ASCO 2021: Biomarker Analysis of Phase IB Trial of Radium-223 and Niraparib in Patients with mCRPC (NiraRad)

(UroToday.com) Radium-223 is an alpha particle emitter that causes DNA double strand breaks and has been FDA-approved for use in mCRPC patients with bone metastases. PARP-1 activity critically supports androgen receptor activity in mCRPC and potentiates androgen receptor-dependent DNA damage response pathways that promote prostate cancer cell survival. Niraparib is a potent and selective PARP-1/2 inhibitor that has shown single-agent clinical activity in mCRPC. Dr. Eddy Yang and colleagues previously reported the safety of targeting the PARP-1/AR axis with niraparib in combination with radium-223 at ASCO 2020. At the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Dr. Yang presented results of an exploratory biomarker analysis in the NiraRad phase Ib clinical trial.


The primary objective of NiraRad is to determine the optimum phase II dose of niraparib plus Rad (55 kBq/kg of body weight IV every 4 weeks x 6) in patients with and without prior chemotherapy (docetaxel). Patients were enrolled to one of three dose levels of niraparib (100, 200, or 300 mg PO daily). All cohorts were combined for exploratory biomarker analysis using Nanostring PanCancer Driver and Immune Pathways panels and the nSolver Advanced analysis module was performed on blood obtained from 23 patients at baseline, cycle (C) 1 day (D) 15, and C3D15. A favorable response was defined as any PSA reduction at week 12 or treatment duration > 18 weeks, the median time on treatment in the cohort of patients analyzed. A threshold of > 2 fold (X) differentially expressed genes was used.

Of the 23 patients with biomarker data, seven (30%) experienced PSA reductions and 11 (48%) received treatment for > 18 weeks, six of which also had PSA reductions. Exploratory analysis revealed that the PI3K/Ras, MAPK, and transcriptional misregulation pathways were differentially regulated in patients who had favorable responses. The top downregulated gene, PAX5, which has been shown to promote prostate cancer growth, was decreased at C1D15 (2.7X, p < 0.01) and C3D15 (4.8X, p < 0.001) in patients with treatment duration > 18 weeks and at baseline in patients who had PSA reductions (3.1X, p < 0.05):

ASCO_NiraRad.png

Immune pathways analysis suggested downregulation of immunosuppressive B-cell (plasma cell) and upregulation of NK and T cell pathways in patients with treatment duration > 18 weeks:

ASCO_PAX5.png

The regulation of FLT3 and ARG1 are as follows:

ASCO_FLT3.png

Dr. Yang concluded this presentation of NiraRad with the following concluding statements:

  • Nanostring exploratory analysis on whole blood suggests potential response biomarkers that warrant further investigation
  • PAX5, which controls MYC and immune pathways, is higher at screening and downregulated in patients with longer treatment duration
  • ARG1, which causes immune suppression, is upregulated in patients with shorter treatment duration
  • FLT3, an oncogenic driver, is upregulated in patients with shorter treatment duration

Clinical trial information: NCT03076203

Presented by: Eddy Shih-Hsin Yang, MD, University of Alabama at Birmingham, Birmingham, AL

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


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ASCO 2020: Radium-223 and Niraparib Treatment in Castrate-Resistant Prostate Cancer Patients with and without Prior Chemotherapy