Phase I Study of DSTP3086S, an Antibody-Drug Conjugate Targeting Six-Transmembrane Epithelial Antigen of Prostate 1, in Metastatic Castration-Resistant Prostate Cancer

  • J Clin Oncol. 2019 Dec 20;37(36):3518-3527. doi: 10.1200/JCO.19.00646.
Daniel C Danila  1 ,  Russell Z Szmulewitz  2 ,  Ulka Vaishampayan  3 ,  Celestia S Higano  4 ,  Ari D Baron  5 ,  Houston N Gilbert  6 ,  Flavia Brunstein  6 ,  Marija Milojic-Blair  6 ,  Bei Wang  6 ,  Omar Kabbarah  6 ,  Michael Mamounas  6 ,  Bernard M Fine  6 ,  Daniel J Maslyar  6 ,  Alexander Ungewickell  6 ,  Howard I Scher  1
Affiliations
  • 1. Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY.
  • 2. The University of Chicago, Chicago, IL.
  • 3. Karmanos Cancer Institute, Detroit, MI.
  • 4. University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA.
  • 5. California Pacific Medical Center, San Francisco, CA.
  • 6. Genentech, South San Francisco, CA.
PMID: 31689155 DOI: 10.1200/JCO.19.00646
Abstract

Purpose: Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is highly expressed in prostate cancers. DSTP3086S is a humanized immunoglobulin G1 anti-STEAP1 monoclonal antibody linked to the potent antimitotic agent monomethyl Auristatin E. This study evaluated the safety and activity of DSTP3086S in patients with metastatic castration-resistant prostate Cancer.

Methods: Patients were enrolled in a 3 + 3 dose escalation study to evaluate DSTP3086S (0.3 to 2.8 mg/kg intravenously) given once every 3 weeks followed by cohort expansion at the recommended phase II dose or weekly (0.8 to 1.0 mg/kg).

Results: Seventy-seven patients were given DSTP3086S once every 3 weeks, and seven were treated weekly. Two patients in the once-every-3-weeks dose escalation had dose-limiting grade 3 transaminitis. Grade 3 hyperglycemia and grade 4 hypophosphatemia were dose-limiting toxicities in one patient treated at 1.0 mg/kg weekly. Initial cohort expansion evaluated dosing at 2.8 mg/kg once every 3 weeks (n = 10), but frequent dose reductions led to testing of 2.4 mg/kg (n = 39) in the expansion phase. Common related adverse events (> 20%) across doses (once every 3 weeks) were fatigue, peripheral neuropathy, nausea, constipation, anorexia, diarrhea, and vomiting. DSTP3086S pharmacokinetics were linear. Among 62 patients who received > 2 mg/kg DSTP3086S once every 3 weeks, 11 (18%) demonstrated a ≥ 50% decline in prostate-specific antigen; two (6%) of 36 with measurable disease at baseline achieved a radiographic partial response; and of 27 patients with informative unfavorable baseline circulating tumor cells ≥ 5/7.5 mL of blood, 16 (59%) showed conversions to favorable circulating tumor cells < 5. No prostate-specific antigen or RECIST responses were seen with weekly dosing.

Conclusion: DSTP3086S has acceptable safety at the recommended phase II dose level of 2.4 mg/kg once every 3 weeks. Antitumor activity at doses between 2.25 and 2.8 mg/kg once every 3 weeks supports the potential benefit of treating STEAP1-expressing metastatic castration-resistant prostate Cancer with an STEAP1-targeting antibody-drug conjugate.

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