A pilot study of supraphysiologic testosterone (T) and oral etoposide (E) in men with castrate-resistant prostate cancer (CRPC)
| Autor: | Alberto Pacheco, Emmanuel S. Antonarakis, Avery Spitz, Samuel R. Denmeade, Haiyi Cao, Hao Wang, Mario A. Eisenberger, Michael A. Carducci, Michael T. Schweizer |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_specialty
Programmed cell death Cancer Research business.industry Cell cycle urologic and male genital diseases medicine.disease Androgen receptor chemistry.chemical_compound Prostate cancer Endocrinology Castration chemistry Oncology Internal medicine medicine Clinical endpoint Oral etoposide business Testosterone |
| Zdroj: | Journal of Clinical Oncology. 32:5052-5052 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.2014.32.15_suppl.5052 |
| Popis: | 45 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 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 248 D (range, 80 to 359 D). Post T, 10/12 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. [Table: see text] |
| Databáze: | OpenAIRE |
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