigue (26.9% all grades, 13.5% grade 1, 7.7% grade 2, and 5.8% grade 3); arthralgia and back pain (13.5% each); and diarrhea, hot flush, and decreased appetite (11.5% each). Drug-related TEAEs (investigator assessed) were reported in 27 pts (51.9%) with the most common (≥5% of pts) being fatigue (17.3%); hot flush (11.5%); and diarrhea, hypophosphatemia, and muscle weakness (5.8% each). 17 pts (32.7%) had ≥1 serious TEAE. Eight drug-related serious TEAEs were reported in five pts (malignant neoplasm progression [3.8%]; acute pancreatitis, rectal haemorrhage, cerebrovascular accident, dysarthria, hemiparesis, and hypertensive crisis [1.9% each]). One (1.9%) death due to acute myocardial infarction (not drug-related) and four (7.7%) due to malignant neoplasm progression (two drug-related) were reported. No notable changes from baseline in clinical laboratory parameters or clinically meaningful abnormalities in vital signs, physical examinations, or electrocardiogram were found. Conclusions: Long-term continued ENZA treatment is generally well tolerated, with a safety profile consistent with that previously reported. Clinical trial information: NCT01534052.

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