ASCO 2021: 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 mCRPC

( HPN424 is a prostate-specific membrane antigen (PSMA)-targeting T cell engager designed to redirect T cells to kill PSMA-expressing prostate cancer cells. It 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. Furthermore, HPN424 is optimized for small size and increased stability compared to other bispecific platforms. The following schematic highlights the mechanism of action of HPN424:


At the 2021 American Society of Clinical Oncology annual meeting, Dr. Johann de Bono and colleagues presented initial results of the ongoing phase 1/2a HPN424-1001 trial assessing HPN424 in mCRPC patients.

This Ph1/2a study is evaluating HPN424 in mCRPC patients who have received > 2 prior systemic therapies. The primary endpoints are safety, tolerability, and determination of maximum tolerated dose and the recommended phase 2 dose. Secondary objectives include pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary anti-tumor activity. HPN424 is administered IV once weekly, and tumor assessments include PSA, CT, and bone scans every 9-weeks. The HPN424-1001 trial schema is as follows:


As of April 23, 2021, 89 patients were dosed in 15 cohorts with target doses ranging from 1.3 to 160 ng/kg fixed-dose, and up to 300 ng/kg with step dosing to the target dose after the initial priming dose. Patients had received a median of 5 prior systemic regimens (a median of 2 prior novel hormonal agents), with 73% having received prior chemotherapy for mCRPC. The median age was 70 (43 – 91) years. The most common grade > 3 treatment-related adverse events were AST increase (21%), anemia (11%), and ALT increase (16%). Dose-limiting toxicities included grade 3 cytokine release syndrome (n = 4), grade 3 elevated lipase (n = 1) and grade 3 seizure (n = 1). These events did not limit escalation, as the maximum tolerated dose has not been reached and escalation continues. All grade cytokine release syndrome occurred in 69% of patients, with grade 3 events occurring after the first administration of the target dose (n = 2 fixed-dose, n = 1 step dose). Transaminase elevation occurred predominantly during Cycle 1, was transient, and had no clinical sequelae. Disease progression was the primary reason for drug discontinuation, with two patients (3%) discontinuing treatment secondary to treatment-related adverse events.

Reduction in circulating tumor cells was seen in 36 of 64 patients (56%) with measurable circulating tumor cells at baseline, including 14 patients who had a CTC0 response. Fifteen of 74 patients with at least 6 months of follow-up have remained on treatment beyond 24 weeks, and one patient experienced confirmed partial response at 160 ng/kg. Fifteen of 74 patients (20%) with >=1 post-baseline value had PSA decreases from baseline ranging from -2% to -76%, including four patients with PSA50 response and two patients with PSA30 response:


In chemotherapy-naïve patients, 6 of 20 (30%) showed PSA declines post-baseline, including three with PSA50 and one with PSA30 response. Eight of 17 patients (47%) chemotherapy-naïve patients in the castrate-resistant state with at least six months of follow-up have remained on treatment beyond 24 weeks:

There were 41 patients of 89 (46%) that had measurable disease at baseline, including 34 patients with >=1 post-treatment protocol scheduled disease assessment. Among these 34 patients, the sum of target lesions in 19 patients (56%) remained stable or showed a reduction, including 1 confirmed partial response.

Dr. de Bono concluded his presentation of the HPN424-1001 trial with the following summary statements:

  • HPN424, a novel half-life extended PSMA-targeting T cell engager, is active and generally well tolerated when administered once weekly
  • HPN424 has antitumor activity including a confirmed partial response, PSA declines, and circulating tumor cell reductions
  • Treatment duration >=24 weeks was observed in 15 of 74 (20%) patients, including 8 of 17 (47%) in chemotherapy-naïve patients
  • Grade 3 cytokine release syndrome was observed in 4% of patients, occurring with the first administration of the target dose
  • The introduction of step dose regimens has allowed for the administration of higher target doses, currently at 300 ng/kg
  • Assessment of optimal target dose and patient population for expansion is ongoing

Clinical trial information: NCT03577028

Presented By: Johann de Bono, MD, MSc, PhD, FRCP, FMedSci, The Institute of Cancer Research and Royal Marsden Hospital, London, United Kingdom

Written By: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021

email news signup