15 Jun Novel PROTAC® Protein Degrader Shows Promise in Resistant Metastatic Prostate Cancer

MedicalResearch.com Interview with:

Dr. Vogelzang

Nicholas J. Vogelzang, MD, FASCO, FACP
Medical Oncologist at Comprehensive Cancer Centers of Nevada
Associate Chair, US Oncology Research Genitourinary Committee 

MedicalResearch.com: What is the background for this study?

Response: According to the American Cancer Society, prostate cancer is the second leading cause of cancer death in men in the U.S. New approaches are needed to target the androgen receptor (AR), a critical driver of metastatic castration resistant prostate cancer (mCRPC).

Current agents work by decreasing androgen levels (abiraterone) or blocking androgen binding to AR (enzalutamide). Despite rapid and dramatic responses to standards of care, all patients with metastatic disease progress to the castration resistant state and their tumors continue to be dependent on the AR signaling axis.¹

Study design:

• “3 + 3” dose escalation; starting dose = 35 mg, orally, once daily with food
• Dose increases dependent on toxicities
  • Range 25% to 100% based on severity of AEs

Inclusion criteria:

• Men with mCRPC, regardless of AR status
• At least two prior systemic therapies, at least one of which was abiraterone or enzalutamide
• Disease progression on most recent therapy
  • Rising PSA or 2+ new lesions upon bone scan

Endpoints:

• Primary:
  • Define the maximum tolerated dose and recommended phase 2 dose
• Secondary:
  • Pharmacokinetics
  • Anti‐tumor activity (PSA50, RECIST criteria)
• Exploratory:
  • Biomarkers
    • ctDNA mutational profiling
    • AR levels in optional paired biopsies
    • AR and AR‐ V7 levels in circulating tumor cells (CTCs) 

MedicalResearch.com: What are the main findings?

Response: Main findings:

• This is the first data demonstrating human efficacy in a completely novel therapeutic modality; ARV-110 is the first PROTAC® protein degrader to show evidence of patient benefit.
• 22 patients evaluated had previously received at least two systemic therapies and had progression of disease through an increasing level of prostate specific antigen (PSA) or additional metastatic lesions.
• Of the 22 patients, seven were treated at dose levels with exposures observed in preclinical studies to be therapeutic and also had forms of androgen receptors that ARV-110 would be expected to degrade.
• Two of the seven patients were confirmed to experience a greater than 50 percent decrease in their PSA level, and one of these two patients demonstrated a greater than 50 percent reduction in tumor burden.

MedicalResearch.com: What should readers take away from your report? 

Response: For patients with mCRPC, who have already progressed through many therapies, the efficacy signals seen in this first-in-human dose escalation study are encouraging. The responses are deep, durable, and ongoing. ARV-110 has a favorable safety profile, is well tolerated, and dose escalation continues. 

MedicalResearch.com: What recommendations do you have for future research as a result of this work?

Response: This is a very exciting milestone and we are still working to determine the maximum tolerated dose. In addition, we look forward to further exploring the biomarker data as our study continues. I anticipate expansion into a Phase II trial once a recommended phase II dose is determined.

¹Cancers 2017, 9, 67; doi:10.3390/cancers9060067 

Citation: ASCO 2020

First-in-human phase I study of ARV-110, an androgen receptor (AR) PROTAC degrader in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following enzalutamide (ENZ) and/or abiraterone (ABI).

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Last Updated on June 15, 2020 by Marie Benz MD FAAD