ARX517 Demonstrates Robust Anti-Tumor Activity with Exceptional Safety Record in Heavily Pretreated mCRPC Patients: Phase 1 APEX-01 Trial Data

Ambrx Biopharma (NASDAQ: AMAM) has released compelling clinical data from the Phase 1 segment of its ongoing APEX-01 trial, showcasing ARX517’s potential as a transformative therapy for patients with metastatic castration-resistant prostate cancer (mCRPC) who have exhausted conventional treatment options. The Phase 1/2 APEX-01 trial represents the only U.S.-based investigation of a PSMA-targeted antibody-drug conjugate (ADC) in this patient population.

Strong Clinical Efficacy Across Multiple Endpoints

The trial enrolled 65 patients with heavily pretreated mCRPC, with a median exposure to four prior systemic therapies and a maximum of 13 preceding treatment lines. At therapeutic dosing levels ranging from 2.0 to 2.88 mg/kg (Cohorts 6-8), ARX517 delivered meaningful anti-cancer responses:

PSA Response Data: Among the studied cohort, 52% of patients (12 out of 23) achieved a PSA reduction of 50% or greater. The dose-dependent response pattern was particularly noteworthy—at the 2.0 mg/kg dose level, 50% of patients (7 of 14) experienced PSA50 reductions, compared to 25% (4 of 16) at the lower 1.4 mg/kg dose. Furthermore, deep PSA responses with 90% or greater reductions were observed in 36% of patients at the 2.0 mg/kg cohort, suggesting dose escalation enhances therapeutic benefit.

Circulating Tumor DNA Outcomes: Beyond PSA metrics, 81% of patients (17 of 21) demonstrated a 50% or greater reduction in circulating tumor DNA (ctDNA), a marker increasingly recognized for its prognostic significance in advanced prostate malignancies. Among patients with measurable target lesions, 50% (2 of 4) exhibited greater than 30% reduction in lesion size, including cases with regression in both hepatic and pulmonary metastases.

Treatment-Experienced Cohort Success: Notably, even among the subset of six patients who had previously undergone PSMA-targeted radionuclide therapy, half achieved PSA50 reductions at therapeutic doses, indicating potential benefit in heavily treatment-resistant disease.

Distinctive Safety Profile

One of the most remarkable aspects of the ARX517 data is its exceptionally favorable safety profile—particularly striking given the advanced disease state and extensive prior treatment exposure of enrolled patients. Across all 65 patients at every evaluated dose level, no treatment-related serious adverse events or dose-limiting toxicities were reported.

Treatment discontinuations attributable to drug toxicity occurred in only 3% of participants (2 of 65). Grade 3 or higher treatment-related adverse events were uncommon, affecting only 9.2% of the overall cohort (6 of 65 patients) and 13% of patients receiving therapeutic doses (4 of 32 at 2.0-2.88 mg/kg). These Grade 3 events included lymphopenia (three cases), transient thrombocytopenia (two cases), and asymptomatic left ventricular dysfunction (one case, not classified as serious).

The absence of Grade 4 or 5 treatment-related adverse events represents a significant safety advantage. Low-grade adverse events occurred at modest frequencies, with dry mouth (24%), dry eye (22%), and fatigue (20%) representing the most common Grade 1-2 toxicities. This tolerability profile contrasts favorably with other systemic therapies in advanced prostate cancer treatment.

Pharmacokinetic Characteristics Support ADC Efficacy

ARX517’s pharmacokinetic profile reinforces its clinical promise. PK data across all tested dose levels demonstrated virtually superimposable total antibody and ADC concentration-time curves, indicating robust ADC stability in circulation. Critically, the compound exhibits minimal premature payload release—serum concentrations of free cytotoxic payload remained exceptionally low, with a molar ratio of free payload to intact ADC of merely 0.06%, suggesting targeted delivery of the active cytotoxic agent specifically to PSMA-expressing malignant cells while minimizing exposure to healthy tissues.

Patient Population Reflects Real-World Unmet Need

The APEX-01 enrollment criteria and resulting cohort composition underscore the severity of disease in patients who might benefit from ARX517. All enrolled patients had previously received at least two FDA-approved systemic therapies for metastatic disease, including mandatory exposure to second-generation androgen receptor pathway inhibitors (ARPIs). Within the cohort, 97% received either abiraterone or enzalutamide, with 48% having received both agents sequentially. Beyond hormonal therapy, 66% had prior taxane exposure, 46% had undergone immunotherapy, and 17% had received prior PSMA-targeted radionuclide therapy. This represents a genuinely end-stage population with limited remaining therapeutic alternatives.

Clinical Perspective and Future Development

Dr. Oliver Sartor, an experienced medical oncologist with over three decades of prostate cancer research and clinical practice, emphasized the significance of these findings: “Patients with late-stage mCRPC face a dearth of effective systemic therapeutic options. The APEX-01 data reveal encouraging PSA declines and ctDNA reductions, both pointing favorably toward clinical utility. Combined with the demonstrated safety profile and preliminary efficacy signals, this investigational agent warrants continued development.”

Dr. John Shen from UCLA, an APEX-01 investigator, added that the PSA response data are particularly encouraging considering the heavily pretreated nature of the study population, noting that enrolled patients had typically exhausted all standard, approved treatment modalities.

Continued Dose Escalation and Trial Progression

The consistent dose-dependent improvement in PSA response, coupled with the absence of dose-limiting toxicities and serious adverse events, has justified continued trial advancement. Cohort 8, evaluating ARX517 at 2.88 mg/kg, remains in the expansion phase. Simultaneously, Cohort 9 at 3.4 mg/kg has initiated escalation, with the goal of identifying the optimal therapeutic dose that maximizes anti-tumor benefit while maintaining the favorable safety profile observed to date. This escalation pathway reflects confidence in ARX517’s therapeutic window based on the September 5, 2023 data cutoff.

The APEX-01 trial commenced enrollment in July 2021 and continues to advance as the sole U.S.-based clinical investigation of a PSMA-targeted ADC for mCRPC. The primary objectives remain assessment of ARX517 safety, tolerability, and establishment of a recommended Phase 2 dose, with results anticipated to inform the next phase of clinical investigation in this challenging patient population.