Impact of DNA Repair Pathway Alterations on Sensitivity to Radium-223 in Bone Metastatic Castration-resistant Prostate Cancer

The Impact of DNA Repair Pathway Alterations Identified by Circulating Tumor DNA on Sensitivity to Radium-223 in Bone Metastatic Castration-Resistant Prostate Cancer

This study investigates how well radium-223 works in treating patients with castration-resistant prostate cancer than has spread to the bones (bone metastases). Prostate cancer is the most common cancer in men and the second leading cause of cancer death. Furthermore, many men with notably advanced disease have been found to have abnormalities in DNA repair. The purpose of this research is to study the role of a DNA repair pathway in prostate cancer, specifically in response to administration of radium-223, an FDA-approved drug known to cause DNA damage to cancerous cells. Understanding how defects in the DNA repair pathway affects radium-223 treatment of prostate, may help doctors help plan effective treatment in future patients.

Study Overview

• Status: Recruiting
• Conditions: Castration-Resistant Prostate Carcinoma; Metastatic Prostate Carcinoma; Stage IV Prostate Cancer AJCC v8; Metastatic Malignant Neoplasm in the Bone; Stage IVA Prostate Cancer AJCC v8; Stage IVB Prostate Cancer AJCC v8
• Intervention / Treatment: Other: Questionnaire Administration; Procedure: Biospecimen Collection; Drug: Radium Ra 223 Dichloride

Detailed Description

OUTLINE:

Patients receive standard of care radium Ra 223 dichloride given by intravenous (IV) bolus every 4 weeks for up to 6 cycles. Patients undergo collection of blood every 1-3 months during radium Ra 223 dichloride treatment.

After completion of study, patients are followed up every 3 months for up to 5 years from the date of treatment completion.

• Study Type: Observational
• Enrollment (Estimated): 60

Contacts and Locations

• Study Contact: Name: Patrick Panlasigui; Phone Number: 206-606-7486; Email: ppanlas2@seattlecca.org

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Recruiting
      • Johns Hopkins University
      • Principal Investigator: Ana Kiess, MD
      • Contact: Noura Radwan; Phone Number: 410-614-1570; Email: Nradwan1@jh.edu
  • Montana
    • Bozeman, Montana, United States, 59715
      • Active, not recruiting
      • Bozeman Health Deaconess Hospital
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Fred Hutch/University of Washington Cancer Consortium
      • Principal Investigator: Evan Y. Yu, MD
      • Contact: Patrick Panlasigui; Phone Number: 206-606-7486; Email: ppanlas2@seattlecca.org
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • Recruiting
      • University of Wisconsin-Madison
      • Principal Investigator: Glenn Liu, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with mCRPC with bone metastases who are undergoing treatment with radium-223

Description

Inclusion Criteria:

• Patient must be >= 18 years of age
• Patient must have histopathologic diagnosis of prostate cancer
• Patient must have castration-resistant prostate cancer
• Patient must have radiographic evidence of bone metastasis
• Patients must be symptomatic from prostate cancer
• Patient must have plans to undergo treatment with radium-223
• Patient must have a PSA level >= 10 ng/mL
• Patient must have castrate testosterone levels demonstrated within the last 3 months prior to screening
• Patient must have anticipated survival > 3 months
• Patient must be willing and able to authorize consent
• Patient must be willing and able to comply with the protocol, including follow-up visits

Exclusion Criteria:

• Patient must not have visceral metastasis

• Patients on regimens of radium-223 in combination with other antineoplastic agents are excluded

  * Bone-targeted only therapy (e.g. denosumab or zoledronic acid) will be allowed

• Patients who have received prior radium-223
• Patients who have received prior platinum containing chemotherapy
• Absolute neutrophil count (ANC) < 1.5 x 10^9/L
• Hemoglobin (HB) < 9 g/dL
• Platelets (PLT) < 100 x 10^9/L
• Any condition which, in the investigator's opinion, makes the subject unsuitable for trial participation

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Observational (biospecimen collection); Patients receive standard of care radium Ra 223 dichloride given by IV bolus every 4 weeks for up to 6 cycles. Patients undergo collection of blood every 1-3 months during radium Ra 223 dichloride treatment.	Other: Questionnaire Administration; Ancillary studies; Procedure: Biospecimen Collection; Undergo collection of blood samples; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Drug: Radium Ra 223 Dichloride; Given IV; Other Names: Alpharadin; BAY 88-8223; BAY88-8223; Radium 223 Dichloride; RADIUM RA-223 DICHLORIDE; Radium-223 Dichloride; Xofigo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate	Response will be defined as having one or both of the following: confirmed prostate specific antigen (PSA) decline of >= 30% from baseline AND/OR confirmed alkaline phosphatase (ALP) decline >= 30% from baseline. Response is evaluated throughout the course of treatment until the post-radium-223 end of treatment laboratory studies. Confirmation of response by PSA and/or ALP requires a second consecutive value obtained >= 2 weeks after the first with sustained >= 30% decline. Characterization of response rate to radium-223 in the DRD patient population will be assessed by binomial proportion with Clopper-Pearson exact 2-sided 95% confidence intervals.	Up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate	Comparison of treatment response (outcome/dependent variable) between cases and controls will be assessed using multivariate logistic regression modelling adjusting for secondary variables as appropriate. Risk estimates will include odds ratios with 95% confidence intervals.	Up to 1 year
Response rate in those with previous PARP inhibitor therapy	A multivariate logistic model with PARP inhibitor status as a secondary independent variable and a sensitivity analysis excluding those exposed to PARP inhibitors.	Up to 1 year
Overall survival	Survival by DRD status will be illustrated using univariate Kaplan-Meier curves. Additionally, Cox-PH model adjusting for age, Eastern Cooperative Oncology Group (ECOG) performance status, Gleason grade score, baseline ALP, PSA, hemoglobin (HB), and lactate dehydrogenase (LDH) will be performed. This analysis may be limited by expected small number of events, thus it may be limited to raw reporting of events by DRD status.	Up to 5 years
Number of radium Ra 223 dichloride		Up to 6 months
Pain assessment	Assessed via Brief Pain Inventory survey	Up to 1 year
Analgesic usage		Up to 1 year
Quality of life (FACT-P survey)	Assessed via FACT-P quality of life survey	Up to 1 year
Incidence of adverse events	To access risk of adverse events by DRD status, 2 logistic models will be used. The first will classify the dependent variable as an adverse event while the second model will classify the dependent variable as an adverse event < grade 3.	Up to 1 year
Response rate	Investigate whether response rates by DRD versus non-DRD patients are modified by germline or somatic alteration status of DNA repair pathways.	Up to 1 year

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: Bayer
• Investigators: Principal Investigator: Evan Y. Yu, MD, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): April 16, 2021
• Primary Completion (Estimated): August 1, 2024
• Study Completion (Estimated): August 1, 2028

Study Registration Dates

• First Submitted: July 23, 2020
• First Submitted That Met QC Criteria: July 23, 2020
• First Posted (Actual): July 28, 2020

Study Record Updates

• Last Update Posted (Actual): August 24, 2023
• Last Update Submitted That Met QC Criteria: August 22, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Prostate
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Urogenital Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Neoplasms; Prostatic Neoplasms; Carcinoma; Antineoplastic Agents; Radium Ra 223 dichloride
• Other Study ID Numbers: RG1006011; NCI-2020-04699 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 10370 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO