deletions and mutations frequently cooccur in prostate cancer with lower frequencies reported in castration-resistant prostate cancer (CRPC). We monitored CHD1 expression during disease progression and assessed the molecular and clinical characteristics of-deleted/-mutated metastatic CRPC (mCRPC). We identified 89 patients with mCRPC who had hormone-naive and castration-resistant tumor samples available: These were analyzed for CHD1, PTEN, and ERG expression by IHC. status was determined by targeted next-generation sequencing (NGS). We studied the correlations between these biomarkers and (i) overall survival from diagnosis; (ii) overall survival from CRPC; (iii) duration of abiraterone treatment; and (iv) response to abiraterone. Relationship with outcome was analyzed using Cox regression and log-rank analyses. CHD1 protein loss was detected in 11 (15%) and 13 (17%) of hormone-sensitive prostate cancer (HSPC) and CRPC biopsies, respectively. Comparison of CHD1 expression was feasible in 56 matched, same patient HSPC and CRPC biopsies. CHD1 protein status in HSPC and CRPC correlated in 55 of 56 cases (98%). We identified 22 patients with somatic mutations, with six of these mutations not reported previously in prostate cancer. mutations and/or CHD1 loss was associated with a higher response rate to abiraterone (SPOP: OR, 14.50 = 0.001; CHD1: OR, 7.30, = 0.08) and a longer time on abiraterone (SPOP: HR, 0.37, = 0.002, CHD1: HR, 0.50, = 0.06). -mutated mCRPCs are strongly enriched for CHD1 loss. These tumors appear highly sensitive to abiraterone treatment..

BackgroundWe have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients.Patients and methodsIn dose escalation, weekly paclitaxel (80 mg/m2) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7 days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7 days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small-cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively.ResultsThe dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m2 paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28–18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25 mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8 months (95% CI: 2.76–21.25).DiscussionIn this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC.Clinical trial registrationClinicialTrials.gov identifier: CNCT02193633

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5508 Background: ctDNA can inform on prognosis, treatment response and survival. We evaluated ctDNA in serial plasma samples from patients enrolled in A.MARTIN (NCT01485861), a randomized phase II study of abiraterone with or without ipatasertib in patients with mCRPC. Methods: Blood was collected in cell-free DNA Streck tubes from 216 patients at 3 time points; baseline, C3D1 and end of treatment. Cell-free DNA (cfDNA) was extracted from plasma using a Circulating DNA Kit (Qiagen) on a QIASymphony machine (Qiagen). 25ng of extracted cfDNA was used in library preparation, constructed with a custom designed, 58 gene, QIAseq Targeted DNA panel (Qiagen) enriched for PI3K/AR pathway genes. Samples were sequenced to mean depth of 3394x on a NextSeq500 machine. Unless otherwise noted, all analyses combine patients across the 3 study arms, and reported p-values are unadjusted. Results: Baseline (BL) ctDNA positivity correlated with radiological progression-free survival (rPFS; HR: 1.8 [95% CI 1.3-2.6], p < 0.01); this association with rPFS was maintained in a multivariate cox model with > 5 baseline clinical variables (HR: 1.6 [95% CI 1.1-2.4]; p = 0.011). Patients with a C3D1 reduction in ctDNA had superior rPFS compared to patients with a C3D1 increase in ctDNA (HR: 2 [95% CI 1.3-3.2], p < 0.01). The rate of ctDNA clearance at C3D1 was higher in the Ipatasertib 400mg arm compared to placebo (56.3% versus 24.4%, p < 0.01). We find that changes in ctDNA associated with best confirmed overall response (p = 0.024); CR patients had the greatest reduction in ctDNA (mean of -23.4%), followed by PR (-16.3%), then SD (-4.1%), and lastly PD patients (-1.3%). Changes in ctDNA levels correlated with SLD changes (rs = 0.289, p = 0.05), and also PSA changes (rs = 0.33, p < 0.01). Changes in ctDNA were associated with rPFS in a multivariate cox analysis that included PSA change (p < 0.01), as well as in a separate multivariate analysis that included SLD change (p < 0.01). Lastly, we explored CNVs and observed emerging resistance mutations in progression samples, including alterations in TP53, AR, FOXA, PTEN, and PI3K/AKT pathway genes. Conclusions: ctDNA analyses may help (i) identify poorer prognosis disease at baseline, (ii) inform on treatment response (CR/PR/SD/PD) and radiological progression free survival (rPFS) in on-treatment (C3D1) samples, and (iii) can elucidate emerging resistance mechanisms at disease progression. Clinical trial information: NCT01485861 .