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Background: In the global ARASENS study (NCT02799602), darolutamide plus androgen‐deprivation therapy (ADT) and docetaxel significantly reduced risk of death by 32.5% versus placebo plus ADT and docetaxel (hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.57–0.80; p < 0.0001), with a favorable safety profile in patients with metastatic hormone‐sensitive prostate cancer (mHSPC). We investigated outcomes in Japanese participants. Methods: Patients were randomized 1:1 to oral darolutamide 600 mg twice daily or placebo, plus ADT and docetaxel. The primary endpoint was overall survival. Results: The Japanese subgroup comprised 148 patients (darolutamide 63, placebo 85). In the Japanese versus overall population, more patients were aged ≥75 years (darolutamide/placebo 35%/22% vs. 16%/17%) and had body mass index <25 kg/m2 (78%/79% vs. 46%/43%), The ECOG performance status 0 (92%/88% vs. 72%/71%), de novo mHSPC (95%/97% vs. 86%/87%), and Gleason score ≥8 (94%/92% vs. 78%/79%). Median treatment duration was 43.3/15.4 months for darolutamide/placebo. The overall survival HR for darolutamide versus placebo was 0.91 (95% CI 0.50–1.64), despite 85% of patients in the placebo group receiving subsequent life‐prolonging therapy. Darolutamide prolonged time to castration‐resistant prostate cancer (HR 0.31; 95% CI 0.17–0.55). Treatment‐emergent adverse event incidences were generally similar between groups. Adverse events known to be associated with docetaxel (e.g., neutropenia) were more frequent in the Japanese versus overall population. Conclusion: In conclusion, efficacy outcomes showed positive trends for darolutamide plus ADT and docetaxel in Japanese patients with mHSPC, consistent with the overall population, despite higher risk factors. The combination was well tolerated, with no new safety signals in Japanese patients. In Japanese patients with metastatic hormone‐sensitive prostate cancer (mHSPC) who participated in the global phase 3 ARASENS study, darolutamide in combination with androgen‐deprivation therapy (ADT) and docetaxel showed favorable trends in efficacy and tolerability over placebo plus ADT and docetaxel, with no new safety concerns. The outcomes were consistent with the findings in the overall study population and support the use of darolutamide in combination with ADT and docetaxel in Japanese patients with mHSPC as a new standard of care. [ABSTRACT FROM AUTHOR]

Background: Inhibition of androgen receptor (AR) signaling is the main treatment strategy in advanced prostate cancer (PCa). A subset of castration resistant prostate cancer (CRPC) bypasses the AR blockade by increased fibroblast growth factor receptor (FGFR) signaling. The first‐ and second‐generation, non‐covalent FGFR inhibitors (FGFRis) have largely failed in the clinical trials against PCa. Purpose: In this study, we tested the drug sensitivity of LNCaP, VCaP, and CWR‐R1PCa cell lines to second‐generation, covalent FGFRis (FIIN1, FIIN2) and a novel FGFR downstream molecule inhibitor (FRS2αi). Methods: 2D and 3D mono‐ and co‐cultures of cancer cells, and cancer‐associated fibroblasts (CAFs) were used to mimic tumor‐stroma interactions in the extracellular matrix (ECM). The treatment responses of the FGFR signaling molecules, the viability and proliferation of cancer cells, and CAFs were determined through immunoblotting, migration assay, cell viability assay, and real‐time imaging. Immunofluorescent and confocal microscopy images of control and treated cultures of cancer cells and CAFs, and their morphometric data were deduced. Results: The FGFRis were more effective in mono‐cultures of the cancer cells compared with co‐cultures with CAFs. The FRS2αi was specifically effective in co‐cultures with CAFs but was not cytotoxic to CAF mono‐cultures as in the case of FIIN1 and FIIN2. At the molecular level, FRS2αi decreased p‐FRS2α, p‐ERK1/2, and activated apoptosis as monitored by cleaved caspase‐3 activity in a concentration‐dependent manner in the co‐cultures. We observed no synergistic drug efficacy in the combination treatment of the FGFRi with ARi, enzalutamide, and darolutamide. The FRS2αi treatment led to a decrease in proliferation of cancer cell clusters in co‐cultures as indicated by their reduced size and Ki67 expression. Conclusions: CAFs exert a protective effect on cancer cells and should be included in the in vitro models to make them physiologically more relevant in screening and testing of FGFRis. The FRS2αi was the most potent agent in reducing the viability and proliferation of the 3D organotypic co‐cultures, mainly by disrupting the contact between CAFs and cancer cell clusters. The next‐generation FGFRi, FRS2αi, may be a better alternative treatment option for overcoming ARi treatment resistance in advanced PCa. [ABSTRACT FROM AUTHOR]

Abstract Background In the global ARASENS study (NCT02799602), darolutamide plus androgen‐deprivation therapy (ADT) and docetaxel significantly reduced risk of death by 32.5% versus placebo plus ADT and docetaxel (hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.57–0.80; p

Abstract Background Inhibition of androgen receptor (AR) signaling is the main treatment strategy in advanced prostate cancer (PCa). A subset of castration resistant prostate cancer (CRPC) bypasses the AR blockade by increased fibroblast growth factor receptor (FGFR) signaling. The first‐ and second‐generation, non‐covalent FGFR inhibitors (FGFRis) have largely failed in the clinical trials against PCa. Purpose: In this study, we tested the drug sensitivity of LNCaP, VCaP, and CWR‐R1PCa cell lines to second‐generation, covalent FGFRis (FIIN1, FIIN2) and a novel FGFR downstream molecule inhibitor (FRS2αi). Methods 2D and 3D mono‐ and co‐cultures of cancer cells, and cancer‐associated fibroblasts (CAFs) were used to mimic tumor‐stroma interactions in the extracellular matrix (ECM). The treatment responses of the FGFR signaling molecules, the viability and proliferation of cancer cells, and CAFs were determined through immunoblotting, migration assay, cell viability assay, and real‐time imaging. Immunofluorescent and confocal microscopy images of control and treated cultures of cancer cells and CAFs, and their morphometric data were deduced. Results The FGFRis were more effective in mono‐cultures of the cancer cells compared with co‐cultures with CAFs. The FRS2αi was specifically effective in co‐cultures with CAFs but was not cytotoxic to CAF mono‐cultures as in the case of FIIN1 and FIIN2. At the molecular level, FRS2αi decreased p‐FRS2α, p‐ERK1/2, and activated apoptosis as monitored by cleaved caspase‐3 activity in a concentration‐dependent manner in the co‐cultures. We observed no synergistic drug efficacy in the combination treatment of the FGFRi with ARi, enzalutamide, and darolutamide. The FRS2αi treatment led to a decrease in proliferation of cancer cell clusters in co‐cultures as indicated by their reduced size and Ki67 expression. Conclusions CAFs exert a protective effect on cancer cells and should be included in the in vitro models to make them physiologically more relevant in screening and testing of FGFRis. The FRS2αi was the most potent agent in reducing the viability and proliferation of the 3D organotypic co‐cultures, mainly by disrupting the contact between CAFs and cancer cell clusters. The next‐generation FGFRi, FRS2αi, may be a better alternative treatment option for overcoming ARi treatment resistance in advanced PCa.

Abstract Enzalutamide, apalutamide, and darolutamide are currently recommended for patients with non‐metastatic castration‐resistant prostate cancer (nmCRPC), but cross‐resistance of androgen receptor‐axis‐targeted therapies (ARAT) occurs. Because darolutamide has a distinct chemical structure to other non‐steroidal antiandrogens, it may be effective for nmCRPC patients resistant to enzalutamide or apalutamide. We retrospectively evaluated the efficacy of switching to darolutamide in patients with nmCRPC. We included nine nmCRPC patients who experienced biochemical progression on enzalutamide or apalutamide and were switched over to darolutamide. Five patients (55.5%) had a PSA response >50% decline after starting darolutamide, with an average of 73% PSA decline. Median progression‐free survival was 6 months. In conclusion, an ARAT switch from enzalutamide or apalutamide to darolutamide might be effective for nmCRPC. Although the validation in a large‐scale cohort is necessary, the switch to darolutamide could be a promising therapeutic option after the progression of 1st line ARAT in nmCRPC patients.

Enzalutamide, apalutamide, and darolutamide are currently recommended for patients with non‐metastatic castration‐resistant prostate cancer (nmCRPC), but cross‐resistance of androgen receptor‐axis‐targeted therapies (ARAT) occurs. Because darolutamide has a distinct chemical structure to other non‐steroidal antiandrogens, it may be effective for nmCRPC patients resistant to enzalutamide or apalutamide. We retrospectively evaluated the efficacy of switching to darolutamide in patients with nmCRPC. We included nine nmCRPC patients who experienced biochemical progression on enzalutamide or apalutamide and were switched over to darolutamide. Five patients (55.5%) had a PSA response >50% decline after starting darolutamide, with an average of 73% PSA decline. Median progression‐free survival was 6 months. In conclusion, an ARAT switch from enzalutamide or apalutamide to darolutamide might be effective for nmCRPC. Although the validation in a large‐scale cohort is necessary, the switch to darolutamide could be a promising therapeutic option after the progression of 1st line ARAT in nmCRPC patients. [ABSTRACT FROM AUTHOR]