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.

INTRODUCTION

Treatment options with clinical benefit for metastatic castration-resistant prostate cancer (mCRPC) have expanded significantly with the addition of abiraterone,^1,2 enzalutamide,³ radium-223,⁴ and cabazitaxel.⁵ The long-term benefit for these agents, however, remains limited and is associated with significant toxicity.^2,3,6,7 Needed are well-tolerated, targeted treatments with improved clinical benefit for patients whose tumors express the therapeutic target.

Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is a multitransmembrane protein believed to act as an ion channel or transporter protein.⁸ As a cell surface protein frequently expressed in prostate cancer, with limited expression in nonprostate tissues,^9-11 STEAP1 is an ideal candidate for antibody-derived therapies in patients with mCRPC.

DSTP3086S is an antibody-drug conjugate (ADC) that contains the humanized immunoglobulin G1 anti-STEAP1 monoclonal antibody MSTP2109A linked through a protease labile linker, maleimidocaproyl-valine-citrulline p-aminobenzyloxycarbonyl, to a potent antimitotic agent, monomethyl auristatin E (MMAE). After antigen-specific binding of the ADC, the complex is internalized, and MMAE is released intracellularly, resulting in inhibition of cell division and cell death.^12-14 Nonclinical efficacy studies in prostate cancer xenografts provided a rationale for investigating DSTP3086S in patients with mCRPC.¹¹

METHODS

Study Design and Patient Selection

This phase I, multicenter, open-label, 3 + 3, dose-escalation study was designed to evaluate the safety and identify the recommended phase II dose (RP2D) of DSTP3086S in patients with mCRPC. Secondary and exploratory objectives included assessment of the antitumor activity of DSTP3086S in association with STEAP1 expression and of the predictive value of measuring circulating tumor cell (CTC) counts during treatment. The study protocol was approved by institutional review boards before patient recruitment and conducted in accordance with International Conference on Harmonization E6 Guidelines for Good Clinical Practice. Each patient provided signed informed consent before study enrollment.

Study eligibility criteria, including paraffin-embedded tissue screening for STEAP1 expression, are described in the Data Supplement (online only). In the initial dose-escalation stage, patients received intravenous DSTP3086S (supplied by Genentech, South San Francisco, CA) at 0.3 to 2.8 mg/kg once every 3 weeks, with dosing calculated by weight and eventually capped during the 2.4 mg/kg expansion for patients with a body mass index > 35 kg/m² because of excess toxicity seen in morbidly obese patients at higher dose levels. After completing the once-every-3-weeks dose escalation, a weekly schedule was evaluated at 0.8 and 1 mg/kg.

The RP2D was determined on the basis of cumulative safety data obtained at the time of cohort expansion. Dose-expansion cohorts were enrolled at RP2D to further characterize safety, tolerability, pharmacokinetics (PK) variability, and signals of clinical activity in 49 patients with STEAP1-expressing tumors (immunohistochemistry [IHC] 3+, predominantly strong staining; IHC 2+, predominantly moderate staining; IHC 1+, predominantly weak staining; IHC 0, very weak or no staining in > 90% of tumor cells). Patients enrolled in the expansion phase were required to have an STEAP1 IHC score of 2+ or 3+ in an archival or a pretreatment tissue biopsy specimen. A second expansion cohort enrolled chemotherapy-naïve patients who had progressed on abiraterone and/or enzalutamide and received daily prednisone concurrent with DSTP3086S.

Safety Assessment

Safety was assessed on the basis of reports of adverse events (AEs) and included clinical laboratory testing, vital signs, physical examinations, and ECG. Patients were assessed for AEs at each study visit and as necessary throughout the study. AEs were graded in severity according to the National Cancer Institute CTCAE (version 4.0). Dose-limiting toxicities (DLTs) were defined as grade ≥ 3 nonhematologic or grade ≥ 4 hematologic toxicities attributed to treatment that occurred in the first cycle (for exceptions and additional details, see the Data Supplement). Patients with DLTs could continue treatment at a lower dose if toxicities resolved to grade < 2. The maximum tolerated dose was defined as the highest dose at which zero or one of six patients experienced a DLT. PK and immunogenicity assessments are described in the Data Supplement.

Clinical Activity

Preliminary efficacy measures included post-therapy prostate-specific antigen (PSA) changes shown by waterfall plots, disease progression according to Prostate Cancer Clinical Trials Working Group criteria,¹⁵ and radiographic response according to RECIST version 1.0.¹⁶ Per the Prostate Cancer Clinical Trials Working Group, treatment beyond PSA progression in the absence of radiographic or clinically progressive disease was allowed.¹⁵ Exploratory measures of activity included changes in CTC counts from unfavorable ≥ 5 cells to favorable ≤ 4 cells/7.5 mL of blood per US Food and Drug Administration clearance for CellSearch (Menarini Silicon Biosystems, Huntingdon Valley, PA).^17-22 STEAP1 IHC was performed as described in the Data Supplement.

Statistical Analysis

This study was designed to obtain preliminary safety, PK, and activity information in the treated populations. As such, the sample sizes in the various dose-escalation and dose-expansion cohorts did not reflect explicit, formal power and type I error considerations. Rather, sample sizes were based on an estimation framework either for the ability to identify AEs with various assumed underlying prevalence or for their ability to initially assess antitumor activity and evaluate benefits and risks in this patient population. For safety analysis, all patients who received DSTP3086S were included. Patients were considered for evaluation for response if the baseline PSA was detectable, they had measurable disease as assessed by computed tomography/magnetic resonance imaging by RECIST version 1.0, or they had baseline CTCs ≥ 5/7.5 mL of blood.

RESULTS

Patient baseline characteristics for each schedule are listed in Table 1. A total of 84 patients were enrolled, including 77 on the once-every-3-weeks dose schedule of whom 28 were enrolled in the dose escalation (0.3 to 2.8 mg/kg), 10 in an initial expansion at 2.8 mg/kg, and 39 at 2.4 mg/kg in two expansion cohorts. The median number of DSTP3086S dose administrations in the once-every-3-weeks cohort was four (range, one to 25). AEs led to dose delays in 29 patients (38%), dose reductions in 12 (16%), and dose discontinuations in 17 (22%). Peripheral neuropathy was the most common AE that led to treatment discontinuation. Dose reductions occurred after one to nine cycles of DSTP3086S treatment in the three highest dose cohorts, including 50% of patients at 2.8 mg/kg (Fig 1).

TABLE 1.

Patient Demographics and Disease Characteristics

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.

Of the seven patients enrolled in the weekly dose schedule, four were enrolled at 0.8 mg/kg, and three were enrolled at 1.0 mg/kg; no expansions were performed in the weekly schedule. The median number of DSTP3086S dose administrations in the weekly cohort was seven (range, one to 32); one patient (14%) had a dose reduction, three patients (43%) had dose delays, and one patient (14%) discontinued treatment because of AEs.

Safety

In the once-every-3-weeks dose escalation, DLTs included grade 3 transaminitis in one patient each at 2.25 mg/kg and 2.8 mg/kg. The maximum tolerated dose was not reached, and the RP2D for DSTP3086S was determined to be 2.4 mg/kg once-every 3 weeks on the basis of tolerability after an initial expansion at 2.8 mg/kg once every 3 weeks was deemed not tolerable and required frequent dose reductions (Fig 1).

The most common treatment-related AEs, defined as having occurred in > 20% patients (15 of 77) over all once-every-3-week dose levels, were fatigue (56%), peripheral neuropathy (51%), nausea (38%), constipation (35%), decreased appetite (34%), diarrhea (26%), and vomiting (25%). Table 2 lists related AEs that occurred in ≥ 10% patients in the once-every-3-weeks dose cohort. AEs reported at a maximum intensity of grade ≥ 3 in ≥ 5% of patients over all once-every-3-weeks dose levels (regardless of attribution to study drug) were hyperglycemia (eight patients; 10% [includes one event of blood glucose increased]); anemia and fatigue (five patients each; 7%); and back pain, neutropenia, and pulmonary embolism (four patients each; 5%). Treatment-emergent grade ≥ 3 AEs reported in at least two patients are listed in the Data Supplement. Grade ≥ 3 AEs that the investigator considered to be related to the study drug were reported in 34% of patients (26 of 77) on the once-every-3-weeks dose schedule (Data Supplement). The most frequently reported grade ≥ 3–related AE was neutropenia (four patients; 5%).

TABLE 2.

Most Common Related Adverse Events (Any and Grade 3/4) That Occurred in 10% or More Patients in the Once-Every-3-Weeks Dose Cohort

Serious AEs are listed in the Data Supplement. Drug-related serious AEs occurred in nine patients at the once-every-3-weeks dose levels, including two fatal events: one as a result of sepsis (at 2.25 mg/kg) and one as a result of sepsis and respiratory failure after initial hospitalization for hyperglycemia (at 2.4 mg/kg). Thirteen patients (17%) had a glucose value consistent with grade ≥ 3 hyperglycemia while in the study, with eight (10%) of the 13 reported as grade ≥ 3 AEs. Of note, fasting glucose levels, which are used when making the CTCAE determinations, were not required for this study.

In the weekly cohort, one patient treated with 1.0 mg/kg developed grade 3 hyperglycemia and grade 4 hypophosphatemia, which were considered DLTs. AEs commonly experienced by the patients who received weekly treatment are listed in the Data Supplement. Treatment-emergent grade ≥ 3 AEs for patients on the weekly dose schedule are listed in the Data Supplement. One of seven patients developed nonfatal serious AEs that included dehydration, hyperglycemia, hypomagnesemia, and hypophosphatemia that led to treatment discontinuation.

Peripheral neuropathy–related AEs, regardless of attribution to study drug (identified using the broad Standardized Medical Dictionary for Regulatory Activities Queries for peripheral neuropathy), were reported in 46 patients (60%) on the once-every-3-weeks dose schedule after a median of 2.8 months of treatment. For patients on the weekly dose schedule, peripheral neuropathy–related AEs were reported in two (29%). Overall, grade 3 peripheral sensory neuropathy was reported in three patients, with one also having grade 3 peripheral motor neuropathy. Overall, nine patients (12%) on the once-every-3-weeks dose schedule and none of the weekly cohort discontinued DSTP3086S treatment because of a peripheral neuropathy–related AE. The majority of peripheral neuropathy AEs were reported as ongoing at the end of the reporting period for the study, which ended 30 days after a patient’s last dose.

PK and Immunogenicity Assessments

Linear PK (0.3 to 2.8 mg/kg) were observed for total antibody (Tab) and antibody-conjugated MMAE (acMMAE [RP2D of 2.4 mg/kg listed in Table 3]). For the once-every-3-weeks regimen, the mean acMMAE maximum concentrations occurred immediately after the infusion, increased with dose, and ranged from 94 to 993 ng/mL. The acMMAE PK showed a multi-exponential decline, with half-life values ranging from 4.6 to 6.4 days. The acMMAE PK was similar to the Tab, with a trend of faster clearance for acMMAE than for the Tab analyte. Unconjugated MMAE levels increased with DSTP3086S dose, and systemic exposure of unconjugated MMAE was consistently low across all time points (approximately 100-fold less than the exposure to acMMAE) and exhibited formation-rate-limited kinetics (Data Supplement). Minimal accumulation was observed for the acMMAE, Tab, and unconjugated MMAE analytes upon repeated dosing on the once-every-3-weeks schedule, and steady state seemed to be reached within the first dose in cycle 1.

TABLE 3.

Pharmacokinetic Parameters for DSTP3086S Tab, acMMAE, and Unconjugated MMAE Analytes in Cycle 1 at 2.4 mg/kg

For the tested weekly regimen of 0.8 and 1.0 mg/kg, dose-proportional maximum concentrations and areas under the curve were observed. On the basis of the limited weekly dosing data, faster clearance was observed for the weekly regimen compared with the once-every-3-weeks regimen. Therefore, no significant accumulation of acMMAE was observed, even when the drug was administrated weekly.

One (1%) of the 75 tested patients who were evaluable for postdose anti-DSTP3086S antibodies was confirmed positive for antidrug antibodies. No differences were observed in the PK profiles, safety features, or efficacy outcomes for this patient (data not shown).

Clinical Activity

For patients on the once-every-3-weeks dosing schedule, a waterfall plot of the best PSA percent change from baseline is shown in Figure 2. In aggregate, 11 (14%; 95% CI, 7% to 24%) of 77 patients met the response criteria of a confirmed PSA reduction of ≥ 50%. After restricting to patients treated with DSTP3086S at doses > 2 mg/kg (n = 62), PSA responses were obtained in one (14%; 95% CI, 0% to 58%) of seven at the 2.25 mg/kg, five (13%; 95% CI, 4% to 27%) of 39 at the 2.4 mg/kg, and five (31%; 95% CI, 11% to 59%) of 16 at the 2.8 mg/kg dose levels. PSA changes relative to baseline for patients with PSA responses are shown in the Data Supplement.

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.

Of the 46 patients with evaluable disease per RECIST at baseline, two (4%) had a partial response (one confirmed) and 24 (52%) stable disease as best radiographic response. Both patients with partial responses belonged to the subset of 36 evaluable patients per RECIST who received DSTP3086S at doses > 2 mg/kg.

Fourteen patients (18%) remained on study treatment for ≥ 6 months (Fig 1), including two patients with a partial response (Fig 3). One was a 72-year-old man with prostatectomy tumor biopsy tissue that demonstrated IHC 2+ STEAP1 expression. This patient had progressive CRPC after successive treatments with bicalutamide, docetaxel, abiraterone, cabozantinib, and palliative radiation therapy. He received DSTP3086S at a starting dose of 2.8 mg/kg and demonstrated a partial response after cycle 4 (confirmed on subsequent imaging), with a maximum PSA decline of 99%. At cycle 10, DSTP3086S dose was reduced to 2.25 mg/kg because of grade 2 peripheral sensory neuropathy, and the patient discontinued study treatment at cycle 13 as a result of disease progression.

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.

The second patient was a 60-year-old man with prostatectomy tumor biopsy tissue that exhibited IHC 3+ STEAP1 expression. This patient had progressive CRPC after bicalutamide, apalutamide, abiraterone, and docetaxel and received DSTP3086S at a starting dose of 2.8 mg/kg, which was reduced to 2.25 mg/kg at cycle 3 because of grade 3 pulmonary embolism. He demonstrated an unconfirmed radiographic partial response after cycle 4 and a maximum PSA decline of 86% from baseline. He continued on study treatment until cycle 8 and discontinued DSTP3086S as a result of disease progression.

In the weekly cohorts, two patients remained on study treatment for ≥ 6 months. No patients achieved a PSA or RECIST response.

Biomarker Analysis

Among the 134 patients screened for the study, tumor STEAP1 protein expression by IHC was as follows: IHC 0 in one (1%), IHC 1+ in 35 (26%), IHC 2+ in 65 (49%), and IHC 3+ in 33 (24%). Given that only patients with IHC 2+ or 3+ tumor were eligible for the expansion cohorts, most had high STEAP1-expressing tumors (Fig 2). Of the 11 patients with PSA declines of ≥ 50% from baseline, one (10%) had IHC 1+, five (45%) had IHC 2+, and five (45%) had IHC 3+ tumors. At doses of > 2 mg/kg, one (20%) of five patients with IHC 1+ tumors, five (14%) of 36 with IHC 2+ tumors, and five (24%) of 21 with IHC 3+ tumors had PSA declines of ≥ 50% from baseline.

Of the 77 patients who received DSTP3086 once every 3 weeks, 38 (49%; 95% CI, 38% to 61%) had baseline CTCs ≥ 5/7.5 mL of blood. CTC conversions from ≥ 5 to < 5 cells/7.5 mL of blood after treatment were observed in 19 (50%; 95% CI, 33% to 67%) of 38 patients and in 16 (59%; 95% CI, 39% to 78%) of 27 patients who received DSTP3086S at doses > 2 mg/kg. By dose level, of the CTC-informative patients, CTC conversions were observed in three (27%; 95% CI, 6% to 61%) of 11 patients treated at doses < 1.5 mg/kg, one (20%; 95% CI, 1% to 72%) of five patients at 2.25 mg/kg, seven (64%; 95% CI, 31% to 89%) of 11 patients at 2.4 mg/kg, and eight (73%; 95% CI, 39% to 94%) of 11 patients at 2.8 mg/kg. Of the 19 CTC converters, the median baseline (pretreatment) CTC count was 31 cells (range, 6 to 304 cells), with 14 (74%) of 19 patients having baseline CTCs > 10/7.5 mL of blood. No patients on the weekly dose schedule demonstrated a CTC conversion.

Among the patients treated once every 3 weeks with DSTP3086S, 53 (69%; 95% CI, 57% to 79%) of 77 had baseline CTCs ≥ 1/7.5 mL of blood, 18 of whom converted to 0 (34%; 95% CI, 22% to 48%) detectable CTCs on DSTP3086S treatment. This represented 18 (45%; 95% CI, 29% to 62%) of 40 patients treated with DSTP3086S > 2 mg/kg once every 3 weeks v zero (0%; 95% CI, 0% to 25%) of 13 patients who received DSTP3086S ≤ 1.5 mg/kg once every 3 weeks.¹⁸

DISCUSSION

ADCs are designed to deliver potent cytotoxic agents directly to tumors that overexpress the target antigen while improving the therapeutic index by reducing normal tissue exposure.²³ DSTP3086S is a novel ADC that targets the STEAP1 antigen frequently expressed in prostate cancer (73% IHC 2+/3+ in patients screened for this trial). In this study, the RP2D of 2.4 mg/kg once every 3 weeks showed preliminary evidence of antitumor activity in patients with progressive mCRPC, including those with prior exposure to microtubule inhibitors. Patients enrolled in the study were enriched for high STEAP1-expressing tumors because they were considered to be the most likely to benefit from DSTP3086S treatment. Antitumor activity was assessed by PSA changes, imaging, and novel CTC-based measurements to broadly investigate potential clinical benefit. Although DSTP3086S would require refinement to optimize its therapeutic index for further clinical development, the phase I data support the feasibility of targeting STEAP1 in mCRPC. As such, the data may be a valuable guide for novel therapeutic modalities, such as improved ADCs, chimeric antigen receptor T cells, and immune cell–recruiting bispecific antibodies that target STEAP1.

Overall, there was a general concordance between measures of antitumor activity (ie, PSA changes, CTC conversions, RECIST changes; Figs 1 to 3). Clinical activity was evident at dose levels > 2 mg/kg as shown by ≥ 50% declines in PSA in 18% of patients, although only two patients who received the highest tested dose of DSTP3086S 2.8 mg/kg once every 3 weeks achieved a partial radiographic response. This clinical activity was also noted in heavily pretreated patients.

Half of the patients who received DSTP3086S once every 3 weeks had informative baseline CTCs ≥ 5/7.5 mL of blood, where CTC conversion to favorable < 5 cells/7.5 mL of blood after treatment was observed in 50% of patients across all dose levels, with an increasing conversion rate of 64% in the 2.4 mg/kg cohort and 73% in the 2.8 mg/kg cohort. A biomarker panel containing CTC conversions has been shown to be a surrogate for survival at the individual-patient level in trials with novel anti-androgens, such as abiraterone acetate (28% of CTC-informative patients converted) and enzalutamide (24% of CTC-informative patients converted).^18,21 Although PSA declines and imaging responses with STEAP1-ADC treatment were not common, half of the patients with evaluable CTCs had CTC conversions, some coupled with prolonged disease stability. This suggests activity for STEAP1-ADC that is reflected by CTC conversion rather than by PSA or imaging responses and warrants further investigation. In general, the number of prior treatments (either docetaxel or androgen receptor directed) correlated with worse response to DSTP3086S. A limited number of chemotherapy-naïve patients enrolled in the initial 2.4 mg/kg expansion cohort. Because of an overlapping mechanism of action and toxicity between systemic taxanes and MMAE delivered by DSTP3086S, an additional 17 patients were enrolled to assess DSTP3086S in those who had received abiraterone and/or enzalutamide but were chemotherapy naïve; notably only one PSA response was observed. This suggests that prior chemotherapy exposure is not the only factor that potentially limits DSTP3086S activity.

The PK of DSTP3086S was linear across all doses assessed, driven mainly by the anti-STEAP1 antibody, and is consistent with the behavior observed with other ADCs. Dosing on a weekly schedule did not improve overall drug safety, tolerability, or efficacy compared with once every 3 weeks. Fatigue, peripheral neuropathy, and GI symptoms were the most frequent related AEs observed. Dosing at 2.8 mg/kg required more dose reductions compared with 2.4 mg/kg dosing. Therefore, 2.4 mg/kg was selected as the RP2D.

The relationship between exposure and safety events (eg, neuropathy) is unclear given the small number of patients treated at different doses. The development of peripheral neuropathy with repeated dosing, a known AE associated with microtubule inhibition, is likely mediated by the MMAE therapeutic payload.^24-27 Hyperglycemia was reported as an AE in 13% of patients in the study. The mechanism for a potential association between DSTP3086S and hyperglycemia remains unclear, although possibly related to MMAE given reports of hyperglycemia with other ADCs conjugated to MMAE.^28-30

Evaluation of STEAP1 IHC scores suggests a potential association between STEAP1 expression and DSTP3086S clinical activity. However, even with high tumor STEAP1 expression (IHC 3+), the majority of patients did not achieve PSA responses, and the underlying reasons behind intrinsic resistance to DSTP3086S are unknown. It is unknown whether acquired loss of STEAP1 expression after DSTP3086S treatment could explain resistance after an initial response. One effort to better understand STEAP1 expression in patients with CRPC subsequently treated with DSTP3086 was anti-STEAP1-desferrioxamine-⁸⁹Zr–based positron emission tomography imaging.³¹

In summary, DSTP3086S demonstrated an acceptable safety profile, with evidence of antitumor activity confirming that the targeting of STEAP1-expressing mCRPC tumors with an ADC is feasible. Although DSTP3086S would require optimization for further clinical development, these data may inform development of novel ADCs, chimeric antigen receptor T cells, and immune cell–recruiting bispecific antibodies that target STEAP1.

AUTHOR CONTRIBUTIONS

Conception and design: Daniel C. Danila, Celestia S. Higano, Houston N. Gilbert, Omar Kabbarah, Michael Mamounas, Bernard M. Fine, Daniel J. Maslyar, Howard I. Scher

Administrative support: Howard I. Scher

Provision of study material or patients: Daniel C. Danila, Russell Z. Szmulewitz, Ulka Vaishampayan, Ari D. Baron, Howard I. Scher

Collection and assembly of data: Daniel C. Danila, Russell Z. Szmulewitz, Ulka Vaishampayan, Celestia S. Higano, Ari D. Baron, Houston N. Gilbert, Marija Milojic-Blair, Omar Kabbarah, Daniel J. Maslyar, Howard I. Scher

Data analysis and interpretation: Daniel C. Danila, Ulka Vaishampayan, Celestia S. Higano, Houston N. Gilbert, Flavia Brunstein, Marija Milojic-Blair, Bei Wang, Omar Kabbarah, Michael Mamounas, Bernard M. Fine, Daniel J. Maslyar, Alexander Ungewickell, Howard I. Scher

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

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Daniel C. Danila

Honoraria: Angle, Bayer AG, ScreenCell

Consulting or Advisory Role: Angle, Bayer AG, Sanador

Research Funding: Prostate Cancer Foundation, Genentech, Janssen Pharmaceuticals (Inst)

Patents, Royalties, Other Intellectual Property: Gene Expression Profile Associated With Prostate Cancer

Travel, Accommodations, Expenses: Cambridge Healthtech Institute, Prostate Cancer Foundation, Angle, Bayer AG, American Austrian Open Medical Institute, Global Technology Community, Oncology Education, ScreenCell, StopCancer

Russell Z. Szmulewitz

Honoraria: Astellas Pharma

Consulting or Advisory Role: AstraZeneca, AbbVie, Exelixis, Merck, Amgen, Janssen Pharmaceuticals, Sanofi, Astellas Pharma, Pfizer

Research Funding: AbbVie, Astellas Pharma, Incyte, Macrogenics, Janssen Pharmaceuticals

Patents, Royalties, Other Intellectual Property: Co-inventor on patent licensed by The University of Chicago to Corcept Therapeutics for combination androgen receptor/glucocorticoid receptor inhibition in prostate cancer

Travel, Accommodations, Expenses: Corcept Therapeutics

Ulka Vaishampayan

Honoraria: Pfizer, Bayer AG, Sanofi, Bristol-Myers Squibb, Exelixis

Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, Exelixis, Bayer AG, EMD Serono

Speakers’ Bureau: Pfizer, Bayer AG, Bristol-Myers Squibb, Exelixis, Sanofi, Eisai

Research Funding: Astellas Pharma, Exelixis, Pfizer, Bristol-Myers Squibb

Celestia S. Higano

Employment: CTI (I)

Leadership: CTI (I)

Stock and Other Ownership Interests: CTI (I)

Consulting or Advisory Role: Bayer AG, Ferring Pharmaceuticals, Astellas Pharma, Blue Earth Diagnostics, Myriad Genetics, Tolmar, Janssen Pharmaceuticals, Hinova Pharmaceuticals, Pfizer, AstraZeneca

Research Funding: Aragon Pharmaceuticals (Inst), AstraZeneca (Inst), Dendreon (Inst), Medivation (Inst), Emergen BioSolutions (Inst), Bayer AG (Inst), Pfizer (Inst), Roche (Inst), Astellas Pharma (Inst)

Travel, Accommodations, Expenses: Bayer AG, Astellas Pharma, Clovis Oncology, Blue Earth Diagnostics, Ferring Pharmaceuticals, Menarini, Myriad Genetics, Pfizer, Hinova Pharmaceuticals

Ari D. Baron

Speakers’ Bureau: Bristol-Myers Squibb, Genentech, Roche, Merck, Eli Lilly, Amgen, Eisai, Johnson & Johnson, AbbVie

Houston N. Gilbert

Employment: Genentech, Roche, Bellicum Pharmaceuticals, Arcus Biosciences

Stock and Other Ownership Interests: Denali Therapeutics, Celgene, Bellicum Pharmaceuticals

Patents, Royalties, Other Intellectual Property: “Methods of Using Anti-STEAP1 Antibodies for the Treatment of Cancer” (or similar). US and European Union patent applications were submitted following exploratory analysis conducted during a trial of DSTP3086S, a vc-MMAE-anti-STEAP1 ADC (Inst)

Flavia Brunstein

Employment: Roche, Genentech

Stock and Other Ownership Interests: Roche, Genentech

Marija Milojic-Blair

Employment: Genentech, Roche

Bei Wang

Employment: Genentech, Roche

Stock and Other Ownership Interests: Genentech, Roche

Omar Kabbarah

Employment: Genentech

Stock and Other Ownership Interests: Genentech

Michael Mamounas

Employment: Genentech, Amgen (I)

Stock and Other Ownership Interests: Genentech, Amgen (I)

Travel, Accommodations, Expenses: Genentech, Amgen (I)

Bernard M. Fine

Employment: Genentech

Stock and Other Ownership Interests: Roche

Travel, Accommodations, Expenses: Genentech

Daniel J. Maslyar

Employment: Genentech, Alector

Stock and Other Ownership Interests: Genentech, Alector

Consulting or Advisory Role: Western Oncolytics

Alexander Ungewickell

Employment: Genentech

Stock and Other Ownership Interests: Seattle Genetics, Bristol-Myers Squibb, Agios, Alnylam, Regeneron Pharmaceuticals, Rosetta Genomics, Genentech, Roche, Alexion Pharmaceuticals, Amicus Therapeutics

Howard I. Scher

Leadership: Asterias Biotherapeutics

Stock and Other Ownership Interests: Asterias Biotherapeutics

Consulting or Advisory Role: Janssen Pharmaceuticals, Amgen, Menarini Silicon Biosystems, WIRB-Copernicus Group, ESSA, OncLive Insights, Physician Education Resource, Sanofi, Ambry Genetics, Konica Minolta, Bayer AG

Research Funding: Janssen Pharmaceuticals (Inst), Innocrin Pharma (Inst), Illumina (Inst), Epic Sciences (Inst), Menarini Silicon Biosystems (Inst), Thermo Fisher Scientific (Inst)

Travel, Accommodations, Expenses: Asterias Biotherapeutics, Physician Education Resource, Menarini Silicon Biosystems, Amgen, WIRB-Copernicus Group, Konica Minolta, OncLive Insights, ESSA, Prostrate Cancer Foundation, Sanofi, Bayer AG

No other potential conflicts of interest were reported.