The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
Michael Thomas Schweizer , Emmanuel S. Antonarakis , Hao Wang , Avery N. Spitz , Haiyi Cao , Alberto Pacheco , Mario A. Eisenberger , Michael Anthony Carducci , Samuel R. Denmeade
Background: Prostate cancer (PC) cells become resistant to chronic castration via an adaptive increase in androgen receptor (AR) expression, a liability that can be exploited therapeutically. Mechanistically, supraphysiologic androgens can induce PC cell death through topoisomerase 2 (topo2) mediated double-strand DNA breaks and disruption of DNA relicensing due to persistence of AR at origins of replication during the cell cycle. Methods: We evaluated parenteral T in combination with the topo2 inhibitor E in men with CRPC and low metastatic burden (≤5 bone and <10 soft tissue metastases). To rapidly cycle from supraphysiologic (>1500 ng/dL) to near castrate T levels, men received intramuscular T cypionate 400 mg on day (D) 1 and oral E 100 mg D 1-14 of a 28 D cycle. After 3 cycles, men with declining PSA could continue T alone every 28 D. The primary endpoint was PSA response, defined as a PSA below baseline, after cycle 3. Secondary endpoints included objective response rates and safety. Results: Sixteen men enrolled of which 14 completed 3 cycles of T+E and were evaluable for response. 7/14 went on the T-only expansion stage. After 3 cycles, 6/14 men had a PSA response. 7 (50%) had a PSA response at any timepoint [4 (29%) had PSA declines ≥50%] (Table). In men with RECIST-evaluable disease, 2 had progressive and 3 had stable disease (SD), 4 had partial (PR) and 1 had a complete response (CR). Median response duration was 343 D (95% CI, 91 to 434 D). Post T, 12/12 men had a PSA decline to subsequent androgen ablative therapies. Most adverse events (AEs) were ≤grade 2 and considered effects of E. One man died from neutropenic sepsis before completing the 1st cycle. AEs possibly related to T included lower extremity edema (n=1), priapism (n=1) and asymptomatic pulmonary embolism (n=2). No one developed new pain on T. Conclusions: T with or without E demonstrated preliminary efficacy in patients with CRPC as manifested by PSA and objective responses. This regimen is generally safe. Cyclic T-based therapies warrant further study. Clinical trial information: NCT01084759.
Subject | Cycles (N) | Maximum PSA change relative to baseline (%) |
RECIST response |
---|---|---|---|
4 | 15 | -86 | PR |
6 | 12 | -48 | PR |
8 | 3 | -46 | SD |
9 | 16 | -78 | NA |
13 | 14 | -97 | PR |
15 | 8 | -18 | PR |
16 | 5 | -98 | CR |
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Abstract Disclosures
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First Author: Michael Thomas Schweizer
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