Prostate cancer is heterogeneous and patients would benefit from methods that stratify those who are likely to respond to systemic therapy. Here, we employ single-cell assays for transposase-accessible chromatin (ATAC) and RNA sequencing in models of early treatment response and resistance to enzalutamide. In doing so, we identify pre-existing and treatment-persistent cell subpopulations that possess regenerative potential when subjected to treatment. We find distinct chromatin landscapes associated with enzalutamide treatment and resistance that are linked to alternative transcriptional programs. Transcriptional profiles characteristic of persistent cells are able to stratify the treatment response of patients. Ultimately, we show that defining changes in chromatin and gene expression in single-cell populations from pre-clinical models can reveal as yet unrecognized molecular predictors of treatment response. This suggests that the application of single-cell methods with high analytical resolution in pre-clinical models may powerfully inform clinical decision-making.

(Klein, 1979; Elder and Catalona, 1984). Bone metastases occur in approximately 85% of patients who die of the disease (McCrea et al., 1958;Jacobs et al., 1983). Although bone-forming metast are charactenrstic of prostate cancer, bone resorption is also accelerated, as evidenced by an increase in the urinary hydroxyproline excretion and by the presence of lytic bone lesions in radiographs (Hopkins et al., 1983;Urwin et al., 1985;Percival et al., 1987;Shimazaki et al., 1990). Also, histomorphometnrc examination of skeletal biopsies has confirmed an enhanced osteolysis (Charhon et al., 1983;Urwin et al., 1985; Clarke et al., 1992;Taube et al., 1994). The main symptom of bone metastases is pain, but lytic lesions may sometimes also lead to pathological fractures and hypercalcaemia. Although most patients with bony metastases respond to the first-line hormonal therapy, the median survival is between 2 and 3 years, and only 30% are alive after 5 years (Murphy et al., 1983).The major structural protein in bone is type I collagen, which is synthesised by osteoblasts and accounts for about 90% of the organic matrix of bone (Risteli et al., 1993 (1988). The types of metastases were evaluated by radiographs, which showed sclerotic metastases without a visible lytic component (S) in 23 patients (58%) and mixed metastases with sclerotic and lytic components (S + L) in 17 patients (42%). Intermittent or constant bone pain had led to

Summary Fifty-seven patients with advanced prostate cancer resistant to first-line hormonal therapy were treated with estramustine and additionally randomized for treatment with clodronate or placebo. Clodronate treatment was started with 5 days intravenous administration (300 mg day-') and followed by oral treatment (1.6 g day-1) for 12 months. Skeletal pain relief was only about 10% better in the clodronate than in the placebo group. The results do not support the superiority of combined intravenous and oral treatment with clodronate compared with oral administration only.

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