Maarten van der Doelen

Impact of DNA damage repair defects on response to radium-223 therapy in mCRPC patients

at the bone surface adjacent to the tumor. (16) This suggests indirect mechanisms of action, such as nonimmunogenic and immunogenic modulation of the tumor micro environment (TME) of bone metastases, to explain the beneficial effects of radium-223. (3, 17) The OS benefit may also be caused by bystander cytotoxicity, an effect in which cells are damaged by being in close proximity to cells exposed to radiation. Radium-223 treatment leads to a PSA response only in 16% of mCRPC patients, indicating only a limited bystander effect. (2) We could not corroborate that patients with pathogenic DDR alterations are more susceptible to bystander cytotoxicity reflected by a higher proportion of PSA or ALP declines. Therefore, alternative mechanisms may be involved, such as immunogenic modulation. The induction of an effective anti-TME might lead to the release of signals inducing neo-antigen presentation and activation of antigen specific T-cells, described as immunogenic cell death (ICD). (18) Radium-223-induced DSBs in prostate cancer cells may trigger ICD, leading to an effective antitumor response, reflected by evidence for immunogenic modulation of circulating blood immune subsets, including reduction of PD-1-expressing T-cells, favoring anti-tumor activity over immunosuppression. (19) The effect of ICD might persist after discontinuation of radium-223 therapy, possibly leading to better responses to other systemic therapies and longer overall survival. Ongoing studies are examining the combined effect of radium-223 and the checkpoint inhibitors pembrolizumab (NCT03093428), and atezolizumab (NCT02814669). In 2015, Mateo et al. reported results from the TOPARP-A study of PARP inhibition in patients with advanced mCRPC, where most responses could be explained by presence of pathogenic DDR defects. (20) These results led to initiation of the TOPARP-B and PROfound trials. Recently, the interim analysis from the phase 3 PROfound trial demonstrated a significantly improved radiological progression-free survival in mCRPC patients with DDR mutations, when treated with olaparib versus enzalutamide or abiraterone. (21) Moreover, interim OS analyses showed a trend towards prolonged OS for the olaparib cohort of patients with BRCA1 , BRCA2 and ATM alterations. Our analyses showed that subsequent PARP inhibitor treatment after radium-223 appeared to have no significant impact on OS in the studied population (Supplementary Data). Clinical trials evaluating combinatory regimens of radium-223 with agents targeting the DNA damage response pathway, including PARP inhibitor olaparib (NCT03317392) as well as ATR inhibitors, are underway.

7

Translational studies implementing DDR alterations and other predictive biomarkers are vital to optimize treatment planning, improve outcome, and minimize unnecessary

187