Impact of DNA Damage Repair Defects on Response to Radium-223 and Overall Survival in Metastatic Castration-Resistant Prostate Cancer - Beyond the Abstract

Prostate cancer is the second leading cancer-related cause of death in men worldwide. Radium-223 is a therapeutic option for metastatic castration-resistant prostate cancer (mCRPC) patients with symptomatic bone metastases and no evidence of visceral metastases. Radium-223 selectively binds to areas of increased bone turnover in bone metastases and emits high-energy alpha particles of short-range, causing double-strand DNA breaks. Patients with deleterious aberrations in DNA damage repair (DDR) genes are convicted to a more error-prone method of repairing genetic alterations, especially double-strand breaks. Following radium-223 treatment, prostate cancer cells with a deficient DDR machinery could accumulate irreparable DNA damage which subsequently may result in cellular death through apoptosis. Therefore, patients with defects in DDR genes might be more vulnerable to radionuclides such as radium-223.

In this two-center retrospective study, we analyzed 93 mCRPC patients who were treated with radium-223 therapy and had undergone a comprehensive analysis of genes directly or indirectly involved in DDR through next-generation sequencing.1 Study endpoints were overall survival, prostate-specific antigen and alkaline phosphatase responses, time to alkaline phosphatase progression, the number of administered radium-223 injections, time to first skeletal-related event, and time to subsequent treatment initiation following radium-223 therapy.

Twenty-eight (30%) patients harbored at least one pathogenic alteration in a predefined DDR gene panel, most frequently in ATM (8.6%), BRCA2 (7.5%), and CDK12 (4.3%) genes. Patients harboring DDR alterations showed prolonged overall survival (median 36.3 versus 17.0 months; hazard ratio 2.29; P-value 0.01). Moreover, a multivariate model included only DDR mutational status as prognostic factor of survival in this cohort. In addition, mCRPC patients harboring DDR alterations more frequently completed all six radium-223 injections when compared to patients without these alterations. Despite the longer survival benefit, biochemical responses did not differ significantly between the subgroups. We found a numerically longer time to alkaline phosphatase progression and time to subsequent treatment initiation following radium-223 therapy. No statistically significant difference was found in the time of the first skeletal-related event.

For mCRPC patients with DDR defects, several therapeutic options appear on the horizon. Recently, olaparib was the first PARP inhibitor approved by the FDA for treatment of mCRPC patients with deleterious germline or somatic homologous recombination repair deficiencies, after prior treatment with enzalutamide or abiraterone.2 Furthermore, platinum-based chemotherapy might result in clinical meaningful responses in patients with DDR deficient tumors, although still off-label and under investigation (NCT03652493, NCT02985021, NCT04038502, NCT02598895, NCT03442556). We provide evidence that the use of alpha-emitters such as radium-223 should also be considered in the armamentarium of DDR-deficient patients. Clinical trials evaluating combinatory regimens of radium-223 with PARP inhibitors olaparib (NCT03317392) and niraparib (NCT03076203) are underway, and also of interest for DDR defective mCRPC. Translational studies are ongoing to more clearly dissect underlying mechanisms, such as immunogenic modulation, that may result in the benefit seen in DDR deficient patients. Results from other studies testing immunotherapy regimens plus radium-223, particularly in patients with DDR alterations, are of further interest.

Written by: Maarten J. van der Doelen and Peter H.J. Slootbeek, Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands


  1. M.J. van der Doelen, P. Isaacsson Velho, P. H. J. Slootbeek, S. Pamidimarri Naga, M. Bormann, S. Van Helvert, L. I. Kroeze, I. M. van Oort, W. R. Gerritsen, E. S. Antonarakis and N. Mehra (2020). Impact of DNA damage repair defects on response to radium-223 and overall survival in metastatic castration-resistant prostate cancer. Eur J Cancer 136: 16-24
  2. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer.
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