Case Report
DNA Repair Pathway Alterations in Metastatic Castration-resistant Prostate Cancer Responders to Radium-223

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Introduction

Recently, there has been a growing interest in the DNA repair pathway in prostate cancer. The high incidence of DNA repair pathway genetic alterations in prostate cancer was initially identified in a study examining the genomic landscape of metastatic castration-resistant prostate cancer (mCRPC). In that study, a surprising 22.7% (34/150) of patients had alterations in a DNA repair gene (eg, BRCA1, BRCA2, and ATM), of which 8.0% (12/150) were germline.1 Another study reported an incidence of germline mutations of 11.8% (82/692) in patients with metastatic prostate cancer.2 These findings are clinically meaningful as specific germline DNA repair mutations, namely BRCA1 and BRCA2, in patients with prostate cancer have been shown to be prognostic for worse overall and cancer-specific survival.3

Furthermore, cancer cells with defects in homologous recombination DNA repair genes, such as BRCA1 and BRCA2, are particularly susceptible to poly ADP ribose polymerase (PARP) inhibitors. These agents inhibit PARP repair of single strand DNA breaks, a mechanism important for DNA repair in patients with homologous recombination deficiency; this demonstrates the concept of synthetic lethality in actual cancer patients.4, 5, 6 In a recent study, patients with mCRPC harboring either a homozygous deletion or a frameshift/missense mutation in a DNA repair pathway treated with a PARP inhibitor, olaparib, had a remarkable response rate of 88% (14/16) to therapy.7 Another mechanism of disruption of cancer cell DNA in mCRPC with DNA repair pathway alteration is to treat with agents that induce double-strand DNA breaks; for example, platinum compounds are alkylating agents that result in DNA damage on target cells. Clinically, patients with mCRPC with BRCA2 homozygous deletions have been shown to have prolonged responses to carboplatin in a recent case series.8 However, neither PARP inhibitors nor platinum compounds have regulatory approval for the management of patients with mCRPC.

Conversely, radium-223 (Ra-223), a bone-targeting radiopharmaceutical, is United States Food and Drug Administration (FDA)-approved for patients with bone metastasis and symptomatic mCRPC. In the phase III Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial, Ra-223 was shown to improve overall survival, time to first symptomatic skeletal-related event, and quality of life in patients with mCRPC.9 Ra-223 exerts its anti-tumor effect through the delivery of high-energy alpha-particle radiation selectively to bone metastases leading to double-stranded DNA breaks.10 Accordingly, patients with mCRPC with alterations in DNA repair pathway genes theoretically should be particularly susceptible to treatment with Ra-223.

For this analysis, we identified 49 patients who received Ra-223 monotherapy at our institution since FDA approval in May 2013. In total, 26 (53.1%) of the 49 patients achieved a response to Ra-223. Response was defined as prostate-specific antigen (PSA) or alkaline phosphatase decline of ≥ 30% or normalization of circulating tumor cell count, as these measures have previously been utilized to assess response in patients treated with Ra-223 or PARP inhibitors.7, 9 Of the 26 patients who achieved a response to Ra-223 based on the above criteria, 10 had undergone DNA genetic sequencing. For this analysis, any DNA sequencing platform that included either whole-exome or targeted next-generation sequencing was included. Four (40%) of the 10 patients who responded to Ra-223 had an alteration in a DNA repair gene. Herein, we describe the clinical course of these 4 patients and the potential implications of this association.

Section snippets

Case Reports

Patient 1 was diagnosed at the age of 67 years with metastatic prostate cancer throughout the axial skeleton and on the scapula. The patient was initially on androgen deprivation therapy (ADT) with leuprolide and bicalutamide, and subsequently underwent bilateral orchiectomy. He developed mCRPC after 21 months of treatment. The patient was then treated with sipuleucel-T followed by ipilimumab in context of a clinical trial. He then received enzalutamide with symptomatic progression after 4

Discussion

Since 2010, several novel therapies (abiraterone acetate, cabazitaxel, enzalutamide, Ra-223, and sipuleucel-T) have been FDA-approved for patients with mCRPC; however, the appropriate sequencing of these treatments leading to the best outcomes is not well understood.11 Therefore, the identification of predictive biomarkers for response to a given therapy is important to guide clinical decision-making. In the ALSYMPCA trial, only 16% of patients had a PSA decline of ≥ 30%, and radiographic

Conclusion

In a small sample size, DNA repair alterations were common in patients who responded to Ra-223 and underwent genetic sequencing. These data are hypothesis-generating, and prospective studies should be considered. Earlier administration of Ra-223 in a patient’s treatment course, particularly in those with DNA repair alterations, may result in optimal patient outcomes.

Disclosure

EYY has received honoraria from Bayer Pharmaceuticals for consulting services. Grant support has been provided by Bayer Pharmaceuticals on behalf of EYY and JDR to our institution. All other authors state that they have no conflicts of interest.

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