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

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.

Trial registration: ClinicalTrials.gov NCT01283373.

FIG 1.

Time on treatment by dosing cohort and corresponding best prostate-specific antigen (PSA) changes in the once-every-3-weeks dose cohort. Dose modifications are represented by changes in color.

FIG 2.

Best response by DSTP3086S once-every-3-weeks dose cohort. Waterfall plot showing best prostate-specific antigen (PSA) change from baseline and corresponding six-transmembrane epithelial antigen of the prostate 1 immunohistochemistry (IHC) and circulating tumor cell (CTC) conversion status. Dashed lines indicate ± 50% change from baseline.

FIG 3.

Patient vignettes. (A) A 72-year-old man with six-transmembrane epithelial antigen of the prostate 1 immunohistochemistry 2+ prostate cancer. This patient received DSTP3086S at 2.8 mg/kg and demonstrated a partial response after cycle 4 that was confirmed on subsequent imaging and a maximum prostate-specific antigen (PSA) decline of 99%. The patient discontinued study treatment at cycle 13 as a result of disease progression on the basis of a rising PSA level. (B) A 60-year-old man with six-transmembrane epithelial antigen of the prostate 1 immunohistochemistry 3+ prostate cancer. This patient received DSTP3086S at 2.8 mg/kg, which was reduced to 2.25 mg/kg at cycle 3 because of grade 3 pulmonary embolism. He demonstrated a maximum PSA decline of 86% and an unconfirmed radiographic partial response after cycle 4. Study treatment continued until cycle 8 and was discontinued as a result of disease progression. CT, computed tomography; CTC, circulating tumor cell; LN, lymph node.