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Enzalutamide (ENZA) in combination with abiraterone acetate (AA) in bone metastatic castration resistant prostate cancer (mCRPC).
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
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.
Abstracts by Eleni Efstathiou:
Effect of selinexor (KPT-330), a novel oral selective inhibitor of nuclear export (SINE), on tumor suppressors and cell cycle proteins in prostate cancer cells and regression of castration-resistant patient-derived xenograft tumor growth.Meeting: 2015 Genitourinary Cancers Symposium | Abstract No: 277
- Meeting: 2015 Genitourinary Cancers Symposium | Abstract No: 187
A phase 3 randomized, placebo-controlled double-blind study of ARN-509 plus abiraterone acetate (AA) in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC).Meeting: 2015 ASCO Annual Meeting | Abstract No: TPS5071