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Radium-223 dichloride (223Ra) is an α-emitter approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) with bone metastases, but without visceral involvement. Despite being a life-prolonging therapy (LPT), 223Ra remains underutilized. A large body of real-world evidence (RWE) for 223Ra has been published in the decade since the pivotal phase 3 ALSYMPCA study, a period during which the treatment landscape has continued to evolve. How to optimize 223Ra use, including how to integrate it into the mCRPC management pathway amongst other current LPTs (i.e., with respect to timing and concurrent, layered, or sequential use), is therefore of considerable interest. RWE studies lack the conventional restraints of clinical trials and can therefore help to build an understanding of how treatments may be best used in routine practice. Here we review RWE studies investigating the efficacy and safety of 223Ra in mCRPC [including in sequence with the recently approved 177-Lutetium conjugated to the ligand prostate-specific membrane antigen (177Lu-PSMA)], as well as response marker development, imaging techniques, and current clinical practice recommendations.

Abstract Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal parenchymal lung disease with limited therapeutic options, with fibroblast‐to‐myofibroblast transdifferentiation and hyperproliferation playing a major role. Investigating ex vivo‐cultured (myo)fibroblasts from human IPF lungs as well as fibroblasts isolated from bleomycin‐challenged mice, Forkhead box O3 (FoxO3) transcription factor was found to be less expressed, hyperphosphorylated, and nuclear‐excluded relative to non‐diseased controls. Downregulation and/or hyperphosphorylation of FoxO3 was reproduced by exposure of normal human lung fibroblasts to various pro‐fibrotic growth factors and cytokines (FCS, PDGF, IGF1, TGF‐β1). Moreover, selective knockdown of FoxO3 in the normal human lung fibroblasts reproduced the transdifferentiation and hyperproliferation phenotype. Importantly, mice with global‐ (Foxo3−/−) or fibroblast‐specific (Foxo3f.b−/−) FoxO3 knockout displayed enhanced susceptibility to bleomycin challenge, with augmented fibrosis, loss of lung function, and increased mortality. Activation of FoxO3 with UCN‐01, a staurosporine derivative currently investigated in clinical cancer trials, reverted the IPF myofibroblast phenotype in vitro and blocked the bleomycin‐induced lung fibrosis in vivo. These studies implicate FoxO3 as a critical integrator of pro‐fibrotic signaling in lung fibrosis and pharmacological reconstitution of FoxO3 as a novel treatment strategy.