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Background: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. Methods: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0–2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m 2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). Findings: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86–107) in the abiraterone trial and 72 months (61–74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8–86·9) in the abiraterone group versus 45·7 months (41·6–52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53–0·73]; pinteraction=0·71) or between-trial heterogeneity (I 2 p=0·70). In the first 5 years of treatment, grade 3–5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (

Purpose:The DNA damage immune response (DDIR) assay was developed in breast cancer based on biology associated with deficiencies in homologous recombination and Fanconi anemia pathways. A positive DDIR call identifies patients likely to respond to platinum-based chemotherapies in breast and esophageal cancers. In colorectal cancer, there is currently no biomarker to predict response to oxaliplatin. We tested the ability of the DDIR assay to predict response to oxaliplatin-based chemotherapy in colorectal cancer and characterized the biology in DDIR-positive colorectal cancer.Experimental Design:Samples and clinical data were assessed according to DDIR status from patients who received either 5-fluorouracil (5-FU) or 5FUFA (bolus and infusion 5-FU with folinic acid) plus oxaliplatin (FOLFOX) within the FOCUS trial (n = 361, stage IV), or neoadjuvant FOLFOX in the FOxTROT trial (n = 97, stage II/III). Whole transcriptome, mutation, and IHC data of these samples were used to interrogate the biology of DDIR in colorectal cancer.Results:Contrary to our hypothesis, DDIR-negative patients displayed a trend toward improved outcome for oxaliplatin-based chemotherapy compared with DDIR-positive patients. DDIR positivity was associated with microsatellite instability (MSI) and colorectal molecular subtype 1. Refinement of the DDIR signature, based on overlapping IFN-related chemokine signaling associated with DDIR positivity across colorectal cancer and breast cancer cohorts, further confirmed that the DDIR assay did not have predictive value for oxaliplatin-based chemotherapy in colorectal cancer.Conclusions:DDIR positivity does not predict improved response following oxaliplatin treatment in colorectal cancer. However, data presented here suggest the potential of the DDIR assay in identifying immune-rich tumors that may benefit from immune checkpoint blockade, beyond current use of MSI status.

Supplementary Results

Figures S1-S9, Tables S1, S2

supplementary methods

Background The effects of regional histopathologic changes on prostate MRI scans have not been accurately quantified in men with an elevated prostate-specific antigen (PSA) level and no previous biopsy. Purpose To assess how Gleason grade, maximum cancer core length (MCCL), inflammation, prostatic intraepithelial neoplasia (PIN), or atypical small acinar proliferation within a Barzell zone affects the odds of MRI visibility. Materials and Methods In this secondary analysis of the Prostate MRI Imaging Study (PROMIS; May 2012 to November 2015), consecutive participants who underwent multiparametric MRI followed by a combined biopsy, including 5-mm transperineal mapping (TPM), were evaluated. TPM pathologic findings were reported at the whole-prostate level and for each of 20 Barzell zones per prostate. An expert panel blinded to the pathologic findings reviewed MRI scans and declared which Barzell areas spanned Likert score 3-5 lesions. The relationship of Gleason grade and MCCL to zonal MRI outcome (visible vs nonvisible) was assessed using generalized linear mixed-effects models with random intercepts for individual participants. Inflammation, PIN, and atypical small acinar proliferation were similarly assessed in men who had negative TPM results. Results Overall, 161 men (median age, 62 years [IQR, 11 years]) were evaluated and 3179 Barzell zones were assigned MRI status. Compared with benign areas, the odds of MRI visibility were higher when a zone contained cancer with a Gleason score of 3+4 (odds ratio [OR], 3.1; 95% CI: 1.9, 4.9

Outcomes inPatients with newly diagnosed mCRC were registered into FOCUS4 and tested forFOCUS4-C was conducted between April 2017 and Mar 2020 during which time 718 patients were registered; 247 (34%) wereIn this phase II randomized trial, adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for

3540 Background: The relevance of individual RAS (KRAS and NRAS) and TP53 mutations in CRC is well described, but the impact of the combination of both mutations together is less understood. RAS/TP53-mutant (mut) patients (pts) were selected in FOCUS 4-C for treatment with Adavosertib (Wee1 inhibitor) due to hypothesised sensitivity due to replication stress and loss of cell cycle checkpoint control. Initial analyses in CRC suggest that RAS/TP53-mut pts may be prognostically distinct from either mutation alone. Here we examine the impact of RAS/TP53-mut status in both early stage and metastatic CRC (mCRC). Methods: RAS and TP53 mutational status were assessed by whole gene targeted NGS or PCR in hotspot regions. Pts with RAS/TP53 status in the following studies were included after exclusion of BRAF-V600E mutants and MSI-H cases: for early-stage, QUASAR2 trial (N = 408) and an Australian community cohort (N = 654); for mCRC, FOCUS (N = 373) and FOCUS4 (N = 721). Biomarker prevalence, clinical characteristics and outcome data in the RAS/TP53-mut group were compared to pts not showing dual RAS/TP53-mut. Results: The prevalence of RAS/TP53-mut was greater in mCRC compared to early CRC (43.9% vs 25.4% respectively, p < 0.001). In early-stage (II & III) cohorts combined, RAS/TP53-mut pts were more likely to be female, have a right-sided primary tumour, and involved lymph nodes. In early CRC RAS/TP53-mut pts had worse outcome: DFS HR = 1.49[1.19-1.88], p = 0.001, and OS HR = 1.48[1.16-1.89], p = 0.001. In FOCUS, RAS/TP53-mut mCRC pts had inferior PFS with 1st line chemotherapy than not dual RAS/TP53-mut: 6.9 vs 8.6 months (HR = 1.44[1.17-1.79], p = 0.001), and also shorter post-progression survival (HR = 1.49, p = 0.001), and overall survival (14.9 vs 18.9 mths [HR = 1.60, p < 0.0005]). Consistently, during 16 weeks of induction chemotherapy for mCRC pts in FOCUS4, 27.4% of RAS/TP53-mut pts had progressive disease, compared with 18.4% in not dual RAS/TP53-mut; PFS from study registration was reduced in RAS/TP53-mut (5.3 vs 6.1 mths;HR = 1.53[1.22-1.94],p < 0.001), but no statistically significant difference in OS (13.6 vs 17.6 mths;HR = 1.27,p = 0.23). Outcomes by each of the four biomarker groups (RAS/TP53 dual mut; RASwt/TP53mut; RASmut/TP53 wt; RAS/TP53 dual wt) will be presented but in all cases the dual mut subgroup had the worst outcomes compared to the other three groups, marginally better than BRAF-V600E CRC. Conclusions: RAS/TP53 dual mutation status provides useful and readily available prognostic information in both early and mCRC, independent of MSI and BRAF status. It is associated with increased risk of recurrence in early CRC, and a higher risk of chemotherapy resistance and inferior outcomes in mCRC. Evaluation of treatment strategies in this sizeable patient group and further understanding of the underlying mechanism of poor outcomes are urgently required.

BACKGROUND Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population. METHODS These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland. Eligible patients (no age restrictions) had high-risk (defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8-10, and prostate-specific antigen [PSA] concentration ���40 ng/mL) or relapsing with high-risk features (���12 months of total ADT with an interval of ���12 months without treatment and PSA concentration ���4 ng/mL with a doubling time of