Rolapitant (VARUBI®), a selective, long-acting neurokinin-1 receptor antagonist (RA), effectively prevented chemotherapy-induced nausea and vomiting in phase 3 trials of patients (pts) receiving highly or moderately emetogenic chemotherapy. BCRP transports potentially harmful substances out of cells and is expressed in the liver, kidneys, gastrointestinal tract, and blood-brain barrier. Drugs that are substrates of BCRP have the potential for drug-drug interactions (DDI) when this transporter is inhibited. Rolapitant is an inhibitor of BCRP. However, rolapitant use is not contraindicated in patients administered concomitant BCRP substrate drugs. This post hoc analysis describes the safety of rolapitant in pts receiving chemotherapy agents that are substrates of BCRP.
In 4 randomized, placebo-controlled trials, pts were randomized 1:1 to a single dose of 180 mg oral rolapitant or placebo before chemotherapy. All pts received an oral 5-HT3 RA + dexamethasone (active control). Treatment-emergent AEs (TEAEs) were recorded in all pts receiving BCRP substrate drugs and compared between the rolapitant and control arms.
1637 pts received concomitant BCRP substrate drugs of any kind. Most common BCRP substrate chemotherapy agents in rolapitant and control arms were doxorubicin (22.5% and 23.3%, respectively), fluorouracil (17.3% and 17.7%), and docetaxel (11.4% and 11.4%). Overall, the percentage of pts with ≥1 treatment-related AEs was similar in both arms in pts receiving any concomitant BCRP substrate chemotherapy agent used in the trials. Overall, we saw no apparent increase in TEAEs between pts receiving and not receiving concomitant BCRP substrates.
|BCRP substrates* (n rolapitant; n control)||Most common TEAEs (%)|
|Docetaxel (147; 148)||Diarrhea (23.8), fatigue (22.4), neutropenia (14.3)||Diarrhea (23.0), fatigue (20.3), constipation (17.6)|
|Doxorubicin (291; 303)||Fatigue (19.2), alopecia (13.7), neutropenia (11.0)||Fatigue (18.2), headache (16.5), alopecia (14.9)|
|Fluorouracil (224; 230)||Fatigue (11.6), constipation (11.2), asthenia (7.6)||Alopecia (10.4), constipation (10.4), fatigue (9.1)|
|Irinotecan (39; 34)||Constipation (10.3), fatigue (10.3), nausea (7.7)||Diarrhea (20.6), alopecia (11.8), constipation (8.8)|
Rolapitant + 5-HT3 receptor antagonist + dexamethasone was safe and well-tolerated in pts receiving concomitant BCRP substrate chemotherapy agents.
Clinical trial identification
NCT01500226, NCT01499849, NCT01500213
Legal entity responsible for the study
L. Schwartzberg: Consulting or Advisory Role: Eisai, Teva, Amgen, Genentech, Bristol-Myers Squibb; Leadership: Vector Oncology; Speakers' Bureau: Genentech, Novartis, Bristol-Myers Squibb; Stock and Other Ownership Interests: Vector Oncology; Research Funding: Eisai. K. Jordan: Consulting or Advisory Role: Merck, MSD, Helsinn Healthcare, Tesaro. B.L. Rapoport: Consulting or Advisory Role: Tesaro, Merck; Speakers' Bureau: Tesaro, Merck; Travel, Accommodations, Expenses: Tesaro, Merck; Honoraria: Tesaro, Merck. I. Schnadig: Advisory Board: Tesaro. S. Arora, D. Powers: Employment: Tesaro, Inc. All other authors have declared no conflicts of interest.