Pharmacokinetics, Safety, and Antitumor Effect of Apalutamide with Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer: Phase 1b Study
Mené sur 57 patients atteints d’un cancer de la prostate résistant à la castration et de stade métastatique, cet essai de phase IB analyse les caractéristiques pharmacocinétiques, l’activité antitumorale et la toxicité de l’apalutamide en combinaison avec de l’acétate d’abiratérone et de la prednisone
Introduction: Apalutamide is a next-generation androgen receptor (AR) inhibitor approved for patients with nonmetastatic castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer. We evaluated the pharmacokinetics, safety, and antitumor activity of apalutamide combined with abiraterone acetate plus prednisone (AA-P) in patients with metastatic CRPC (mCRPC). Materials and Methods: Multicenter, open-label, phase Ib drug-drug interaction study conducted in 57 mCRPC patients treated with 1,000-mg AA plus 10-mg P daily beginning on cycle 1 day 1 (C1D1) and 240-mg apalutamide daily starting on C1D8 in 28-day cycles. Serial blood samples for pharmacokinetic analysis were collected on C1D7 and C2D8. Results: Systemic exposure to abiraterone, prednisone, and prednisolone decreased 14%, 61%, and 42%, respectively, when apalutamide was coadministered with AA-P. No increase in mineralocorticoid excess-related adverse events was observed. Patients without prior exposure to AR signaling inhibitors had longer median treatment duration and greater mean decrease in prostate-specific antigen (PSA) from baseline compared with those who had received prior therapy. Confirmed PSA reductions of ?50% from baseline at any time were observed in 80% (12/15) of AR signaling inhibitor-naïve patients and 14% (6/42) of AR signaling inhibitor-treated patients. Conclusion: Treatment with apalutamide plus AA-P was well tolerated and showed evidence of antitumor activity in patients with mCRPC, including those with disease progression on AR signaling inhibitors. No clinically significant pharmacokinetic interaction was observed between abiraterone and apalutamide; however, apalutamide decreased exposure to P. These data support development of 1,000-mg AA plus 10-mg P daily with 240-mg apalutamide daily in patients with mCRPC.