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Novel PSMA-targeted agent HPN424 shows antitumor activity in mCRPC


HPN424, a tri-specific half-life extended prostate-specific membrane antigen (PSMA)-targeting T cell engager, was well tolerated and demonstrated antitumor activity in patients with metastatic castration-resistant prostate cancer (mCRPC).

The findings from an ongoing phase 1/2a dose escalation study (NCT03577028) were presented at the 2021 American Society of Clinical Oncology annual meeting by Johann De Bono, MB CHB, PhD, MSC, head of drug development at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust.1

According to the study’s abstract, HPN424 is “engineered with three binding domains: anti-PSMA for tumor cell engagement, anti-albumin for half-life extension, and anti-CD3 for T cell engagement.”

The phase 1/2a study evaluated the agent in patients with mCRPC who have received more than 2 prior systemic therapies. The median age was 70 years (range, 43-91) and the median number of prior therapies was 5 (range, 1-12), with 73% of the men having received prior chemotherapy. A majority (78%) of the patients were White, whereas 9% were Black, 2% were Asian, and 11% were classified as other/not reported.

The mean and median PSA were 464 and 129 ng/mL, respectively (range, 0.1-5000). As a reason for entering the study, 27 (42%) men had PSA progression, 3 (5%) had PSA and clinical progression, 10 (16%) had PSA and radiographic progression, and 24 (38%) had radiographic progression.

The primary end points include safety, tolerability, and determination of maximum-tolerated dose (MTD)/recommended phase 2 dose. Secondary objectives included pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity.

The study included a fixed dose arm comprised of 70 patients and a step dose arm comprised of 19 patients. As of the April 23 cutoff date, 89 patients had received the treatment. The highest target doses assessed to date are 160 mg/kg in the step dose arm and 300 mg/kg in the fixed dose arm.

Confirmed RECIST partial response, PSA decline, and circulating tumor cell (CTC) reduction were observed across both arms. Reduction in CTC was observed in 32 (57%) of 56 evaluable patients, including 14 CTC0 responses.

“Overall, across the entire study, 15 of 74 patients…with at least 6 months of follow-up have remained on treatment beyond 24 weeks. PSA declines from baseline have been observed in 20% of evaluable patients, including 4 PSA50 and 2 PSA30 responses,” de Bono said.

Cytokine release syndrome (CRS) and transaminitis were the most common treatment-related adverse events (AEs), and they occurred most often in cycle 1, according to de Bono. Other cytokine-related AEs included chills, pyrexia, hypotension, infusion-related reaction, flushing, and hypoxia.

Liver function tests revealed all-grade and grade 3+ aspartate aminotransferase increases in 28 (31%) and 19 (21%) men, respectively, and all-grade and grade 3+ alanine aminotransferase increases in 26 (29%) and 14 (16%) men, respectively. Other reported AEs included fatigue, nausea, vomiting, anemia, headache, back pain, tachycardia, constipation, and decreased appetite.

“HPN424 has been generally well tolerated. Two patients discontinued due to treatment-related adverse events. The MTD has not yet been reached for either the step dose or fixed dose arms,” de Bono commented.

The most common dose-related toxicities were grade 4 transaminitis and grade 3 CRS. No grade 4/5 CRS or grade 5 treatment-related AEs were observed.


1. De Bono JS, Fong L, Beer TM, et al. Results of an ongoing phase 1/2a dose escalation study of HPN424, a tri-specific half-life extended PSMA-targeting T-cell engager, in patients with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 39, 2021 (suppl 15; abstr 5013).

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