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Darolutamide in Combination with Radium-223 Exhibits Synergistic Antitumor Efficacy in LNCaP Prostate Cancer Models
Urs B Hagemann1, Christoph A Schatz1, Mari I Suominen2
1Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany.
Abstract:
Despite treatment, prostate cancer commonly progresses into castration-resistant prostate cancer (CRPC), which remains largely incurable, requiring the development of new interventions. Darolutamide is an orally administered second-generation androgen receptor inhibitor indicated for patients with non-metastatic CRPC or metastatic hormone-sensitive prostate cancer. Here, we evaluated the effect of androgen receptor (AR) inhibition by darolutamide in combination with DNA double-strand-break-inducing targeted radium-223 alpha therapy in vitro and in an intratibial LNCaP xenograft model mimicking prostate cancer metastasized to bone. The results highlight the synergistic antitumor efficacy of darolutamide in combination with radium-223 both in vitro and in vivo. This effect was most likely driven by the downregulation of genes involved in DDR signaling, which was demonstrated in vitro by a gene set enrichment analysis. The combination treatment also reduced pathological tumor-induced effects in bone by decreasing the number of osteoblasts and osteoclasts and reducing abnormal bone formation in tumor-bearing bone. Additionally, it was shown that darolutamide does not affect the uptake of radium-223 into bone tissue. These results support the investigation of darolutamide in combination with radium-223 for the treatment of patients with CRPC metastasized to bone.
Insights
Combining darolutamide with radium-223 shows synergistic effects against castration-resistant prostate cancer (CRPC) bone metastases. This combination therapy reduces tumor growth and bone damage, offering a promising new treatment strategy for CRPC patients.
Area of Science:
- Oncology
- Radiotherapy
- Pharmacology
Background:
- Prostate cancer frequently progresses to castration-resistant prostate cancer (CRPC), a largely incurable stage.
- Current treatments for CRPC are limited, necessitating novel therapeutic approaches.
- Androgen receptor (AR) signaling is a key driver in prostate cancer progression.
Purpose of the Study:
- To evaluate the combined efficacy of darolutamide, an AR inhibitor, and radium-223, an alpha-emitting therapeutic agent.
- To investigate the synergistic antitumor effects of this combination in preclinical models of bone-metastatic CRPC.
- To explore the underlying mechanisms of action for the combination therapy.
Main Methods:
- In vitro studies assessing the effects of darolutamide and radium-223 on prostate cancer cells.
- In vivo evaluation using an intratibial LNCaP xenograft model in mice, mimicking bone metastasis.
- Gene set enrichment analysis to identify molecular pathways affected by the treatment.
- Histopathological analysis of bone tissue to assess tumor-induced changes and treatment effects.
Main Results:
- Darolutamide and radium-223 demonstrated synergistic antitumor efficacy both in vitro and in vivo.
- The combination treatment downregulated genes involved in DNA damage response (DDR) signaling.
- Pathological bone remodeling, including osteoblast and osteoclast activity and abnormal bone formation, was reduced.
- Darolutamide did not impede the uptake of radium-223 into bone tissue.
Conclusions:
- The combination of darolutamide and radium-223 exhibits significant synergistic antitumor activity against CRPC bone metastases.
- This combination therapy effectively mitigates tumor-induced bone pathology.
- These findings support further clinical investigation of darolutamide plus radium-223 for treating CRPC with bone metastasis.
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