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Summary Background Taxane–platinum combinations have shown promising activity in metastatic castration-resistant prostate cancers in single-group clinical studies but not in randomised trials. Distinct biological subsets of the disease might derive the greatest benefit from the addition of platinum. We aimed to determine whether adding carboplatin to cabazitaxel would improve the outcomes of men with metastatic castration-resistant prostate cancer. Methods We did a phase 1–2, open label, randomised study at two centres in men with progressive metastatic castration-resistant prostate cancer. In phase 1, patients received intravenous cabazitaxel 20–25 mg/m2 and intravenous carboplatin area under the curve (AUC) 3–4 mg/mL per min every 21 days. The maximum tolerated dose was defined as the highest dose cohort studied in which one of six or fewer patients experienced a dose-limiting toxicity. In phase 2, patients were randomly assigned (1:1) centrally by a computerised algorithm to intravenous cabazitaxel 25 mg/m2 with or without intravenous carboplatin AUC 4 mg/mL per min. All patients received growth factor support and oral prednisone 10 mg daily. The primary endpoints were the maximum tolerated dose of the combination in phase 1 and investigator-assessed progression-free survival in phase 2. This trial is registered at ClinicalTrials.gov , number NCT01505868 . Findings Between Aug 17, 2012, and May 11, 2015, nine patients completed phase 1 as planned, and 160 were randomly assigned to cabazitaxel (n=79) or cabazitaxel plus carboplatin (n=81) in phase 2. During phase I, grade 3 adverse events were anaemia (n=2), fatigue (n=1), thrombocytopenia (n=1), hypomagnesaemia (n=1), diarrhoea (n=1), hypokalaemia (n=1), anorexia (n=1), and dehydration (n=1), and no grade 4 adverse events occurred. No dose-limiting toxicities were observed, therefore, a maximum tolerated dose of cabazitaxel of 25 mg/m2 and carboplatin of AUC 4 mg/mL per min was selected for phase 2. At a median follow-up of 31·0 months (IQR 20·5–37·1), the combination improved the median progression-free survival from 4·5 months (95% CI 3·5–5·7) to 7·3 months (95% CI 5·5–8·2; hazard ratio 0·69, 95% CI 0·50–0·95, p=0·018). In the phase 2 study, the most common grade 3–5 adverse events were fatigue (7 [9%] of 79 in the cabazitaxel group vs 16 [20%] of 81 in the combination group), anaemia (3 [4%] vs 19 [23%]), neutropenia (3 [4%] vs 13 [16%]), and thrombocytopenia (1 [1%] vs 11 [14%]). There were no treatment-related deaths. Interpretation Carboplatin added to cabazitaxel showed improved clinical efficacy compared with cabazitaxel alone for men with metastatic castration-resistant prostate cancer. Although adverse events were more common with the combination, the treatment was safe and generally well tolerated. Our data suggest that taxane–platinum combinations have a clinically beneficial role in advanced prostate cancer and a randomised phase 3 study is planned. Funding Sanofi Genzyme, University of Texas MD Anderson Cancer Center Prostate Cancer Moon Shot Program, Solon Scott III Prostate Cancer Research Fund, National Institutes of Health, and National Cancer Institute.

Background Immune checkpoint inhibitors (ICIs) are being increasingly utilised in the front-line (1L) setting of metastatic clear-cell renal cell carcinoma (mccRCC). Limited data exist on responses and survival on second-line (2L) vascular endothelial growth factor–receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy after 1L ICI therapy. Patients and methods This is a retrospective study of mccRCC patients treated with 2L VEGFR-TKI after progressive disease (PD) with 1L ICI. Patients were treated at MD Anderson Cancer Center or Memorial Sloan Kettering Cancer Center between December 2015 and February 2018. Objective response was assessed by blinded radiologists' review using Response Evaluation Criteria in Solid Tumours v1.1. Descriptive statistics and Kaplan–Meier method were used. Results Seventy patients were included in the analysis. Median age at mccRCC diagnosis was 59 years; 8 patients (11%) had international metastatic database consortium favourable-risk disease, 48 (69%) had intermediate-risk disease and 14 (20%) had poor-risk disease. As 1L therapy, 12 patients (17%) received anti–programmed death ligand-1 (PD-(L)1) monotherapy with nivolumab or atezolizumab, 33 (47%) received nivolumab plus ipilimumab and 25 (36%) received combination anti–PD-(L)1 plus bevacizumab. 2L TKI therapies included pazopanib, sunitinib, axitinib and cabozantinib. On 2L TKI therapy, one patient (1.5%) achieved a complete response, 27 patients (39.7%) a partial response and 36 patients (52.9%) stable disease. Median progression-free survival (mPFS) was 13.2 months (95% confidence interval: 10.1, NA). Forty-five percent of subjects required a dose reduction, and twenty-seven percent of patients discontinued treatment because of toxicity. Conclusions In this retrospective study of patients with mccRCC receiving 2L TKI monotherapy after 1L ICI, we observed 2L antitumour activity and tolerance comparable to historical data for 1L TKI.

Objectives Multimodal kidney‐preserving (MKP) strategies may be an option for patients with localised or locally advanced high‐risk upper tract urothelial carcinoma (UTUC) who have a relative contraindication for nephroureterectomy (NU). Materials and methods We studied patients with UTUC who were managed with MKP strategies, consisting of systemic anticancer therapy, with or without local/topical strategies after endoscopic control of intraluminal tumours. Primary end points were overall survival (OS) and progression‐free survival (PFS). Results Fourteen patients received MKP treatment between August 2013 and April 2020. Median baseline estimated glomerular filtration rate was 43 mL/min/1.73m2. MKP was mainly pursued to avoid dialysis (10/14, 71%), followed by low performance status and/or comorbidities (2/14, 14%). All patients had received systemic therapy: chemotherapy (64%) and immunotherapy (36%). Endoscopic control and/or laser ablation was feasible in 7 (50%) patients. Calculated overall risk of non‐organ confined disease was 35%. Predicted 2‐year and 5‐year relapse‐free probability (RFP) was 74% (24–92%) and 62% (10–85%), respectively. Median follow‐up was 31 months (95% CI: 22.6, NE), median OS was 48.1 months (95% CI: 48.1, NE) and 2‐year OS probability was 0.89 (95% CI: 0.71, 1). Median metastases‐free survival was 48.1 months (95% CI: 26.8, NE), median PFS was 22.4 months (95% CI: 15.6, NE) and 2‐year PFS probability was 0.48 (0.26, 0.89). Conclusion Management of high‐risk localised or locally advanced UTUC with MKP strategies was associated with good tolerance, preservation of renal function, and comparable PFS and OS to predicted in vulnerable patients. Prospective studies with more patients are needed to evaluate these possible benefits relative to current standards.

Introduction Two separate antiangiogenic tyrosine kinase inhibitors (TKIs) and immunotherapy (IO) combinations are FDA‐approved as front‐line treatment for metastatic renal cell carcinoma (mRCC). Little is known about off‐protocol and post‐front‐line experience with combination TKI–IO approaches. Methods We conducted a retrospective analysis of mRCC patients who received combination TKI–IO post‐first‐line therapy between November 2015 and January 2019 at MD Anderson Cancer Center and Duke Cancer Institute. Chart review detailed patient characteristics, treatments, toxicity, and survival. Independent radiologists, blinded to clinical data, assessed best radiographic response using RECIST v1.1. Results We identified 48 mRCC patients for inclusion: median age 65 years, 75.0% clear cell histology, 68.8% IMDC intermediate risk, and median two prior systemic therapies. TKI–IO combinations included nivolumab–cabozantinib (N +C; 24 patients), nivolumab–pazopanib (N+P; 13), nivolumab–axitinib (6), nivolumab–lenvatinib (2), and nivolumab–ipilimumab–cabozantinib (3). The median progression‐free survival was 11.6 months and the median overall survival was not reached. Response data were available in 45 patients: complete response (CR; n = 3, 6.7%), partial response (PR; 20, 44.4%), stable disease (SD; 19, 42.2%), and progressive disease (3, 6.7%). Overall response rate was 51% and disease control rate (CR+PR+SD) was 93%. Only one patient had a grade ≥3 adverse event. Conclusion To our knowledge, this is the first case series reporting off‐label use of combination TKI–IO for mRCC. TKI–IO combinations, particularly N+P and N+C, are well tolerated and efficacious. Although further prospective research is essential, slow disease progression on IO or TKI monotherapy may be safely controlled with addition of either TKI or IO., Real world use of combination anti‐angiogenic tyrosine kinase inhibitor (TKI)—anti‐PD1 immunotherapy (IO) is feasible, well tolerated and efficacious for metastatic renal cell carcinoma in the second line setting and beyond. Although further prospective research is essential to define optimal use of salvage TKI‐IO, slow disease progression on IO or TKI monotherapy may be safely controlled with addition of either a TKI or IO.

18F-Fluciclovine PET/CT has become a common diagnostic imaging study used in the evaluation of biochemical recurrence in prostate cancer since its approval in 2016. We present a case report of an 82-year-old man with history of both prostate and bladder cancer who presented for a fluciclovine study due to rising PSA levels. There was incidental detection of focal penile activity, and a subsequent urethral biopsy performed showed urothelial carcinoma, which was also seen on a subsequent MRI study.

Long-term androgen-deprivation therapy (ADT) is the standard of care in combination with radiation therapy (RT) in high-risk prostate cancer (PC), despite substantial toxicity from the resulting hypogonadism. We hypothesized that a combination of more potent but shorter-term androgen inhibition in men with intermediate- or high-risk localized PC would synergize with definitive RT to provide short-term testosterone recovery and improve disease control.This prospective phase 2 single-arm trial enrolled men with low-volume unfavorable intermediate or high-risk localized PC. Treatment included 6 months of ADT concurrent with abiraterone acetate plus prednisone (AAP) once daily and RT to prostate and seminal vesicles. The primary endpoint was the proportion of men with an undetectable prostate-specific antigen (PSA) at 12-months; secondary objectives included biochemical progression-free survival (PFS), testosterone recovery, toxicity, and sexual and hormonal quality of life.We enrolled 37 men between January 2014 and August 2016, 45% of whom were high risk. All patients had T1-2 disease and PSA20 ng/mL. Median follow-up is 37 months (95% confidence interval [CI], 35.7-39.1). Treatment noted 32% grade 3 toxicities related to AAP, predominantly hypertension, with no toxicities ≥G4. The rate of undetectable PSA at 12 months was 55% (95% CI, 36%-72%). With 46 months of median follow-up, 2 of 37 patients developed PSA progression (36-month PFS = 96%; 95% CI, 76%-99%), and 81% of patients recovered testosterone with a median time to recovery of 9.2 months. Hormonal or sexual function declined at 6 months with subsequent improvement by 24 months.The combination of RT and 6 months of ADT and AAP demonstrated acceptable toxicity and a high rate of testosterone recovery with restoration of quality of life and excellent disease control in men with low-volume, intermediate- or high-risk localized prostate cancer. Prospective comparative studies are justified.

Background Investigating genome evolution in response to therapy is difficult in human tissue samples. To address this challenge, we develop an unbiased whole-genome plasma DNA sequencing approach that concurrently measures genomic copy number and exome mutations from archival cryostored plasma samples. This approach is applied to study longitudinal blood plasma samples from prostate cancer patients, where longitudinal tissue biopsies from the bone and other metastatic sites have been challenging to collect. Results A molecular characterization of archival plasma DNA from 233 patients and genomic profiling of 101 patients identifies clinical correlations of aneuploid plasma DNA profiles with poor survival, increased plasma DNA concentrations, and lower plasma DNA size distributions. Deep-exome sequencing and genomic copy number profiling are performed on 23 patients, including 9 patients with matched metastatic tissues and 12 patients with serial plasma samples. These data show a high concordance in genomic alterations between the plasma DNA and metastatic tissue samples, suggesting the plasma DNA is highly representative of the tissue alterations. Longitudinal sequencing of 12 patients with 2–5 serial plasma samples reveals clonal dynamics and genome evolution in response to hormonal and chemotherapy. By performing an integrated evolutionary analysis, minor subclones are identified in 9 patients that expanded in response to therapy and harbored mutations associated with resistance. Conclusions This study provides an unbiased evolutionary approach to non-invasively delineate clonal dynamics and identify clones with mutations associated with resistance in prostate cancer.

Immune checkpoint therapy is being tested in the neoadjuvant setting for patients with localized urothelial carcinoma1,2, with one study reporting data in cisplatin-ineligible patients who received anti-PD-L1 monotherapy2. The study reported that patients with bulky tumors, a known high-risk feature defined as greater than clinical T2 disease, had fewer responses, with pathological complete response rate of 17%2. Here we report on the first pilot combination neoadjuvant trial ( NCT02812420 ) with anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab) in cisplatin-ineligible patients, with all tumors identified as having high-risk features (n = 28). High-risk features were defined by bulky tumors, variant histology, lymphovascular invasion, hydronephrosis and/or high-grade upper tract disease3–5. The primary endpoint was safety and we observed 6 of 28 patients (21%) with grade ≥3 immune-related adverse events, consisting of asymptomatic laboratory abnormalities (n = 4), hepatitis and colitis (n = 2). We also observed pathological complete response of 37.5% and downstaging to pT1 or less in 58% of patients who completed surgery (n = 24). In summary, we provide initial safety, efficacy and biomarker data with neoadjuvant combination anti-PD-L1 plus anti-CTLA-4, which warrants further development for patients with localized urothelial carcinoma, especially cisplatin-ineligible patients with high-risk features who do not currently have an established standard-of-care neoadjuvant treatment. Neoadjuvant combination of immune checkpoint therapy in patients with cisplatin-ineligible bladder cancer achieves clinical efficacy and uncovers immune features as potential predictive biomarkers of treatment response.

The overall goal of this study was to elucidate the role of FGFR1 induction in acquired resistance to MET and VEGFR2 inhibition by cabozantinib in prostate cancer (PCa) and leverage this understanding to improve therapy outcomes. The response to cabozantinib was examined in mice bearing patient-derived xenografts in which FGFR1 was overexpressed. Using a variety of cell models that reflect different PCa disease states, the mechanism underpinning FGFR1 signaling activation by cabozantinib was investigated. We performed parallel investigations in specimens from cabozantinib-treated patients to confirm our in vitro and in vivo data. FGFR1 overexpression was sufficient to confer resistance to cabozantinib. Our results demonstrate transcriptional activation of FGF/FGFR1 expression in cabozantinib-resistant models. Further analysis of molecular pathways identified a YAP/TBX5-driven mechanism of FGFR1 and FGF overexpression induced by MET inhibition. Importantly, knockdown of YAP and TBX5 led to decreased FGFR1 protein expression and decreased mRNA levels of FGFR1, FGF1, and FGF2. This association was confirmed in a cohort of hormone-naïve patients with PCa receiving androgen deprivation therapy and cabozantinib, further validating our findings. These findings reveal that the molecular basis of resistance to MET inhibition in PCa is FGFR1 activation through a YAP/TBX5-dependent mechanism. YAP and its downstream target TBX5 represent a crucial mediator in acquired resistance to MET inhibitors. Thus, our studies provide insight into the mechanism of acquired resistance and will guide future development of clinical trials with MET inhibitors.

Purpose To determine whether cotargeting poly (ADP-ribose) polymerase-1 plus androgen receptor is superior to androgen receptor inhibition in metastatic castration-resistant prostate cancer (mCRPC) and whether ETS fusions predict response. Patients and Methods Patients underwent metastatic site biopsy and were stratified by ETS status and randomly assigned to abiraterone plus prednisone without (arm A) or with veliparib (arm B). Primary objectives were: confirmed prostate-specific antigen (PSA) response rate (RR) and whether ETS fusions predicted response. Secondary objectives were: safety, measurable disease RR (mRR), progression-free survival (PFS), and molecular biomarker analysis. A total of 148 patients were randomly assigned to detect a 20% PSA RR improvement. Results A total of 148 patients with mCRPC were randomly assigned: arm A, n = 72; arm B, n = 76. There were no differences in PSA RR (63.9% v 72.4%; P = .27), mRR (45.0% v 52.2%; P = .51), or median PFS (10.1 v 11 months; P = .99). ETS fusions did not predict response. Exploratory analysis of tumor sequencing (80 patients) revealed: 41 patients (51%) were ETS positive, 20 (25%) had DNA-damage repair defect (DRD), 41 (51%) had AR amplification or copy gain, 34 (43%) had PTEN mutation, 33 (41%) had TP53 mutation, 39 (49%) had PIK3CA pathway activation, and 12 (15%) had WNT pathway alteration. Patients with DRD had significantly higher PSA RR (90% v 56.7%; P = .007) and mRR (87.5% v 38.6%; P = .001), PSA decline ≥ 90% (75% v 25%; P = .001), and longer median PFS (14.5 v 8.1 months; P = .025) versus those with wild-type tumors. Median PFS was longer in patients with normal PTEN (13.5 v 6.7 months; P = .02), TP53 (13.5 v 7.7 months; P = .01), and PIK3CA (13.8 v 8.3 months; P = .03) versus those with mutation or activation. In multivariable analysis adjusting for clinical covariates, DRD association with PFS remained significant. Conclusion Veliparib and ETS status did not affect response. Exploratory analysis identified a novel DRD association with mCRPC outcomes.

BackgroundProstate cancer is ”immunologically cold,” with enrichment of myeloid populations, immunosuppressive cytokines, and few T cells within the tumor microenvironment (TME). CD38 is expressed on myeloid cells, T cells, plasma B cells, and NK cells. Macrophage colony-stimulating factor-1 receptor (CSF-1R) controls macrophage differentiation and function. We hypothesized that either anti-CD38 (daratumumab) or CSF-1R inhibitor (edicotinib) would be safe and well-tolerated for primary prostate cancer, with successful target modulation on immune populations within the TME.MethodsIn this single-center, open-label, presurgical study, patients were enrolled into Arm A (daratumumab, four weekly doses pre-surgery) or Arm B (edicotinib, orally daily for four weeks pre-surgery). Patients had high-risk localized or locally advanced prostate cancer (at least 1 core Gleason ≥8) appropriate for radical prostatectomy (RP), ≥3 biopsies involved with cancer, and no radiographic evidence of metastatic disease. Treated and untreated (Gleason-matched) fresh and formalin-fixed paraffin-embedded prostatectomy specimens and paired blood (PBMCs), bone marrow biopsies (BMBx) and aspirates (BMA) were evaluated for target modulation using IHC (prostate, BMBx) and flow cytometry (prostate, BMA, PBMCs). The primary endpoint was incidence of adverse events (AEs). The secondary endpoint was pathologic complete remission (pCR) rate.ResultsTwenty-five patients were treated (Arm A, n=15; Arm B, n=10) and completed four doses of daratumumab or four weeks of edicotinib prior to RP. The most common AEs were Arm A: daratumumab infusion reaction (33%, 5/15); Arm B: increased aspartate aminotransferase (40%, 4/10). Grade 3 related AEs in Arm A occurred in 3 patients (12%; infusion reaction, n=2; urticaria, n=1), with no Grade 4/5 related events. No ≥Grade 3 related AEs occurred in Arm B. All patients completed surgery, however no patients achieved pCR. IHC revealed lower density of CD38+ cells in daratumumab-treated vs. untreated prostate tumors and in patient-matched post-treatment vs. pre-treatment BMBx. Similarly, flow cytometry showed decreased frequency of CD38+ T cells and macrophages in daratumumab-treated vs. untreated prostate tumors and patient-matched post-treatment vs. pre-treatment PBMCs and BMAs. Edicotinib did not demonstrate an impact on CSF-1R+ immune cells in prostate, bone marrow, or PBMCs.ConclusionsDaratumumab and edicotinib were safe and well-tolerated as presurgical therapy for high-risk localized prostate cancer, with no pCRs. Evidence of target modulation was consistently observed in prostate tumors, bone marrow, and PBMCs for daratumumab, but not edicotinib. Myeloid-targeted agents such as daratumumab alone are insufficient to generate anti-tumor responses in prostate cancer.Trial RegistrationNCT03177460Ethics ApprovalThis study was approved by MD Anderson Cancer Center Institutional Review Board; protocol numbers 2017–0103 and PA13-0291.

Purpose/objective(s) Androgen deprivation therapy (ADT) and radiotherapy (RT) are synergistic, and the combination results in improved survival outcomes for aggressive prostate cancers. However, long-term ADT carries substantial burden of toxicity and morbidity. We hypothesized that a combination of definitive prostate RT and short-term complete androgen blockade (CAB) in men with unfavorable intermediate or favorable high-risk localized PC would provide excellent biochemical control and allow high rates of testosterone recovery. This combination would allow an escalation of therapy for unfavorable intermediate risk and de-escalation for favorable high-risk patients. We tested this hypothesis in a prospective trial of neoadjuvant/concurrent/adjuvant abiraterone acetate, prednisone, and LHRH agonist given for 6 months in conjunction with definitive prostate external beam RT. We now report the mature results of this trial. Materials/methods 37 men were enrolled in an IRB-approved NCT-registered prospective multi-center single arm investigator-initiated trial between January 2014 and August 2016. Eligibility required unfavorable intermediate risk of low volume high risk (NCCN) prostate cancer. All men were treated with 6 months of abiraterone acetate (1000mg daily), prednisone (5mg daily), and depot LHRH agonist initiated 8 weeks prior to standard fractionation RT to prostate/seminal vesicles +/- pelvis. Endpoints included PSA and testosterone (T) kinetics, biochemical progression-free survival (PFS), metastasis-free survival (MFS), overall survival (OS), and patient-reported quality-of-life. Results Enrolled patients were low volume (T1-2 disease and PSAs Conclusion For select men with aggressive prostate cancer, short course CAB with abiraterone acetate plus prednisone in combination with definitive prostate RT allows rapid T recovery and can provide excellent biochemical control up to 5 years. Short-course CAB is feasible for favorable high risk prostate cancer and may support optimization of patient quality of life. Prospective randomized trials should be considered.

Although myeloid growth factors are commonly used to treat metastatic castration-resistant prostate cancer (mCRPC), the optimal timing of administration has not been well studied. We assessed the effects of same-day pegfilgrastim, a neutrophil stimulator, after cabazitaxel treatment with or without carboplatin in patients with mCRPC. We also evaluated the frequency of urinary tract inflammation during treatment.Between September 2010 and September 2014, 151 consecutive patients with mCRPC underwent cabazitaxel treatment with or without the addition of carboplatin at a single institution. We assessed absolute neutrophil count recovery, incidence of neutropenia, neutropenic fever, antibiotic usage, treatment delays or discontinuation, dose reduction, and hospitalization with pegfilgrastim administration. Radiologists blinded to therapy reviewed computed tomography scans to detect urinary tract inflammation.The median patient age was 69 years (range, 41-88 years); 78% of patients were white, and 54% had a Gleason score ≥ 9. Median overall survival was 9 months (95% confidence interval, 8-11 months). One patient (1%) had neutropenia; 38 patients (25%) had infection. During cycle 1, a significantly higher proportion of patients receiving pegfilgrastim after 24 hours developed infection than did those receiving pegfilgrastim the same day (26% vs. 6%; P = .01).Same-day pegfilgrastim administration after cabazitaxel treatment with or without carboplatin in patients with mCRPC is feasible. The urinary tract inflammation rate (21%) was higher than that reported anecdotally. Results need to be prospectively validated.

Background Pazopanib is associated with increased progression-free survival (PFS) in clear-cell renal cell carcinoma (RCC) and has become a standard of care in this disease. The drug is used in metastatic non–clear-cell RCC, but data on outcomes in this setting are limited. Patients and Methods We conducted a retrospective data analysis of records of consecutive metastatic non–clear-cell RCC patients who received pazopanib in front-line and salvage settings between November 2009 and November 2012. Tumor response rate was assessed by a blinded radiologist using Response Evaluation Criteria in Solid Tumors version 1.1. PFS and overall survival (OS) times were estimated using Kaplan–Meier methods. Results Twenty-nine patients were identified with non–clear-cell metastatic RCC, 9 received pazopanib in the front-line setting, 20 in the salvage setting after progression of disease with other targeted therapies. Seven patients (24%) had papillary RCC, 4 (14%) had chromophobe, 5 (17%) had unclassified histopathology, and 13 (45%) had other subtypes including collecting duct, translocation Xp11.2, and various subtypes with sarcomatoid differentiation. All patients discontinued pazopanib before analysis. Median PFS was 8.1 months (95% CI, 5.7-NA [not available]) in the front-line group, and 4 months (95% CI, 2.1-9.9) in the salvage group. Median OS was 31 months (95% CI, 9.2-NA) in the front-line group, and 13.6 months (95% CI, 6.4-NA) in the salvage group. Conclusion Pazopanib showed efficacy in patients with metastatic non–clear-cell RCC in the front-line and salvage settings. Toxicity was mild to moderate and manageable. Further studies are needed to evaluate pazopanib's role in non–clear-cell RCC in terms of efficacy and safety.

Cell division cycle 6 (CDC6), an androgen receptor (AR) target gene, is implicated in regulating DNA replication and checkpoint mechanisms. CDC6 expression is increased during prostate cancer (PCa) progression and positively correlates with AR in PCa tissues. AR or CDC6 knockdown, together with AZD7762, a Chk1/2 inhibitor, results in decreased TopBP1-ATR-Chk1 signaling and markedly increased ataxia-telangiectasia-mutated (ATM) phosphorylation, a biomarker of DNA damage, and synergistically increases treatment efficacy. Combination treatment with the AR signaling inhibitor enzalutamide (ENZ) and the Chk1/2 inhibitor AZD7762 demonstrates synergy with regard to inhibition of AR-CDC6-ATR-Chk1 signaling, ATM phosphorylation induction, and apoptosis in VCaP (mutant p53) and LNCaP-C4-2b (wild-type p53) cells. CDC6 overexpression significantly reduced ENZ- and AZD7762-induced apoptosis. Additive or synergistic therapeutic activities are demonstrated in AR-positive animal xenograft models. These findings have important clinical implications, since they introduce a therapeutic strategy for AR-positive, metastatic, castration-resistant PCa, regardless of p53 status, through targeting AR-CDC6-ATR-Chk1 signaling.

Purpose: In this study, we addressed the underlying mechanisms for the association between enzalutamide (ENZ) treatment and neuroendocrine prostate cancer (NEPC), and the critical involvement of MYCN, and loss of RB1 function in neuroendocrine differentiation (NED) of prostatic epithelial cells, and the development of NEPC. We further sought to determine whether PARP inhibition could suppress NEPC, and to identify molecular determinants of this therapeutic activity. Experimental Design: We used a novel prostate cancer patient–derived xenograft (PDX) treatment model, prostatic adenocarcinoma and NEPC cell lines, an NEPC organoid line, and NEPC xenograft models to address the mechanistic basis of ENZ-induced NED, and to analyze suppression of NED and NEPC growth by PARP inhibition. Results: We identified an ENZ treatment–associated glucocorticoid receptor (GR)–MYCN–CDK5–RB1–E2F1 signaling pathway that drives NED in prostatic adenocarcinoma PDX and cell line models. Mechanistically, long-term ENZ treatment transcriptionally upregulates signaling of the GR–MYCN axis, leading to CDK5R1 and CDK5R2 upregulation, Rb1 phosphorylation, and N-Myc–mediated and E2F1-mediated NED gene expression. Importantly, olaparib (OLA) or talazoparib (TALA) suppressed these activities, and the combination of OLA and dinaciclib (DINA), an inhibitor of CDK2 and CDK5, which also inhibits Rb1 phosphorylation, suppressed NED and significantly improved therapeutic efficiency in NEPC cells in vitro and in NEPC tumors in vivo. Conclusions: The results of our study indicate an important role of GR–MYCN–CDK5R1/2–RB1–NED signaling in ENZ-induced and PARP inhibitor–suppressed NEPC. We also demonstrated efficacy for OLA+DINA combination therapy in NEPC xenograft models.

4543 Background: The prognosis in patients with metastatic SCUC (mSCUC) remains poor with median survival around 1 year with systemic chemotherapy. We aimed to investigate the impact of ICI on survival of patients with mSCUC. Methods: Patients who received systemic therapy at MD Anderson Cancer Center (MDACC) for de novo or metachronous mSCUC after completing local management. within 12 months of neoadjuvant or adjuvant chemotherapy were included in this cohort, with overall survival (OS) calculated from the time of receipt of initial chemotherapy. Hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated using logrank test. Results: 102 patients with mSCUC received systemic therapy at MDACC between April 2006 and June 2020. Median age was 66 (range 24 – 86 years), male to female ratio was 5. Bladder was the primary site in 85 (83%), 45 (44%) had prior cystectomy and 9 (9%) had prior nephroureterectomy. Histologies included 51 (50%) with predominant small cell (SC) features, 28 (27%) with focal SC features, 20 (20%) with pure SC, and 3 (3%) mixed with large cell component. Thirty-nine (38%) received ICI during their disease course: 29 (28%) following front-line chemotherapy (15 of whom within 12 months of neoadjuvant/adjuvant platinum therapy), 5 (5%) combined with front-line chemotherapy, and 5 (5%) received ICI front-line (two of whom were able to receive second-line chemotherapy). ICI agents used included anti-PD-1 (n=19), anti-PD-L1 (n=12), anti-PD-1/anti-CTLA-4 (n=5), anti-PD-1/anti-TIM3 (n=1), anti-PD-1/anti-STAT3 (n=1), anti-PD-L1/PARPi (n=1). Those who received ICI at any time had an improved median OS compared to those treated with chemotherapy alone (20.1 vs 12 months), [HR=0.45, 95% CI 0.27-0.72, p=0.003]. When we limited the analysis to those with de novo mSCUC (n=36), those who received ICI at any time (n=13) had an improved median OS compared to those treated with chemotherapy alone (n=23) (not reached vs 9.41 months), [HR=0.28, 95% CI 0.12-0.68, p=0.03]. Among patients who received ICI (n=39), median OS in those with liver metastases (n=11) was numerically shorter than those without (n=28) (13.1 vs 21.6 months), [HR=1.83, 0.59-5.7, p=0.21]. Conclusions: ICI improves OS for patients with mSCUC. Although clinical trials remain difficult in these rare variants, further prospective studies are indicated to confirm this finding.

Liquid biopsies hold potential as minimally invasive sources of tumor biomarkers for diagnosis, prognosis, therapy prediction or disease monitoring. We present an approach for parallel single-object identification of circulating tumor cells (CTCs) and tumor-derived large extracellular vesicles (LEVs) based on automated high-resolution immunofluorescence followed by downstream multiplexed protein profiling. Identification of LEVs &gt, 6 µm in size and CTC enumeration was highly correlated, with LEVs being 1.9 times as frequent as CTCs, and additional LEVs were identified in 73% of CTC-negative liquid biopsy samples from metastatic castrate resistant prostate cancer. Imaging mass cytometry (IMC) revealed that 49% of cytokeratin (CK)-positive LEVs and CTCs were EpCAM-negative, while frequently carrying prostate cancer tumor markers including AR, PSA, and PSMA. HSPD1 was shown to be a specific biomarker for tumor derived circulating cells and LEVs. CTCs and LEVs could be discriminated based on size, morphology, DNA load and protein score but not by protein signatures. Protein profiles were overall heterogeneous, and clusters could be identified across object classes. Parallel analysis of CTCs and LEVs confers increased sensitivity for liquid biopsies and expanded specificity with downstream characterization. Combined, it raises the possibility of a more comprehensive assessment of the disease state for precise diagnosis and monitoring.

TPS365 Background: Sitra is a spectrum-selective receptor tyrosine kinase inhibitor (TKI) that targets TAM receptors (TYRO3, AXL, MERTK), VEGFR2, c-Kit, and c-MET. Sitra has shown antitumor activity in accRCC, and reduces type 2 tumor-associated macrophages, regulatory T-cells and myeloid-derived suppressor cells and enhances T cell–mediated antitumor immune responses. The combination of sitra with anti-PD1 immune checkpoint inhibitors (ICIs), such as nivo, has an acceptable safety profile and demonstrates efficacy across multiple tumor types, including accRCC (Msaouel et al. J Clin Oncol, 2020, abstr 612). Ipi enhances the efficacy of nivo through distinct but complementary pathways to those targeted by sitra. We hypothesize that the triple combination of sitra + nivo + ipi will lead to more potent antitumor responses. This study is designed to determine the optimal dose of sitra when combined with nivo + ipi, and assess the safety as well as the preliminary efficacy of this combination in accRCC, and potentially other cancers, that have shown favorable responses to nivo + ipi. Methods: This phase I/Ib study (NCT04518046) is evaluating sitra + nivo + ipi in frontline advanced or metastatic ccRCC or other solid malignancies. The primary endpoint of the trial is safety and tolerability of this regimen. Secondary endpoints include: objective response rate (RECIST 1.1), duration of response, progression-free survival, overall survival, and pharmacokinetic measurements. The phase I dose escalation portion of the trial will enroll approximately 30 pts with intermediate- or poor-risk accRCC by International Metastatic RCC Database Consortium (IMDC) criteria, who will receive escalating doses of sitra (starting dose 35 mg orally QD) following the Time-to-Event Bayesian Optimal Interval (TITE-BOIN) design (Yuan et al. Clin Cancer Res, 2018), combined with nivo 3 mg/kg and ipi 1 mg/kg (NIVO3/IPI1) every 3 weeks (wks) for up to 4 doses, followed by maintenance nivo (240 mg every 2 wks or 480 mg every 4 wks). The phase Ib dose expansion cohorts will be initiated following identification of the recommended dose of sitra in combination with NIVO3/IPI1 and will enroll up to 31 pts for each of 2 cohorts: pts with intermediate-/poor-risk accRCC (Cohort A) and pts with favorable-risk accRCC (Cohort B). Pts will receive study treatment until disease progression, unacceptable adverse events, or pt withdrawal of consent. Future dose expansion cohorts may be added to include other solid tumors in which favorable activity has been previously demonstrated with nivo + ipi, such as metastatic urothelial carcinoma, melanoma, non–small-cell lung cancer, hepatocellular carcinoma, and colorectal cancer. The study is currently enrolling at 1 US site and additional sites may be added at dose expansion. At the time of the abstract submission, 3 pts have been enrolled. Clinical trial information: NCT04518046 .

83 Background: Most prostate cancers are driven by the androgen receptor (AR) and have significant responses to AR inhibition. However, approximately 20-30% respond poorly to AR signaling inhibitors and have an atypical and virulent clinical course. Previous studies have shown that early declines in PSA and CTC on treatment are linked with “AR-responsiveness” in metastatic castration resistant prostate cancer (mCRPC). Few non-androgen directed therapies are approved for AR-unresponsive patients though combination cabazitaxel and carboplatin showed efficacy in this patient population in a phase I/II trial (Corn et al. Lancet Oncol, 2019). We hypothesized that early addition of chemotherapy in AR-unresponsive patients would improve outcomes. Methods: In a modular phase II trial (NCT02703623), men with mCRPC treated with abiraterone acetate plus prednisone and apalutamide were classified at week 8 as having a ‘satisfactory’ decline in PSA (≥ 50% from baseline) and CTC (≤5/7.5mL) or ‘unsatisfactory’. Patients with ‘unsatisfactory’ declines had carboplatin and cabazitaxel added to the AR inhibitors. Primary objectives included the estimation of the overall survival (OS) of patients in this cohort. Results: 198 men were registered. 59 (31.5%) of 187 evaluable had ‘unsatisfactory’ marker declines. Patients were primarily white/non-Hispanic men (81%) over the age of 60 (78%) with ECOG score of 0 (75%). Median baseline PSA and CTC were 11.3 ng/mL and 9.0 cells/mL respectively. Median follow-up was 31.7 months with median OS 19.2 months (95% CI 14.8-27.8). Median TTF was 9.0 months (6.9-11.0). Related adverse events included decreased WBC (39%; 15% G3+), anemia (56%; 7% G3+), and lymphopenia (59%; 8% G3+). There was one grade 5 sepsis of unknown attribution. Conclusions: Although early platinum-based chemotherapy offers a durable response in a subset of AR unresponsive patients, there were patients that continued to have rapid progression. We will present additional clinical and molecular data (IHC, RNA-seq, WES) in an attempt to further differentiate AR responders from AR non-responders. Clinical trial information: NCT02703623.

72 Background: Improved understanding of how host factors influence the efficacy and toxicity of ASI could improve outcomes. Adiposity increases the risk for recurrence and lethal disease in men with localized prostate cancer. Few studies have evaluated the influence of adiposity in metastatic prostate cancer, and in these studies, adiposity was associated with improved outcomes, a potential “obesity paradox”. Herein, we assess whether adiposity is associated with response to maximal ASI in mCRPC and assess how individual body composition measurements interact to influence outcomes. Methods: Men with mCRPC uniformly treated on a prospective clinical trial with abiraterone acetate plus apalutamide were included in this post-hoc analysis (NCT02703623). Responders were defined as those with a decrease in PSA of > 50% after 8 weeks of therapy. Body composition was assessed at the level of L3 on baseline CT scan at trial registration using Slice-O-Matic version 5.0. Body composition indices were normalized for height (m2). Non-parametric Kruskal-Wallis test was used to evaluate associations between continuous baseline measures. A multivariable CART model was used to determine if baseline measures could divide patients into distinct risk groups. Results: In 186 men with mCRPC, responders to maximal ASI (n = 128) had higher subcutaneous adiposity (SATi, 79.3 vs. 67.6, p = 0.02), visceral adiposity (VATi, 76.4 vs. 61.5, p = 0.03), and body mass index (BMI, 30.3 vs. 29.2, p = 0.04). There was a strong correlation between BMI and SAT (r = 0.81). In exploratory multivariable modeling, BMI and VATi had the strongest associations with response to ASI. Specifically, men with a BMI ≥ 26.73 had a higher response rate (75% vs. 46%). For men with a BMI < 26.73, a VATi ≥ 24.7 enriched for response to therapy (86% vs. 26%). Conclusions: Elevated subcutaneous and visceral adiposity is associated with improved response to maximal ASI in men with mCRPC. In hypothesis-generating models, visceral adiposity had the strongest association with response to ASI in men with lower BMI. Further studies need to assess how and when adiposity becomes favorable for outcomes in advanced prostate cancer.

Background Resistance to novel androgen signaling inhibition and metastatic castration-resistant prostate cancer (mCRPC) progression is likely dependent on tumor microenvironment interactions. The Src pathway and neoangiogenesis have been implicated in prostate cancer progression. We studied the effect of adding the targeted agents dasatinib and sunitinib to abiraterone acetate (AA) in men with mCRPC. Patients and Methods In this open-label randomized phase 2 study, mCRPC patients received AA. At resistance to AA, they were randomized 1:1 to combination with dasatinib or sunitinib. At second progression, patients crossed over. The primary end point was time to treatment failure (TTF), defined as time to progression or death. Secondary end points included overall survival and safety. Results From March 2011 to February 2015, a total of 179 patients were enrolled and 132 subsequently randomized. Median TTF was 5.7 months in the dasatinib group and 5.5 months in the sunitinib group. There was no difference between the two groups in terms of TTF (hazard ratio, 0.85; 95% confidence interval, 0.59-1.22). Median overall survival from study entry was 26.3 months in the dasatinib group and 27.7 months in the sunitinib group (hazard ratio, 1.02; 95% confidence interval, 0.71-1.47). Grade 3 or higher adverse events related to study medication were more frequent with sunitinib (n = 44, 46%) compared to dasatinib (n = 26, 24%). At data cutoff, 7 patients were experiencing a continuous response to AA, with a median duration of treatment of 5.7 years. Conclusion There is no difference in overall survival and TTF between dasatinib and sunitinib combined with abiraterone in the treatment of patients with bone mCRPC.

Caveolin-1 (Cav-1) is overexpressed in aggressive and metastatic prostate cancer (PCa) and induces PCa cell proliferation. Androgens mediate lipid synthesis through acetyl-CoA carboxylase-1 (ACC1) and fatty acid synthase (FASN). We investigated the Cav-1-mediated lipid synthesis in the development of castration resistance, and identified novel therapeutic opportunities. Using the PBCre+;Ptenloxp/loxp;PBCav-1+ mouse model we found that Cav-1 induction increased cancer incidence and growth, and ACC1-FASN expression in intact and castrated mice. We demonstrated that Cav-1 regulated ACC1 and FASN expression in an AR-independent way and increased palmitate synthesis using western blot analysis, qRT-PCR and mass spectrometry in vitro. By using FASN siRNA and C-75, we found that FASN inhibition was more effective in Cav-1-overexpressing cells. This inhibition was abrogated by ACC1si RNA, revealing the role of malonyl-CoA, an ACC1 product, as a mediator of cytotoxicity. Cav-1 was associated with ACC1 in human tumors and ACC1, FASN, and Cav-1 expression were increased in metastatic PCa compared to primary tumors and normal prostate epithelium. Palmitoleate and oleate levels were higher in BMA from patients with metastatic PCa who responded poorly to abiraterone acetate. Our findings suggest that Cav-1 promotes hormone resistance through the upregulation of ACC1-FASN and lipid synthesis under androgen deprivation, suggesting that FASN inhibition could be used to treat PCa that demonstrates Cav-1 overexpression.

White adipose tissue (WAT) overgrowth in obesity is linked with increased aggressiveness of certain cancers. Adipose stromal cells (ASCs) can become mobilized from WAT, recruited by tumours and promote cancer progression. Mechanisms underlying ASC trafficking are unclear. Here we demonstrate that chemokines CXCL1 and CXCL8 chemoattract ASC by signalling through their receptors, CXCR1 and CXCR2, in cell culture models. We further show that obese patients with prostate cancer have increased epithelial CXCL1 expression. Concomitantly, we observe that cells with ASC phenotype are mobilized and infiltrate tumours in obese patients. Using mouse models, we show that the CXCL1 chemokine gradient is required for the obesity-dependent tumour ASC recruitment, vascularization and tumour growth promotion. We demonstrate that αSMA expression in ASCs is induced by chemokine signalling and mediates the stimulatory effects of ASCs on endothelial cells. Our data suggest that ASC recruitment to tumours, driven by CXCL1 and CXCL8, promotes prostate cancer progression., Adipose stromal cells (ASC) have been shown to migrate to tumours and promote tumour growth. Using animal models and human tissue samples, the authors show here that ASC recruitment to prostate cancers is mediated by the chemokine CXCL1, which is secreted from tumour cells, and acts on CXCR1 on ASCs.

Background Gene expression profiling (GEP) suggests there are three subtypes of muscle-invasive urothelial cancer (UC): basal, which has the worst prognosis; p53-like; and luminal. We hypothesized that GEP of transurethral resection (TUR) and cystectomy specimens would predict subtypes that could benefit from chemotherapy. Objective To explore clinical outcomes for patients treated with dose-dense (DD) methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) and bevacizumab (B) and the impact of UC subtype. Design, setting, and participants Sixty patients enrolled in a neoadjuvant trial of four cycles of DDMVAC + B between 2007 and 2010. TUR and cystectomy specimens for GEP were available from 38 and 23 patients, respectively, and from an additional confirmation cohort of 49 patients treated with perioperative MVAC. Outcome measurements and statistical analysis Relationships with outcomes were analyzed using multivariable Cox regression and log-rank tests. Results and limitations Chemotherapy was active, with pT0N0 and ≤pT1N0 downstaging rates of 38% and 53%, respectively, and 5-yr overall survival (OS) of 63%. Bevacizumab had no appreciable impact on outcomes. Basal tumors had improved survival compared to luminal and p53-like tumors (5-yr OS 91%, 73%, and 36%, log-rank p =0.015), with similar findings on multivariate analysis. Bone metastases within 2 yr were exclusively associated with the p53-like subtype (p53-like 100%, luminal 0%, basal 0%; p ≤ 0.001). Tumors enriched with the p53-like subtype at cystectomy suggested chemoresistance for this subtype. A separate cohort treated with perioperative MVAC confirmed the UC subtype survival benefit (5-yr OS 77% for basal, 56% for luminal, and 56% for p53-like; p =0.021). Limitations include the small number of pretreatment specimens with sufficient tissue for GEP. Conclusion GEP was predictive of clinical UC outcomes. The basal subtype was associated with better survival, and the p53-like subtype was associated with bone metastases and chemoresistant disease. Patient summary We can no longer think of urothelial cancer as a single disease. Gene expression profiling identifies subtypes of urothelial cancer that differ in their natural history and sensitivity to chemotherapy.

Purpose Evolving treatments, disease phenotypes, and biology, together with a changing drug development environment, have created the need to revise castration-resistant prostate cancer (CRPC) clinical trial recommendations to succeed those from prior Prostate Cancer Clinical Trials Working Groups. Methods An international expert committee of prostate cancer clinical investigators (the Prostate Cancer Clinical Trials Working Group 3 [PCWG3]) was reconvened and expanded and met in 2012-2015 to formulate updated criteria on the basis of emerging trial data and validation studies of the Prostate Cancer Clinical Trials Working Group 2 recommendations. Results PCWG3 recommends that baseline patient assessment include tumor histology, detailed records of prior systemic treatments and responses, and a detailed reporting of disease subtypes based on an anatomic pattern of metastatic spread. New recommendations for trial outcome measures include the time to event end point of symptomatic skeletal events, as well as time to first metastasis and time to progression for trials in the nonmetastatic CRPC state. PCWG3 introduces the concept of no longer clinically benefiting to underscore the distinction between first evidence of progression and the clinical need to terminate or change treatment, and the importance of documenting progression in existing lesions as distinct from the development of new lesions. Serial biologic profiling using tumor samples from biopsies, blood-based diagnostics, and/or imaging is also recommended to gain insight into mechanisms of resistance and to identify predictive biomarkers of sensitivity for use in prospective trials. Conclusion PCWG3 moves drug development closer to unmet needs in clinical practice by focusing on disease manifestations most likely to affect prognosis adversely for therapeutics tested in both nonmetastatic and metastatic CRPC populations. Consultation with regulatory authorities is recommended if a trial is intended to seek support for drug approval.

Purpose: Morphologically heterogeneous prostate cancers that behave clinically like small-cell prostate cancers (SCPC) share their chemotherapy responsiveness. We asked whether these clinically defined, morphologically diverse, “aggressive variant prostate cancer (AVPC)” also share molecular features with SCPC. Experimental Design: Fifty-nine prostate cancer samples from 40 clinical trial participants meeting AVPC criteria, and 8 patient-tumor derived xenografts (PDX) from 6 of them, were stained for markers aberrantly expressed in SCPC. DNA from 36 and 8 PDX was analyzed by Oncoscan for copy number gains (CNG) and losses (CNL). We used the AVPC PDX to expand observations and referenced publicly available datasets to arrive at a candidate molecular signature for the AVPC. Results: Irrespective of morphology, Ki67 and Tp53 stained ≥10% cells in 80% and 41% of samples, respectively. RB1 stained Conclusions: Clinically defined AVPC share molecular features with SCPC and are characterized by combined alterations in RB1, Tp53, and/or PTEN. Clin Cancer Res; 22(6); 1520–30. ©2015 AACR.

Background: Advanced androgen signaling inhibition, a prevailing therapy approach in advanced prostate cancer, incurs variable response Therapy selection guided by predictors is an unmet need Methods: We reviewed MDACC GU department and Hellenic Sister Institute records for Abiraterone Acetate (AA) treated mCRPC patients (pts) with extraordinary response (absence of radiographic/clinical progression for ≥3 years) We compared to reported findings for COU-AA-302 and real world experience to identify candidate predictors of outcome We applied a previously proposed COU-AA-302 response prognostic model Archived diagnostic and subsequent tumor specimens were retrieved for molecular characterization Results: Forty four of 430 reviewed mCRPC pts had extraordinary response Table depicts features Median time to AA discontinuation was 5 8 yr (range 3-12 5+) and 20 pts are on treatment Safety profile is acceptable with no overt increase in fractures or cardiovascular, metabolic morbidity All pts experienced >50% PSA decline with nadir ≤0 1 in 80%, occurring within 5mo (median) (range

e17090 Background: Two immunotherapy (IO) and tyrosine kinase inhibitor (TKI) combinations are FDA-approved for patients (pts) with metastatic renal cell carcinoma (mRCC). Here we present a multicenter off-protocol experience with IO/TKI combinations after progression on monotherapy. Methods: We performed a retrospective analysis of pts with mRCC who received combination non-FDA approved off-protocol IO/TKI combination therapy from 11/2015 – 1/2019 at MD Anderson Cancer Center and Duke Cancer Institute. Results: 48 pts met criteria for study inclusion. At therapy start: median (med) age 65 years; 75% clear cell histology; 68.8% IMDC intermediate risk (20.8% favorable, 10.4% poor); 81.3% prior nephrectomy; med metastatic sites: 2; med prior systemic treatments: 2; most common metastatic sites: lung (58.3%), lymph node (52.1%), and bone (43.8%). Pts received nivolumab (nivo) in combination with the following: cabozantinib (n = 24, 50%), pazopanib (13, 27.1%), axitinib (6, 12.5%), lenvatinib (2, 4.2%), ipilimumab/cabozantinib (3, 6.3%). Med PFS was 13.7 months and med OS was not reached. The two largest cohorts received nivo + cabozantinib (N+C; med dose 40 mg daily) or nivo + pazopanib (N+P; med dose 400 mg daily). The N+C cohort had higher med metastatic sites (3 vs 2) and was more pretreated with agents unique to their IO/TKI combination (med 2 vs 0). In the N+P group, more pts had started on TKI prior to addition of nivo at progression (69.2% vs 45.8%), and fewer had IO monotherapy with TKI addition (30.8% vs 50%). With a med follow up of 14.0 months after combination start, the N+C cohort had a med PFS of 7.3 months (initiated TKI first: 4.8, IO first: 8.2) and med OS of 18.2 months (TKI first: 11.8, IO first: 24.3). The N+P cohort had med follow up of 20.5 months after combination, med PFS of 21.3 months (TKI first: 16.5, IO first: 21.8), and med OS was not reached. In the N+C group, 87.5% experienced any grade adverse event (AE), most common included fatigue (79.2%), diarrhea (42.7%), nausea (29.2%), hypertension (29.2%), and weight loss (25.0%). In the N+P group, 92.3% experienced any grade AE, including fatigue (76.9%), hypertension (38.5%), diarrhea (30.8%), nausea (30.8%), and weight loss (30.8%). There were no grade ≥3 AEs. Conclusions: Slow disease progression on nivo or TKI may be safely controlled with addition of IO/TKI therapy. Med PFS after addition of nivo to TKI appears similar (N+C) and improved (N+P) compared to nivo monotherapy (Checkmate-025). Med PFS after addition of TKI to IO was also similar (N+C) and improved (N+P) compared to historical controls.

5504 Background: Novel androgen signaling inhibitors (ASI) with medical castration may improve outcomes in LHRPC. We previously reported relapse free survival association with pathologic measures of tumor regression. However a wide range of persistent cancers was recorded. To build on our findings and test candidate predictors of outcome, we conducted a study examining APA effect in LHRPC. Methods: This is a phase II neoadjuvant study of 6 months APA+LHRHa +/- AA (randomized 1:1) in LHRPC (≥ cT2 + Gleason Score ≥ 8 or ≥ cT2b + Gleason ≥ 7 + PSA > 10 ng/mL) followed by radical prostatectomy (RP). We studied treatment effect by pathology measures [path. stage, tumor volume (TV), tumor cellularity % (TC), tumor epithelial volume (TEV: TC x TV)]. Tumor expression of candidate markers of outcome was assessed in the diagnostic biopsy by IHC [AR signaling (AR-N, ARC19, ARV7, PSA), PTEN, glucocorticoid receptor (GR), Ki67, p53, RB] and DNA/RNA seq. A previously identified candidate predictive molecular signature (AR-N overexpression, nARV7 absence, no GR overexpression, Ki67 ≤10%) was tested. Univariate (Fisher’s exact, Wilcoxon) and multivariate (logistic, linear models) analyses employed. Results: Sixty three -of 65 pts enrolled- had RP. PS-ECOG 0, median age 65 (43-77). Treatment was well tolerated with Grade 3 hypertension in 7 (2 APA + LHRHa). Presurgical PSA was ≤0.1 in 62/63 (98%). Organ confined disease (≤ypT2N0) found in 13/32(41%) APA+LHRHa vs. 12/31 (39%) APA+AA+LHRHa treated. 2 (3%) had pathologic complete remission (APA+AA+LHRHa), 6 (10%) minimal residual disease (5 on APA +LHRHa). Despite uniformity in PSA response, we recorded heterogeneity in measures of tumor viability: TV (0-11.5cc), TC (1-80%), TEV (0-6.1cc). ≤ypT2N0 associates with diagnostic biopsy positivity for the prespecified molecular signature (p

156 Background: AVPC are morphologically heterogeneous tumors that share clinical features with the rare, virulent, androgen-indifferent and platinum-sensitive, small cell histologic variant. The AVPC-ms is composed of ≥2 defects in TP53, RB1 and PTEN, is detectable in »30% of advanced prostate cancers and predicts for benefit from platinum combinations (Corn et al. Lancet Oncol, 2019). Preclinical studies link the AVPC-ms with androgen indifference, but a prospective clinical association with decreased sensitivity to androgen signaling inhibitors is lacking. Methods: In a phase II trial (NCT02703623), men with metastatic castration resistant prostate cancer (mCRPC) treated with abiraterone and apalutamide were classified at week 8 as having a ‘satisfactory’ decline in PSA (≥ 50% from baseline) and CTC (≤5/7.5mL) or ‘unsatisfactory’. Pretreatment biopsies were obtained for immunohistochemistry (IHC) for TP53, RB1 and PTEN and RNA sequencing. Results: 198 men were registered. 59 (31.5%) of 187 evaluable had ‘unsatisfactory’ marker declines. Age, race/ethnicity, and baseline ECOG, PSA and LDH were similar between the groups. Men in the ‘unsatisfactory’ group had higher median total alkaline phosphatase (120 vs. 86; p=0.002), bone-specific alkaline phosphatase (21 vs. 16; p=0.01), CTC (9 vs. 1; p

612 Background: Sitra is a receptor tyrosine kinase (RTK) inhibitor targeting TAM receptors (Tyro3, Axl, MerTK), split family receptors (VEGFR2 and c-Kit) and c-Met. Inhibition of these RTKs has direct biological activity against aCCRCC and can also enhance immunotherapy with nivo by reducing immunosuppressive regulatory T-cells, myeloid derived suppressor cells, and type 2 tumor-associated macrophages. We therefore hypothesized that the addition of sitra to nivo will produce higher clinical activity than nivo alone. Methods: The objective of this phase I/II trial is to evaluate the safety and efficacy of sitra + nivo in pts with aCCRCC that progressed on up to two prior VEGF-targeted therapies. Eligibility criteria were similar to those used for CheckMate 025. The late-onset Bayesian EffTox design is used to account for potential late-onset immune-related toxicities, and allow optimal dose-finding of sitra from four dose levels (60, 80, 120, 150 mg/day) continuously based on both efficacy and toxicity. Additional objectives include estimation of survival times and correlative biomarkers. Results: A total of 38 pts have enrolled as of 22 October 2019 with 34 pts evaluable for response at ≥12 weeks. Tumor reductions have been noted in 28/34 pts (82.3%) with objective responses demonstrated in 13/34 pts (ORR = 38.2%), median progression-free survival of 10.5 months (95% CI 7.6 – 13.5), and 23/34 pts (67.6%) achieving disease control ≥ 6 months. Toxicities requiring dose-reduction of sitra within 12 weeks from treatment initiation have been noted in 14/34 pts (41.2%). The most common treatment-related adverse events include fatigue, diarrhea, palmar-plantar erythrodysesthesia, hypertension, and elevated lipase. There was one nivo-related Grade 5 event (myasthenia gravis). Updated dose-finding, safety and efficacy data will be presented. Conclusions: The combination of sitra + nivo has not demonstrated unexpected safety signals and produces higher objective responses and longer disease control compared with what is historically expected with nivo alone in pts with aCCRCC that progressed on prior VEGF-targeted therapy. Clinical trial information: NCT03015740.

Author(s): Armstrong, AJ; Antonarakis, ES; Taplin, M-E; Kelly, WK; Beltran, H; Fizazi, K; Dahut, WL; Shore, N; Slovin, S; George, D; Carducci, MA; Corn, P; Danila, D; Dreicer, R; Heath, E; Rathkopf, D; Liu, G; Nanus, D; Stein, M; Smith, MR; Sternberg, C; Wilding, G; Nelson, PS; Halabi, S; Kantoff, P; Clarke, NW; Evans, CP; Heidenreich, A; Mottet, N; Gleave, M; Morris, MJ; Scher, HI

Resistance to currently available targeted therapies significantly hampers the survival of patients with prostate cancer with bone metastasis. Here we demonstrate an important resistance mechanism initiated from tumor-induced bone. Studies using an osteogenic patient-derived xenograft, MDA-PCa-118b, revealed that tumor cells resistant to cabozantinib, a Met and VEGFR-2 inhibitor, reside in a “resistance niche” adjacent to prostate cancer-induced bone. We performed secretome analysis of the conditioned medium from tumor-induced bone to identify proteins (termed “osteocrines”) found within this resistance niche. In accordance with previous reports demonstrating that activation of integrin signaling pathways confers therapeutic resistance, 27 of the 90 osteocrines identified were integrin ligands. We found that following cabozantinib treatment, only tumor cells positioned adjacent to the newly formed woven bone remained viable and expressed high levels of pFAK-Y397 and pTalin-S425, mediators of integrin signaling. Accordingly, treatment of C4-2B4 cells with integrin ligands resulted in increased pFAK-Y397 expression and cell survival, whereas targeting integrins with FAK inhibitors PF-562271 or defactinib inhibited FAK phosphorylation and reduced the survival of PC3-mm2 cells. Moreover, treatment of MDA-PCa-118b tumors with PF-562271 led to decreased tumor growth, irrespective of initial tumor size. Finally, we show that upon treatment cessation, the combination of PF-562271 and cabozantinib delayed tumor recurrence in contrast to cabozantinib treatment alone. Our studies suggest that identifying paracrine de novo resistance mechanisms may significantly contribute to the generation of a broader set of potent therapeutic tools that act combinatorially to inhibit metastatic prostate cancer. Cancer Res; 75(22); 4949–59. ©2015 AACR.

Background The purpose of this study was to determine the prevalence of MET amplification and mutation among GU malignancies and its association with clinical factors and responses to c-MET inhibitors. Patients and Methods Patients with GU malignancies referred to our Phase I Clinical Trials Program were evaluated for MET mutation and amplification and outcomes using protocols with c-MET inhibitors. Results MET amplification was found in 7 of 97 (7.2%) patients (4/27 renal [all clear cell], 1/18 urothelial, and 2/12 adrenocortical carcinoma), with MET mutation/variant in 3 of 54 (5.6%) (2/20 renal cell carcinoma [RCC] [1 clear cell and 1 papillary] and 1/16 prostate cancer). No demographic characteristics were associated with specific MET abnormalities, but patients who tested positive for mutation or amplification had more metastatic sites (median, 4 vs. 3 for wild type MET ). Median overall survival after phase I consultation was 6.1 and 11.5 months for patients with and without a MET alteration, respectively (hazard ratio, 2.8; 95% confidence interval, 1.1 to 6.9; P = .034). Twenty-nine (25%) patients were treated according to a c-MET inhibitor protocol. Six (21%) had a partial response (prostate and RCC) and 10 (34%) had stable disease as best response. Median time to tumor progression was 2.3 months (range, 0.4-19.7) for all treated patients with no responses in patients with a MET abnormality or single-agent c-MET inhibitor treatment. Conclusion MET genetic abnormalities occur in diverse GU malignancies and are associated with a worse prognosis in a phase I setting. Efficacy of c-MET inhibitors was more pronounced in patients without MET abnormalities and when combined with other targets/drugs.

Context Multiple single-agent therapies improving survival are approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC), including two chemotherapies, two androgen-signaling axis-targeting agents, an immunotherapeutic vaccine, and a radiopharmaceutical. Combination therapy can target multiple oncogenic pathways simultaneously, while potentially curbing the development of treatment resistance. Objective To provide a succinct overview of taxane-based combination therapies currently being evaluated for the treatment of metastatic prostate cancer. Evidence acquisition We searched MEDLINE/PubMed ® and relevant congress databases for literature focused on taxane-based combination therapies being evaluated for the treatment of metastatic prostate cancer. In addition, a systematic search of www.clinicaltrials.gov was performed to gather information regarding ongoing taxane-based combination trials in prostate cancer. This search included phase II or III trials starting after January 1, 2010, which included the terms "docetaxel" or "cabazitaxel" and "prostate", and was then manually filtered for combination studies. Evidence synthesis Single-agent therapy yields modest increments in survival. The success of combining docetaxel with androgen deprivation to improve overall survival (OS) for metastatic hormone-sensitive disease suggests the potential of similar approaches in mCRPC. Several classes of biological drugs have previously been combined with docetaxel for mCRPC in clinical trials without improvement in OS. However, combining docetaxel or cabazitaxel with newer agents with established single-agent benefit, such as radium-223, second-generation androgen pathway-targeted agents, or other chemotherapies, has the potential to benefit patients when compared with taxane chemotherapy alone. Our search revealed that the majority of trials currently assessing taxanes are focused on combination therapies: a combination approach is being evaluated in 37 of 47 trials assessing docetaxel and in 18 of 34 trials assessing cabazitaxel. Conclusions Despite prior failures, novel taxane-based combination therapies have the potential to improve outcomes in mCRPC. Challenges include the absence of validated predictive biomarkers for the selection of suitable patients and the potential for enhanced toxicity. Patient summary Patients with metastatic prostate cancer have access to multiple therapies improving survival. Many advanced epithelial cancers are treated with combinations of drugs; however, prostate cancer has remained an exception. A number of clinical studies have shown that combining chemotherapy with other classes of therapy may improve patient outcomes in prostate cancer. Here, we summarize the various combinations that are tested in the clinic and review the results.

Purpose: We investigated MYCN-regulated molecular pathways in castration-resistant prostate cancer (CRPC) classified by morphologic criteria as adenocarcinoma or neuroendocrine to extend the molecular phenotype, establish driver pathways, and identify novel approaches to combination therapy for neuroendocrine prostate cancer (NEPC). Experimental Design and Results: Using comparative bioinformatics analyses of CRPC-Adeno and CRPC-Neuro RNA sequence data from public data sets and a panel of 28 PDX models, we identified a MYCN–PARP–DNA damage response (DDR) pathway that is enriched in CRPC with neuroendocrine differentiation (NED) and CRPC-Neuro. ChIP-PCR assay revealed that N-MYC transcriptionally activates PARP1, PARP2, BRCA1, RMI2, and TOPBP1 through binding to the promoters of these genes. MYCN or PARP1 gene knockdown significantly reduced the expression of MYCN–PARP–DDR pathway genes and NED markers, and inhibition with MYCNsi and/or PARPsi, BRCA1si, or RMI2si significantly suppressed malignant activities, including cell viability, colony formation, and cell migration, in C4-2b4 and NCI-H660 cells. Targeting this pathway with AURKA inhibitor PHA739358 and PARP inhibitor olaparib generated therapeutic effects similar to those of gene knockdown in vitro and significantly suppressed tumor growth in both C4-2b4 and MDACC PDX144-13C subcutaneous models in vivo. Conclusions: Our results identify a novel MYCN–PARP–DDR pathway that is driven by N-MYC in a subset of CRPC-Adeno and in NEPC. Targeting this pathway using in vitro and in vivo CRPC-Adeno and CRPC-Neuro models demonstrated a novel therapeutic strategy for NEPC. Further investigation of N-MYC–regulated DDR gene targets and the biological and clinical significance of MYCN–PARP–DDR signaling will more fully elucidate the importance of the MYCN–PARP–DDR signaling pathway in the development and maintenance of NEPC. Clin Cancer Res; 24(3); 696–707. ©2017 AACR.

Maintenance of genomic stability is a critical determinant of cell survival and is necessary for growth and progression of malignant cells. Interstrand crosslinking (ICL) agents, including platinum-based agents, are first-line chemotherapy treatment for many solid human cancers. In malignant cells, ICL triggers the DNA damage response (DDR). When the damage burden is high and lesions cannot be repaired, malignant cells are unable to divide and ultimately undergo cell death either through mitotic catastrophe or apoptosis. The activities of ICL agents, in particular platinum-based therapies, establish a "molecular landscape," i.e., a pattern of DNA damage that can potentially be further exploited therapeutically with DDR-targeting agents. If the molecular landscape created by platinum-based agents could be better defined at the molecular level, a systematic, mechanistic rationale(s) could be developed for the use of DDR-targeting therapies in combination/maintenance protocols for specific, clinically advanced malignancies. New therapeutic drugs such as poly(ADP-ribose) polymerase (PARP) inhibitors are examples of DDR-targeting therapies that could potentially increase the DNA damage and replication stress imposed by platinum-based agents in tumor cells and provide therapeutic benefit for patients with advanced malignancies. Recent studies have shown that the use of PARP inhibitors together with platinum-based agents is a promising therapy strategy for ovarian cancer patients with "BRCAness", i.e., a phenotypic characteristic of tumors that not only can involve loss-of-function mutations in either BRCA1 or BRCA2, but also encompasses the molecular features of BRCA-mutant tumors. On the basis of these promising results, additional mechanism-based studies focused on the use of various DDR-targeting therapies in combination with platinum-based agents should be considered. This review discusses, in general, (1) ICL agents, primarily platinum-based agents, that establish a molecular landscape that can be further exploited therapeutically; (2) multiple points of potential intervention after ICL agent-induced crosslinking that further predispose to cell death and can be incorporated into a systematic, therapeutic rationale for combination/ maintenance therapy using DDR-targeting agents; and (3) available agents that can be considered for use in combination/maintenance clinical protocols with platinum-based agents for patients with advanced malignancies.

We evaluated the patterns of progression and determined clinical predictors of survival in patients with castration-resistant prostate cancer (CRPCa) who received sipuleucel-T. We retrospectively analyzed 56 consecutive patients with asymptomatic or minimally symptomatic CRPCa treated with sipuleucel-T. Age, number of bone metastases, history of prior systemic treatment, and alkaline phosphatase level (ALP) were tested as predictors of survival in a multivariate Cox proportional hazards regression model. The Kaplan–Meier method was used to estimate event-free probabilities. The 56 patients were a median age of 67 years (range 51–84 years). After sipuleucel-T treatment, 25 patients developed bone progression after a median of 22 months of follow-up (54% of patients were event free at 2 years) and 10% (6/56 patients) developed rapid progression. Eleven deaths were observed after a median of 28 months of follow-up. Forty-eight patients were included in the multivariate analysis for overall survival. The analysis showed that age >70 years (p = 0.012), number of bone metastases >20 (p = 0.018), prior systemic treatment (p = 0.018), and ALP level >90 IU/L (p = 0.010) significantly predicted worse overall survival. Two-year overall survival was 36% among the 16 patients with two or more of these factors and was 93% among the 32 patients with one or none of these factors (p = 0.0004). CRPCa patients with age (>70 years), increased tumor burden in bone (>20 metastases and/or elevated ALP level), and/or prior systemic treatment are more likely to experience rapid deterioration after sipuleucel-T. These results need to be prospectively validated.

Cancers with loss-of-function mutations in BRCA1 or BRCA2 are deficient in the DNA damage repair pathway called homologous recombination (HR), rendering these cancers exquisitely vulnerable to poly(ADP-ribose) polymerase (PARP) inhibitors. This functional state and therapeutic sensitivity is referred to as “BRCAness” and is most commonly associated with some breast cancer types. Pharmaceutical induction of BRCAness could expand the use of PARP inhibitors to other tumor types. For example, BRCA mutations are present in only ~20% of prostate cancer patients. We found that castration-resistant prostate cancer (CRPC) cells showed increased expression of a set of HR-associated genes, including BRCA1 , RAD54L , and RMI2 . Although androgen-targeted therapy is typically not effective in CRPC patients, the androgen receptor inhibitor enzalutamide suppressed the expression of those HR genes in CRPC cells, thus creating HR deficiency and BRCAness. A “lead-in” treatment strategy, in which enzalutamide was followed by the PARP inhibitor olaparib, promoted DNA damage–induced cell death and inhibited clonal proliferation of prostate cancer cells in culture and suppressed the growth of prostate cancer xenografts in mice. Thus, antiandrogen and PARP inhibitor combination therapy may be effective for CRPC patients and suggests that pharmaceutically inducing BRCAness may expand the clinical use of PARP inhibitors.

Purpose Cabozantinib (XL184), an oral inhibitor of multiple receptor tyrosine kinases such as MET and VEGFR2, was evaluated in a phase II nonrandomized expansion study in castration-resistant prostate cancer (CRPC). Patients and Methods Patients received open-label cabozantinib at daily starting doses of 100 mg or 40 mg until disease progression or unacceptable toxicity. The primary end point was bone scan response, defined as ≥ 30% reduction in bone scan lesion area. Other efficacy end points included overall survival, pain, analgesic use, and biomarkers. Results One hundred forty-four patients sequentially enrolled in either a 100-mg (n = 93) or 40-mg (n = 51) study cohort. Ninety-one patients (63%) had a bone scan response, often by week 6. Treatment resulted in clinically meaningful pain relief (57% of patients) and reduction or discontinuation of narcotic analgesics (55% of patients), as well as improvements in measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Improvements in each of these outcomes were observed in both cohorts: bone scan response in 73% and 45%, respectively; reductions in measurable soft tissue disease in 80% and 79%, respectively. Median overall survival was 10.8 months for the entire population. Most common grade 3 or 4 adverse events were fatigue (22%) and hypertension (14%). Fewer dose reductions because of toxicity were required in the 40-mg group. Conclusion The evidence suggests that cabozantinib has clinically meaningful activity in CRPC. Cabozantinib resulted in improvements in bone scans, pain, analgesic use, measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Taken together, these phase II observations warrant further development of cabozantinib in prostate cancer.

BACKGROUND Radiopharmaceutical use may improve the survival time of patients with castrate-resistant prostate cancer and bone metastases. Whether androgen-deprivation therapy (ADT) combined with bone-targeted therapy provides a clinical benefit to patients with advanced castrate-sensitive prostate cancer has not been investigated. METHODS Eighty male patients were enrolled, and 79 were randomized: 40 to the control arm and 39 to the strontium-89 (Sr-89) arm. After randomization, patients in both study arms received ADT, doxorubicin, and zoledronic acid. Kaplan-Meier methodology was used to evaluate the progression-free survival (PFS) time. Multivariate Cox proportional hazards regression was used to evaluate the effects of Sr-89 after controlling for the number of bone metastases. RESULTS The median follow-up time for the 29 patients alive at the last follow-up was 76.9 months (range, 0.07-103.4 months). The median PFS time was 18.5 months (95% confidence interval, 9.7-49.4 months) for the control arm and 12.9 months (95% confidence interval, 8.9-72.5 months) for the Sr-89 arm (P = .86). No patient developed myelodysplastic syndrome or a hematologic malignancy. An unplanned subgroup analysis suggested increased efficacy of bone-targeted therapy with a greater extent of bone involvement (ie, >6 bone metastases vs ≤6 bone metastases on the bone scan). CONCLUSIONS The data showed that bone-targeted therapy using 1 dose of Sr-89 combined with chemohormonal ablation therapy did not favorably affect the PFS of patients with castrate-sensitive prostate cancer. The combined therapy was feasible and safe. Whether such bone-targeted therapy provides a favorable outcome for those patients with a greater tumor burden in the bone warrants further investigation. Cancer 2015;121:69–76. © 2014 American Cancer Society.

DNA damage response (DDR) includes the activation of numerous cellular activities that prevent duplication of DNA lesions and maintain genomic integrity, which is critical for the survival of normal and cancer cells. Specific genes involved in the DDR such as BRCA1/2 and P53 are mutated during prostate cancer progression, while various oncogenic signaling such as Akt and c-Myc are activated, enhancing the replication stress and increasing the genomic instability of cancer cells. These events may render prostate cancer cells particularly sensitive to inhibition of specific DDR pathways, such as PARP in homologous recombination (HR) DNA repair and Chk1 in cell cycle checkpoint and DNA repair, creating opportunities for synthetic lethality or synergistic cytotoxicity. Recent reports highlight the critical role of androgen receptor (AR) as a regulator of DDR genes, providing a rationale for combining DNA-damaging agents or targeted DDR inhibitors with hormonal manipulation or AR inhibition as treatment for aggressive disease. The aims of this review are to discuss specific DDR defects in prostate cancer that occur during disease progression, to summarize recent advances in understanding the regulation of DDR in prostate cancer, and to present potential therapeutic opportunities through combinational targeting of the intact components of DDR signaling pathways.

Purpose: Orteronel (TAK-700) is an investigational, nonsteroidal, oral, inhibitor of androgen synthesis with greater specificity for 17,20-lyase than for 17α-hydroxylase. We investigated orteronel without steroids in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC; M0). Experimental Design: Patients with nmCRPC and rising prostate-specific antigen (PSA) received orteronel 300 mg twice daily until PSA progression, metastases, or unacceptable toxicity. The primary endpoint was percentage of patients achieving PSA ≤0.2 ng/mL (undetectable levels) at 3 months. Secondary endpoints included safety, PSA response, time to metastases, and correlated endpoints. Results: Thirty-nine patients with a median baseline PSA doubling time of 2.4 months (range, 0.9–9.2) received a median of fourteen 28-day treatment cycles. PSA decreased >30% in 35 patients and 6 (16%) achieved PSA ≤ 0.2 ng/mL at 3 months. Median times to PSA progression and metastasis were 13.8 and 25.4 months, respectively. Kaplan–Meier estimates of freedom from PSA progression were 57% and 42% at 12 and 24 months, and of freedom from metastasis were 94% and 62% at 12 and 24 months, respectively. At 3 months, median testosterone declined by 89% from baseline. Adverse events led to therapy discontinuation in 12 patients and grade ≥3/4 adverse events occurred in 22 patients. Most frequent all-cause adverse events included fatigue (64%), hypertension (44%), diarrhea (38%), and nausea (33%), which were primarily grade 1/2. Conclusions: Single-agent orteronel produced marked and durable declines in PSA in patients with nmCRPC. Orteronel has moderate but manageable toxicities and its chronic administration without steroids appears feasible. Clin Cancer Res; 20(16); 4218–27. ©2014 AACR.

We identified sunitinib alternative schedules that maintained dose intensity while decreasing adverse events in patients with metastatic renal cell cancer. We also determined the impact of alternative schedules on clinical outcomes.We retrospectively reviewed the records of patients 18 years old or older with clear cell metastatic renal cell cancer who received first line sunitinib between January 26, 2006 and March 1, 2011 at our major comprehensive cancer center. A subset of patients was switched at the first intolerable adverse event from the traditional schedule of 28 days on and 14 days off to a schedule of 14 days on and 7 days off or other alternative schedules. A control group underwent standard dose reduction. We estimated progression-free and overall survival by the Kaplan-Meier method. Predictors of progression-free and overall survival were analyzed using Cox regression.A total of 187 patients were included in analysis, of whom 87% were on the traditional schedule at baseline. During treatment 53% of patients continued on the traditional schedule and 47% began or were transitioned to alternative schedules. Baseline characteristics were similar. Adverse events prompting schedule modification included fatigue in 64% of cases, hand-foot syndrome in 38% and diarrhea in 32%. Median time to alternative schedules was 5.6 months. Median overall survival was 17.7 months (95% CI 10.8-22.2) on the traditional schedule compared to 33.0 months (95% CI 29.3-not estimable) on alternative schedules (p0.0001). On multivariable analysis poor Eastern Cooperative Oncology Group (ECOG) performance status, increased lactate dehydrogenase, decreased albumin, unfavorable Heng criteria and the traditional schedule were associated with decreased overall survival (p0.05).Sunitinib administered on alternative schedules may mitigate adverse events while achieving outcomes comparable to those of the traditional schedule in patients with metastatic renal cell cancer. Prospective investigations of alternate dosing schemas are warranted.

A subset of castration-resistant prostate cancer (CRPC) patients present with atypical clinical features and aggressive disease behavior. These patients have a poor prognosis and may derive increased benefit from platinum-based chemotherapy. Heterogeneity in clinical presentations and insufficient understanding of biological drivers of progression underscore the need for more precise molecular stratification methods. We hypothesized that genomic characterization of circulating tumor cells (CTCs) at the single cell level would identify biomarkers relevant to the classification of aggressive CRPC tumors. Peripheral blood samples were collected before initiation of cabazitaxel +/- carboplatin from a cohort of 62 metastatic CRPC patients with and without clinically defined aggressive variant prostate cancer (AVPC) enrolled in NCT01505868. Samples were processed and analyzed for CTCs using the Epic Sciences detection and characterization platform in a CLIA-like environment. After CTC detection, single cells were picked and individually sequenced to assess gene gains and losses and genomic large-scale segment transitions (LST). Of 62 collected blood samples, 49 were positive for CTCs. Patients with more rapidly progressive disease (as assessed by a clinician) had higher CTC/mL, higher AR+CTC/mL, and higher median LST per CTC (p-values: 0.00669, 0.0358, and 0.00623, respectively). AVPC status, as marked by clinical features, was also associated with a higher number of LSTs in CTCs (median 24 per patient CTC vs. 10.5 in non-AVPC, p = 0.02672), whereas no difference in AR+CTC/mL or CTC/mL enumeration was observed. CTC count and LST were additive to prognosticate death by 12 months (AUC = 0.753 combined). The individual copy number was further assessed across 574 genes to identify alterations more commonly associated with poor prognosis. Myc gain, TP53 loss, and other aberrations in genes affecting DNA repair, resistance to anchorage-independent apoptosis, and cell motility showed significant positive association with LST. The presence of high genomic LST, a marker of genomic instability, in individual CTC was associated with more aggressive CRPC behavior (faster rate of progression, shorter survival) and specific gene copy number aberrations. High LST added independent prognostic significance to CTC enumeration. These data suggest that single CTC genomic analysis may provide clinically relevant insights and point to genomic instability in CTCs as a candidate marker of poor prognosis in advanced prostate cancer. Citation Format: Paymaneh D. Malihi, Ryon P. Graf, Carmen Ruiz Velasco, Anand Kolatkar, Angel E. Rodriguez, Jerry Lee, Ramsay Sutton, Paul G. Corn, Christopher Logothetis, Ana Aparicio, James Hicks, Ryan Dittamore, Amado Zurita, Peter Kuhn. Genomic instability as a marker of poor prognosis in advanced prostate cancer: Subclonal insights from whole-genome sequencing of single circulating tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 448.

5052 Background: AVPC are a subset of prostate cancers (PC) that share clinical features with the small-cell prostate carcinomas, a rare morphological variant with atypical and virulent behavior. They are estimated to represent 30% of lethal PC and are characterized by a molecular signature of combined defects (≥2) in Tp53, RB1 and PTEN (AVPC_MS). The AVPC_MS is associated with androgen indifference in preclinical models and predicts for benefit from the addition of carboplatin to cabazitaxel in men with castration resistant prostate cancer (CRPC). The prevalence and significance of the AVPC_MS in castration sensitive M1PC is unknown. Methods: In a Phase II trial 119 men with M1PC treated with 6 months of standard systemic therapy (SST) were randomized to the addition of local therapy. PCa samples obtained at diagnosis and after 6 months of SST were stained for markers including Tp53, RB1 and PTEN, and subject to whole genome sequencing. Tp53 was considered defective if expressed in ≥ 10% of tumor cells, and RB1 and PTEN if in ≤ 10%. Progression free survival (PFS) was estimated from SST start. Results: To date specimens from 38 men have been evaluated. Immunohistochemistry (IHC) results are shown below. The median PFS of men with AVPC_MSPOSITIVE vs AVPC_MSNEGATIVEbaseline prostate tumors was 9.3 vs 15 months (HR 1.09, 95%CI 0.42-2.87, P=0.852). Conclusions: The rate at which the AVPC molecular signature is detected in castration sensitive M1PCa appears similar to that in CRPC. This may have therapeutic implications. Updated molecular and outcome data will be presented upon acceptance. [Table: see text]

5055 Background: Given the absence of biologically based biomarkers current therapy allocation strategies for men with mHNPCa are based on anatomic distribution and volume of metastases. We sought to determine the strength of the association between clinical predictors (including met volume) and outcomes in men with mHNPCa at extremes of response to initial systemic therapy (ST). Methods: Data from a population screened for a phase II trial of Best ST +/- local therapy in mHNPCa was analyzed (NCT01751438). Pts had to have sustained responses to ST (≥6 mos) in order to be randomized. Early Progressors (EP, castration resistant progression median for the 109 randomized pts. Baseline demographics were compared between groups (Fisher’s exact test for categorical and Wilcoxon rank-sum test for continuous variables) and Kaplan Meier estimates of OS determined. Immunohistochemistry and genomic sequencing of untreated tumor biopsies are ongoing. Results: Of 208 screened pts, 27 (13%) were identified as EPs, with a median PFS of 5.9 mos (95%CI: 5.3-6.5). The median PFS for the randomized cohort was 16.8 mos (95%CI: 12.7-37.6). 55 (50%) pts were identified as PRs, with median PFS not reached (NR) at a median follow up of 31 mos (range: 7.5-75). Patients’ demographics are below (Table), grouped by EP and PR cohorts. Median OS was 24.8 mos vs NR in the Eps compared to PRs (p

e14118 Background: A rare and often fatal spectrum of NM immune-related adverse events (irAEs) includes myositis, myocarditis, and myasthenia gravis (MG). A deeper understanding of their clinical and immunologic features may improve outcomes. Methods: Sixteen patients (pts) with genitourinary cancers who were treated with ICI and developed myositis, myocarditis, MG, or overlap syndrome (≥2) were identified. Diagnostic criteria included serum CK (n=16), aldolase (n=14), troponin (n=12), BNP (n=15), autoantibodies (n=16), and cytokines (n=9). Biopsies of skeletal muscle (n=13) and endomyocardium (n=4) were also obtained. Immune profiling is being performed on blood and tissue for pts consented to an institutional-approved laboratory protocol. Results: ICI-associated NM irAEs consisted of isolated myositis (n=8, 50%), myocarditis (n=1, 6%), MG (n=1, 6%), or overlap syndrome (n=6, 38%), with the most common presenting symptom being weakness (n=9, 56%). CK levels were elevated in 15 (94%) pts, and autoantibodies were detected in 9 (56%). Muscle biopsies showed predominantly T cell infiltration. All 16 pts received corticosteroids, 12 (75%) were treated with other immunosuppressive agents, and 14 (88%) underwent plasmapheresis. Five pts (50%) with isolated irAEs achieved symptom resolution, and none in the overlap group. (Table) Conclusions: NM irAEs occurred more frequently with combination ICI, and were associated with weakness, and elevated CK level and serum autoantibodies. Both T and B cells appear to drive disease pathogenesis. The presence of one toxicity on the spectrum warrants evaluation for associated irAEs. Compared to isolated NM irAEs, the overlap syndrome appears to be more treatment refractory. Current guidelines require refinement to identify effective treatments to improve outcomes. [Table: see text]