FDA Grants Fast Track Designation to HP518 for AR+ TNBC

The FDA has granted fast track designation to HP518 as a potential therapeutic option for patients with androgen receptor (AR)–positive triple-negative breast cancer (TNBC).¹

HP518 is a potent AR PROTAC degrader designed to degrade wild-type AR and AR ligand-binding domain mutations such as L702H. In preclinical studies using AR-positive TNBC animal models, the agent showed antitumor activity, including significant tumor reduction, and favorable safety.

“We are thrilled to receive fast track designation from the FDA for HP518,” Yuanwei Chen, PhD, chief executive officer of Hinova Pharmaceuticals, stated in a news release. "This designation underscores the significant need for new treatment options for patients with TNBC and highlights the potential of our investigational therapy to make a meaningful impact on this devastating disease. The discovery of HP518’s novel mechanism of action provides new hope for effective treatment. We look forward to working closely with the FDA to advance HP518 through the clinical development process as efficiently as possible.”

In February 2023, the FDA cleared an investigational new drug (IND) application for HP518 for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).2 Hinova Pharmaceuticals announced that it will update the existing IND application to include the development of the agent for patients with TNBC.¹

Findings from a phase 1 trial (NCT05252364) being conducted in Australia for patients with mCRPC were presented at the 2024 ASCO Annual Meeting. Among enrolled patients (n = 22), 3 patients achieved at prostate-specific antigen (PSA) response, defined as at least a 50% reduction in PSA from baseline (PSA50), including 2 patients who had partial responses with durations of 36 weeks and 60 weeks.³

No dose-limiting toxicities were observed. Ten serious adverse effects (AEs) were reported, although only 1 serious AE of vomiting was considered related to HP518. Twelve grade 3 or higher AEs occurred; 1 instance of vomiting was the only event classified as a treatment-related AE (TRAE).

The rates of grade 1, grade 2, and grade 3 AEs were 50%, 42%, and 8%, respectively. Grade 1, grade 2, and grade 3 TRAEs were reported in 55%, 43%, and 2% of patients, respectively. The most common grade 1 to 3 TRAEs included vomiting (n = 15), nausea (n = 11), fatigue (n = 8), and anorexia (n = 4).

The study enrolled patients with histologically confirmed mCRPC without known small cell or neuroendocrine differentiation. Patients were required to have PSA or radiographic disease progression during treatment with androgen-deprivation therapy, androgen biosynthesis inhibitors, or second-generation AR inhibitors. Other key inclusion criteria consisted of castrate testosterone levels at screening, an ECOG performance status of 0 or 1, and adequate organ function.

Patients were excluded if they received more than 1 line of chemotherapy for prostate cancer. Concomitant treatment with enzalutamide (Xtandi) or other AR inhibitors; abiraterone acetate (Zytiga); or any other anticancer treatments, including chemotherapy, immunotherapy, radiotherapy, or other investigational agents, was not permitted within 4 weeks of the first dose of HP518.

During the dose-escalation study, patients received oral HP518 once per day at 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg.

The primary end points of the study were safety and tolerability, as well as determining the maximum tolerated dose and recommended phase 2 dose. Secondary end points included pharmacokinetics, PSA50 response, time to PSA progression, radiographic progression per RECIST 1.1 and Prostate Cancer Working Group 3 criteria, and objective response rate.

A phase 1 trial (NCT06155084) in China is also assessing the safety, pharmacokinetics, and antitumor activity of HP518 in patients with mCRPC.¹

References

1. Hinova Pharmaceuticals receives FDA fast track designation for HP518 for treatment of AR+ triple-negative breast cancer (TNBC). News release. Hinova Pharmaceuticals. July 5, 2024. Accessed July 22, 2024. https://www.hinovapharma.com/en/news/202407/242.html
2. Hinova receives FDA proceed authorization for its IND application for HP518, an orally bioavailable chimeric degrader targeting androgen receptor for prostate cancer treatment. News release. Hinova Pharmaceuticals. February 1, 2023. Accessed July 22, 2024. https://www.hinovapharma.com/en/news/202302/223.html
3. Azad A, Underhill CR, Gurney H, et al. Biomarker assessment and pharmacology of HP518, an AR PROTAC degrader from the phase 1 dose-escalation study in patients with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2024;42(suppl 16):5058. doi:10.1200/JCO.2024.42.16_suppl.5058