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

University of Washington48 enrolled

Overview

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.

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

Conditions

Castration-Resistant Prostate Carcinoma Metastatic Malignant Neoplasm in the Bone Metastatic Prostate Carcinoma Stage IVB Prostate Cancer AJCC v8

Eligibility

Sex: MALEMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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.

Time frame: Up to 1 year

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: Up to 5 years

Number of radium Ra 223 dichloride

Time frame: Up to 6 months

Pain assessment

Assessed via Brief Pain Inventory survey

Time frame: Up to 1 year

Analgesic usage

Time frame: Up to 1 year

Quality of life (FACT-P survey)

Assessed via FACT-P quality of life survey

Time frame: 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.

Time frame: 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.

Time frame: Up to 1 year

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

Overview

Conditions

Interventions

Eligibility

Locations (4)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts