Enzalutamide (ENZA) in combination with abiraterone acetate (AA) in bone metastatic castration resistant prostate cancer (mCRPC).

Genitourinary (Prostate) Cancer
Session Type and Session Title: 
Oral Abstract Session, Genitourinary (Prostate) Cancer
Abstract Number: 
J Clin Oncol 32:5s, 2014 (suppl; abstr 5000)
Eleni Efstathiou, Mark Anton Titus, Sijin Wen, Aileen SanMiguel, Anh Hoang, Angela De Haas-Amatsaleh, Frank Perabo, De Phung, Patricia Troncoso, Taoufik Ouatas, Christopher Logothetis; Alexandra General Hospital of Athens, Oncology Department, Department of Clinical Therapeutics, Medical School, University of Athens, Athens, Greece; The University of Texas MD Anderson Cancer Center, Houston, TX; West Virginia University Health Science Center, Morgantown, WV; Astellas Global Development, Northbrook, IL; Astellas Pharma Global Development, Inc., Northbrook, IL; Astellas Pharma Global Development, Inc., Leiderdorp, Netherlands; Astellas Pharma Global Development, Leiden, Netherlands

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Abstract Disclosures


Background: Co-targeting the androgen receptor (AR) and paracrine androgen biosynthesis in mCRPC may be more effective than either alone. This study aims to evaluate safety, pharmacokinetic (PK) drug-drug interactions (DDI), androgen signaling and steroid metabolome modulation and efficacy of ENZA with AA in mCRPC Methods: We enrolled patients (pts) with progressive bone mCRPC, castrate level serum testosterone (≤ 50 ng/dl) consenting to bone marrow (BM) biopsy. Pts were treated with ENZA 160 mg QD and AA 1g QD + prednisone 5 mg bid and monitored every 4-week with CBC, chemistry, physical exams. mCRPC was assessed clinically by PSA, ALP and imaging. Tumor was characterized by IHC and LC mass spectrometry (blood and BM). Ctroughplasma concentrations of AA were measured on days 4 & 29, and ENZA and its active metabolite M2 on d29 in pt subset. Results: We enrolled (07/12-09/13) 60 pts with median age 66 yrs (range 40-82), PS-ECOG 1 (range 0-2) and PSA 20.8 ng/ml (range1-670). Gleason Score (GS) at diagnosis ≥ 8 in 38/53 (72%), [GS ≥ 9 29/53 (55%)/7 unknown]. Thirty (50%) had > 20 bone lesions, 19/60 (32%) lymph node lesions and 2/60 (3%) visceral metastases. Interim data on evaluable pts: PSA changes for 49 pts: maximum PSA decline ≥ 50% (37/49 [76%]), ≥ 90% (22/49 [45%]), PSA ≤ 0.1ng/ml (5/49 [10%]) and PSA progression (6 [12%]). Grade 3 adverse events: ALT rise (5), hypertension (5), ALP rise (4 ), arthralgia (3), bone pain (2). No Grade 4 AEs reported. At ENZA steady state (d29), Ctrough of AA was ~23% lower than d4 (pt n=14; LS means ratio 77.67 %; 90% CI 47.51-126.98) and Ctroughfor ENZA, M2, and the sum of both (pt n=15) were comparable to those reported previously. Following 8 weeks treatment, serum and BM testosterone were undetectable (<1pg/ml) in 29/39 (74%) and 31/36 (86%) evaluated pts respectively, and androstenedione in all pts. Nuclear AR expression was reduced following treatment in 5/6 of evaluable paired tumor specimens. Conclusions: ENZA+ AA combination has a favorable safety profile, without clinically meaningful PK DDI. Feedback mechanisms observed by either agent are dissipated. These promising findings are indicative of more efficacious androgen signaling inhibition in men with mCRPC. Clinical trial information: NCT01650194.