Pharmacokinetics, Safety, and Antitumor Effect of Apalutamide with Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer: Phase Ib Study

Abstract

Purpose: Apalutamide is a next-generation androgen receptor (AR) inhibitor approved for patients with nonmetastatic castrationresistant prostate cancer (CRPC) and metastatic castrationsensitive 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).Patients and Methods: Multicenter, open-label, phase Ib drugdrug interaction study conducted in 57 patients with mCRPC treated with 1,000 mg abiraterone acetate plus 10 mg prednisone 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 mineralo-corticoid 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-na€ ve patients and 14% (6/42) of AR signaling inhibitor-treated patients.Conclusions: 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 prednisone. These data support development of 1,000 mg abiraterone acetate plus 10 mg prednisone daily with 240 mg apalutamide daily in patients with mCRPC.

Randomized Phase III Study of Enzalutamide Compared With Enzalutamide Plus Abiraterone for Metastatic Castration-Resistant Prostate Cancer (Alliance A031201 Trial)

“…24 In that study, the primary end point was rPFS, which was longer in the combination arm ( ACIS did not include a pharmacokinetic component, although an earlier phase I study observed no significant pharmacokinetic interaction between abiraterone and apalutamide. 25 Our data, however, raise the possibility that a pharmacokinetic effect may be at play, if examined in a larger and more robust study. The same might apply to the PLATO trial, in which men who had been treated with enzalutamide as first-line treatment for mCRPC were randomly assigned to receive either enzalutamide plus AAP or placebo and AAP in the second-line setting.…”

A narrative review of the role of glucocorticoid receptors in prostate cancer: developments in last 5 years

“…We chose studies from the ClinicalTrial database and EudraCT database and some retrospective studies from the NCBI database published in the last 5 years. The selected studies explored the effect of dexamethasone (70)(71)(72)(73)(74)(75)(76), prednisone (77)(78)(79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93), and prednisolone (94) (see Table 2).…”

“…PSA response rate: A decline of PSA ≥50%. CRPC, castration-resistant prostate cancer; PSA, prostate-specific antigen; PFS, progression free survival; OS, overall survival; po, oral; QD, quaque die; QAM, every morning; QPM, every evening; BID, twice daily; ivgtt, intravenous drip; ONCE, only once.docetaxel, cabazitaxel, Ra-223, orteronel, dutasteride, and apalutamide(77)(78)(79)(80)(81)(82)(83)(84)92,93,95,96). Yu et al(88) evaluated the effectiveness of intravenous apatorsen with oral prednisone (5 mg, twice daily) or prednisone alone, and observed a PSA decrease ≥50% in 47% of patients in the apatorsen with prednisone group compared to a decrease of 24% in the prednisone only group.…”

EZH2-TROAP Pathway Promotes Prostate Cancer Progression Via TWIST Signals

“…Prostate cancer is the most common malignant tumor in men and ranks as the leading cause of cancer-related mortality in most countries of the world ( 1 , 2 ). Although multiple therapeutic strategies, including surgery, ADT, and chemotherapy, are initially highly effective, progression eventually occurs years later ( 3 , 4 ).…”