bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a risk calculator of recurrence in inguinal lymph node metastatic (ILNM) patients with surgically resected penile squamous cell carcinoma (PSCC).
Authors: Bandini Marco , Zhu Yao , Ye Dingwei , Ornellas Antonio Augusto , Watkin Nick , Ager Michael , Hakenberg Oliver W. , Heidenreich Axel , Raggi Daniele , Catanzaro Mario , Marandino Laura , Haidl Friederike , Montorsi Francesco , Chipollini Juan , Azizi Mounsif , Albersen Maarten , Salvioni Roberto , Brouwer Oscar , Spiess Philippe E. , Necchi Andrea
Published: February 2020

1

Background: ILNM PSCC patients (pts) have heterogeneous outcomes. We aimed to identify risk factors of early recurrence in order to optimize the selection of pts for adjuvant (adj) therapies (tx). Methods: In a multicenter database of 924 pts who underwent ILN dissection, we identified 311 ILNM pts. Pts treated with neoadj chemo (CT) and/or radiotherapy (RT) were excluded. Multivariable Cox regression analyses (MVA) tested for predictors of recurrence, after adjusting for adj tx, age, type of surgery of the primary and smoking status. As primary endpoint, a risk calculator predicting early (24-month) risk of recurrence was developed. As secondary endpoint, the overall survival (OS) benefit of adj tx was examined according to the risk calculator-derived tertiles using Kaplan-Meier analysis. Results: Overall, 159 pts (51.1%) had pN1-2 and 203 (65.3%) pT2-4 disease. Overall, 195 (62.7%) and 78 (25.1%) received partial or total penectomy, whereas 6 (1.9%) local excision and 32 (10.3%) other procedures. Median number of removed and positive ILN were 15 (IQR 9-21) and 2 (IQR 1-3). Pelvic LND was performed in 154 (49.5%) pts, and 39% of them had pelvic LNM. In MVA, ILN ratio (HR: 1.01, p= 0.04), pN3 (HR: 2.53, p=0.002) and positive proximal margin of the primary (HR: 2.13, p=0.02) were significantly associated with recurrence. The c-index of our 3-variable risk calculator was 68%, with a net benefit higher that treat-all option from 20% to 90% threshold-probabilities. Within the cohort of adj CT and/or RT (N=127) pts, intermediate-high tertile had similar median OS (NR vs 107m) compared to pts in the low tertile (p=0.1). Conversely, intermediate-high tertile pts who received observation alone had shorter OS (NR vs 40m) compared to the same pts in the lower tertile (p<0.001). Similar results were obtained for CT and RT separately analyzed. Conclusions: We developed and internally validated a risk calculator to predict early recurrence in ILNM surgically-resected PSCC pts. According to our risk-calculator, pts with intermediate/higher risk of early recurrence may benefit from adj tx. Our risk calculator can be used for counseling and enrolment in ongoing studies.
Analysis of the prognostic significance of circulating tumor DNA (ctDNA) in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Shaya Justin , Randall James Michael , Millard Frederick E. , Kurzrock Razelle , Parsons J Kellogg , Tamayo Pablo , McKay Rana R.
Published: February 2020

110

Background: Given the technical limitations of obtaining tissue next-generation sequencing, there has been interest in blood ctDNA to assess genomic alterations in mCRPC. We examined the genomic landscape and prognostic significance of ctDNA in mCRPC. Methods: Single center retrospective analysis of mCRPC patients who underwent ctDNA genomic profiling using Guardant360. Overall survival (OS) and time to progression (TTP) were examined and stratified by the presence of tumor suppressor mutations (p53, PTEN, Rb), androgen receptor (AR) amplification or mutation, number of genomic alterations, and highest allelic fraction of detected mutations. Results: At the time of ctDNA collection, all patients (n=46) had mCRPC with bone metastases present in 100% of patients and visceral metastases present in 17.3%. Median age at ctDNA collection was 71 years, median time from CRPC diagnosis to ctDNA was 13 months (range 0-45), and median follow-up time from CRPC diagnosis was 17.5 months (4-40). The most common alterations present were TP53 mutation (41.3%), AR amplification (30.4%), and CDK6 amplification (21.7%). Actionable mutations were detected in BRCA1 (4.3%), BRCA2 (4.3%), ATM (2.2%), and PMS2 (2.2%). The median number of genomic alterations was 2 (0-8) and the median ctDNA allelic fraction was 4.6% (0-86.9%). Median OS of the cohort was 36 months. The presence of a tumor suppressor mutation, > 2 genomic alterations, and >5% mutation allelic fraction was associated with inferior OS (Table). In terms of time to progression on 1st line abiraterone or enzalutamide, the presence of an AR amplification or mutation was associated with significantly worse median TTP of 6.9 vs 13.5 months ( p- 0.015). Conclusions: ctDNA is frequently detected in mCRPC; and the type, number and frequency of alterations are potentially prognostic of OS in mCRPC. Ongoing studies are needed to assess concordance of ctDNA with tissue NGS and the predictability of ctDNA.[Table: see text]
Phase Ib study of niraparib plus androgen receptor-targeted therapy (ART) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Saad Fred , Chi Kim N. , Shore Neal D. , Graff Julie Nicole , Posadas Edwin M. , Espina Byron M. , Zhu Eugene , Hazra Anasuya , Bradic Branislav , Cheng Shinta , Hayreh Vinny , Rezazadeh Arash
Published: February 2020

122

Background: Poly ADP-ribose polymerase (PARP) inhibitor and abiraterone acetate + prednisone (AA+P) has activity in pts with mCRPC regardless of DNA repair gene defects (DRD). Methods: This phase 1b study (Bedivere; NCT02924766) began with a 3+3 dose escalation of niraparib (Part 1), followed by expansion (Part 2) of the recommended phase 2 dose (RP2D) of nira + AA+P. Pts with mCRPC received nira 200 or 300 mg/day with AA+P. Dose-limiting toxicities (DLTs) were evaluated the first 28 days. Serial PK for nira were collected on cycle 1 day 1 (C1D1) over 24 h; PK for nira and abiraterone were collected on C2D1 over 10 h. Results: Nira 200 mg + 1000 mg AA+P was selected as the RP2D dose. 4 pts in 200 mg cohort and 8 pts in 300 mg cohort were enrolled in Part 1. During Part 1, 1 patient in the 300 mg cohort had two DLTs: Gr 3 fatigue and Gr 4 increased gamma glutamyltransferase. Therefore, the 200 mg dose was evaluated in 15 pts in Part 2. In 19 total pts treated with 200 mg niraparib, 12 (63%) pts had Gr 3-4 AEs, 5 (26%) pts had an AE with outcome of drug discontinuation and 1 (5%) patient had an AE with outcome of death (general physical health deterioration; unrelated). AEs of special interest were: 6 pts (32%) thrombocytopenia, 6 pts (32%) hypertension, 5 pts (26%) anemia and 3 pts (16%) neutropenia of any grade. 21% pts in 200 mg cohort had treatment emergent serious AE (TESAE) while 50% treated with 300 mg had TESAE. The exposure (AUC24h) on Day 1 of Cycle 2 for 200 mg niraparib with 1000 mg of AA were 17745±9380 ng.h/mL and 712±140 ng.h/mL, respectively. These exposures are consistent with single agent PK. Summaries of all responses will be provided, including a patient with primarily bone disease and carrying an ATM mutation who had a circulating tumor cell conversion and was on study treatment for 22.1 mo. Conclusions: The safety and PK findings support the choice of nira 200 mg in combination with AA+P in pts with mCRPC. The efficacy of nira + AA+P is being evaluated in an ongoing phase 3 MAGNITUDE study (NCT03748641). Clinical trial information: NCT02924766.
Revision of CHAARTED and LATTITUDE criteria among Japanese de novo metastatic prostate cancer patients.
Authors: Sakamoto Shinichi , Yamada Yasutaka , Rii Junryo , Yamamoto Satoshi , Kamada Shuhei , Imamura Yusuke , Nakamura Kazuyoshi , Komiya Akira , Nakatsu Hiroomi , Ichikawa Tomohiko
Published: February 2020

132

Background: Based on the high response rate to the standard androgen deprivation therapy (ADT), the Japanese cohort in LATTITUDE study failed to show the survival benefit by early Abiraterone. In order to identify the "true high-risk" patients, we studied the prognostic factors among Japanese de novo metastatic prostate cancer patients who fit CHAARTED and LATITUDE criteria. Methods: We retrospectively studied patients who fit CHAARTED (292 patients) and LATITUDE (294 patients) criteria from Japanese multi-institutions. All patients received ADT with bicalutamide as an initial treatment. Factors related to overall survival (OS) and progression-free survival (PFS) were statistically analyzed. Results: The median OS was 56 mo and 57 mo in patients who met the CHAARTED and the LATITUDE criteria, respectively. In patients who met CHAARTED criteria, LDH (HR2.6, p < 0.00001) and CRP (HR1.7, p = 0.042) were independent risk factors for OS. In patients who met LATTITUDE criteria, GS≥9 (HR1.7, p = 0.0378) and LDH (HR2.9, p < 0.0001) were independent risk factors for OS. Modified CHAARTED criteria by adding LDH and CRP showed a significant difference in OS (HR2.8, p < 0.0001) with a comparative median OS (30 mo) to placebo of CHAARTED trial (32 mo). Modified LATTITUDE criteria by adding GS≥9 and LDH, showed a significant difference in OS (HR2.7, p < 0.0001) with a comparative median OS (33 mo) to placebo of LATTITUDE trial (34 mo). Conclusions: Modified criteria may potentially elucidate the true "high-volume" and "high-risk" patients in the Japanese cohort who require early intensive therapy.[Table: see text]
ADRB2 expression in progressive metastatic castration-resistant prostate cancer.
Authors: Kwon Daniel , Zhang Li , Foye Adam , Chen William S. , Feng Felix Y , Bailey Adina , Huang Jiaoti , Quigley David A. , Stuart Josh , Friedl Verena , Weinstein Alana , Beer Tomasz M. , Alumkal Joshi J. , Rettig Matthew , Gleave Martin , Lara Primo , Li Patricia , Lui Austin , Small Eric Jay , Aggarwal Rahul Raj
Published: February 2020

145

Background: The net oncogenic effect of the G protein-coupled receptor β2 adrenergic receptor ADRB2, which may induce neuroendocrine differentiation via cyclic AMP and protein kinase A and whose expression is epigenetically regulated by EZH2, is controversial. ADRB2 expression and associated clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC) are unknown. Methods: This was a retrospective analysis of a cohort of men with mCRPC who were prospectively enrolled in the multi-center SU2C/PCF/AACR West Coast Prostate Cancer Dream Team study, in which biopsies of a metastatic site were obtained at disease progression. Specimens underwent laser capture microdissection and RNA-seq. ADRB2 expression was stratified by histology and transcriptional cluster based on prior unsupervised hierarchical transcriptome clustering, and correlated with EZH2 expression. ADRB2 expression (lowest quartile) was correlated with OS from time of biopsy by log rank test and a multivariable Cox proportional hazard model. Results: One-hundred and twenty-seven men with progressive mCRPC underwent metastatic biopsies and had sufficient tumor for RNA-seq. ADRB2 expression was lowest in the small cell-enriched transcriptional cluster (P<0.001), and correlated inversely with EZH2 expression (r=-0.28, P<0.01). Men with low ADRB2 expression had a shorter median OS than those with high (9.5 vs 18.9 mo, P=0.02). In multivariable analysis adjusting for small cell histology, performance status, LDH, and visceral metastases, high ADRB2 expression was associated with a trend towards longer OS (HR=0.65, 95% CI 0.41-1.02, P=0.06). Conclusions: Low ADRB2 expression is associated with worse OS in men with progressive mCRPC, and may be a means by which EZH2 confers resistance to antiandrogen therapy. Indirect ADRB2 stimulation with EZH2 inhibitors may improve outcomes. Validation in independent cohorts is necessary.
Gene expression in circulating tumor cells (CTC) and plasma androgen receptor (AR) gene copy number (CN) for castration-resistant prostate cancer (CRPC) patients (pts) treated with cabazitaxel.
Authors: Gurioli Giorgia , Conteduca Vincenza , Basso Umberto , Fornarini Giuseppe , Mosca Alessandra , Nicodemo Maurizio , Banna Giuseppe Luigi , Lolli Cristian , Schepisi Giuseppe , Gargiulo Stefania , Altavilla Amelia , Testoni Sara , Scarpi Emanuela , De Giorgi Ugo
Published: February 2020

154

Background: Cabazitaxel demonstrated overall survival (OS) benefit for the treatment of CRPC progressing after docetaxel. CTC profiling could help to establish novel predictive biomarkers. In this prospective study (NCT03381326), we evaluated the prognostic role of CTC biomarkers expression and the association with plasma AR CN in pts treated with cabazitaxel. Methods: We enrolled pts receiving cabazitaxel from January 2015 to December 2018. Plasma DNA was isolated and digital PCR was performed to assess AR CN status. CTC enrichment was evaluated with AdnaTest EMT-2/StemCell kit. Expression analyses using real time PCR were performed for 17 genes and CTC positivity (CTC+) was defined as the expression of at least 1 of the following 7 relevant markers: AR-V7, AKT, AR, EPCAM, PSMA, PI3KCA, PSCA. Results: We enrolled 100 pts, 80 fully evaluable for this analysis. Median age was 72 years (range 49-82). All pts received prior docetaxel and 85% prior abiraterone and/or enzalutamide. Median OS and progression-free survival (PFS) were 16.4 months (mo) (95% CI 11.1-27.0) and 6.7 mo (95% CI 5.2-8.3), respectively. Fifty-eight (72.5%) showed CTC+ at baseline, whose 15 (26%) had >3 markers expressed in CTC. Significantly worse OS was observed in pts with >3 markers expressed in CTC compared to those with ≤3 markers and CTC negative pts [4.7 mo vs 15.2 vs 31.7 mo respectively, hazard ratio (HR) 6.05 (95% CI 2.07-17.73), p=0.004]. No significant difference was observed for PFS and PSA response. AR-V7 was expressed in 11 (19%) CTC+ pts, whose 10 (91%) had >3 markers expressed in CTC (p=0.0274), and 8 (73%) had plasma AR CN gain (p=0.048). A shorter OS was observed in AR-V7+ vs AR-V7- pts [10.6 vs 18.1 mo, HR 2.48 (95% CI 1.00-6.18), p=0.051]. Significantly worse OS and PFS were found in AR CN gain pts compared to AR normal [11.1 mo vs 27.0 mo, HR 2.28 (95% CI 1.19-4.38), p=0.013 and 5.9 mo vs 8.5 mo, HR 1.81 (95% CI 1.05-3.13), p=0.032], respectively. Conclusions: Liquid biopsy profiling may improve prognostication of CRPC patients treated with cabazitaxel. Further larger studies are warranted. Funding: Partially funded by Sanofi Genzyme. Clinical trial information: NCT03381326.
Combination of AMG 160, a PSMA x CD3 half-life extended bispecific T-cell engager (HLE BiTE) immune therapy, with an anti-PD-1 antibody in prostate cancer (PCa).
Authors: Paweletz Katherine L. , Li Shyun , Bailis Julie M. , Juan Gloria
Published: February 2020

155

Background: AMG 160 is an HLE BiTE immune therapy that binds prostate-specific membrane antigen (PSMA) on tumor cells and CD3 on T cells, leading to T cell activation, cytokine production, and tumor cell lysis. A phase 1 study of AMG 160 in patients with metastatic castration-resistant PCa is ongoing (NCT03792841). We investigated whether the combination of AMG 160 and an anti-PD-1 antibody could increase AMG 160 cytotoxicity against PCa cells in vitro and ex vivo. Methods: C4-2B human PCa cells engineered to overexpress PD-L1 were treated with a range of AMG 160 doses (0.144–30,000 pM) +/– a fixed dose of anti-PD-1 in the presence of activated human T cells. Cell viability was assessed by Steady-Glo after 1 day. PD-1 expression on T cells was evaluated by flow cytometry. A human tumor explant model consisting of thin sections of fresh surgically resected human PCa tumors was also used to evaluate the AMG 160 + anti-PD-1 combination. Explants were incubated in media over 2 days and treated with buffer alone, AMG 160, or AMG 160 + anti-PD-1 at fixed doses. Activation of autologous T cells within the tumor slices was assayed by flow cytometry, and secretion of cytokines into culture supernatants was measured by Meso Scale Discovery (MSD). Immune-response profiles of the culture tissues were assessed by NanoString. Results: In the PCa in vitro study, AMG 160 treatment induced upregulation of PD-1 on T cells. Cotreatment with AMG 160 + anti-PD-1 increased the potency of cell killing by 2–5x and killed a greater percentage of cells than AMG 160 alone. In the tumor explant model, which preserves tumor architecture and microenvironment, AMG 160 treatment induced activation of the autologous infiltrating T cells, and this activation was increased by cotreatment with anti-PD-1. AMG 160 treatment increased cytokine production, and cotreatment of tumor explants with AMG 160 + anti-PD-1 increased cytokine production further. Conclusions: Together these data suggest that antitumor efficacy of the AMG 160 HLE BiTE immune therapy can be increased by co-treatment with anti-PD-1. These data provide a rationale for evaluating this combination in future clinical studies.
Linking the Aggressive Variant Prostate Cancer (AVPC) molecular signature (-ms) to androgen indifference in a prospective clinical trial.
Authors: Viscuse Paul Vincent , Zhang Miao , Liu Jingjing , Slack Tidwell Rebecca , Subudhi Sumit Kumar , Zurita Amado J. , Corn Paul Gettys , Tu Shi-Ming , Araujo John C. , Wang Jennifer , Efstathiou Eleni , Wang Jianbo , Pilie Patrick Glen , Troncoso Patricia , Zhang Jianhua , Logothetis Christopher , Aparicio Ana
Published: February 2020

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<0.001), and urine n-telopeptides (338.5 vs 182.5; p=0.003) levels. Unsupervised clustering of RNA profiles from 45 tumor biopsies revealed two distinct clusters. The top enriched gene set (FDR q-val<0.000) included ‘epithelial mesenchymal transition’, ‘E2F targets’ and ‘G2M checkpoint’ genes in one (n=18) and ‘androgen response’ in another (n=27) cluster. Six (33.3%) and 9 (33.3%) of the samples respectively belonged to patients in the ‘unsatisfactory’ decline group. IHC and RNA sequencing of the remaining samples are ongoing. Conclusions: Signaling pathways associated with androgen indifference can be identified in the tumor biopsies of men with early mCRPC, prior to exposure to secondary androgen signaling inhibitors. Their association with the AVPC-ms and patient outcomes will be presented. If confirmed, these markers could be used to inform therapy selection. Clinical trial information: NCT02703623.
Doublecortin expression in prostate adenocarcinoma and neuroendocrine tumors.
Authors: Tabrizi Shervin , Alshalalfa Mohammed , Mahal Brandon Arvin Virgil , Davicioni Elai , Liu Yang , Mouw Kent William , Feng Felix Y , Nguyen Paul L. , Muralidhar Vinayak
Published: February 2020

161

Background: Recent work using prostate cancer mouse models implicated doublecortin (DCX)-expressing neural progenitor cells in prostate adenocarcinoma, reporting a strong association between DCX expression and disease progression and outcome. We sought to evaluate the relationship between DCX expression and these outcomes in human prostate cancer. Methods: DCX expression was measured in transcriptome-wide microarray data from 18,501 patients with localized prostate cancer and 290 patients with metastatic castration-resistant prostate cancer (mCRPC). Pairwise comparisons were performed using the Mann–Whitney U test. Metastasis-free survival (MFS) and overall survival (OS) were analyzed using Cox-proportional hazards. Results: DCX expression was not significantly different between normal prostate (n=29), primary prostate cancer (n=131), or metastases (n=19) (p > 0.5), and did not differ across Gleason score in a large cohort of RP samples (n=17,967, p=0.21). The lack of difference persisted after adjusting for stromal contribution using a 141-gene stromal signature. Those with DCX expression above and below the median did not have significant differences in MFS (HR 1.2 [0.84-1.7], p=0.3) or OS (HR 1.15 [0.7-1.84], p =0.56). In a cohort of untreated prostate cancer, DCX expression was higher in neuroendocrine tumors (n=10) compared to Gleason 9-10 prostate adenocarcinoma (n=110) (p=0.007). Similarly, in two cohorts with mCRPC (n=290), DCX expression was higher in lesions with neuroendocrine features than adenocarcinoma (p<0.001). Consistently, in a patient-derived xenograft model subjected to host castration, DCX expression was initially low, but increased significantly once tumors underwent neuroendocrine differentiation and treatment escape. Conclusions: Contrary to recent data using mouse models, DCX expression did not differ by disease state, grade, or outcome in a dataset of human patients with prostate adenocarcinoma. However, DCX expression appeared to correlate with neuroendocrine prostate cancers, a subgroup that can arise de novo or in the castrate-resistant setting. Further work is needed to define the role of DCX expression and its prognostic significance in prostate cancer.
MicroRNA-based biomarkers of the radiation response in prostate cancer.
Authors: Weidhaas Joanne B. , Telesca Donatello , Kishan Amar Upadhyaya , Guldvik Ingrid Jenny , Schulz-Jaavall Melanie-Birte , Stensvold Andreas , Tran Phuoc T. , Lilleby Wolfgang
Published: February 2020

163

Background: Intermediate and high-risk prostate cancer can be cured with radiation (RT) to the prostate and pelvic lymph nodes with androgen deprivation therapy (ADT), but both acute and late toxicity of the GU and GI systems are common. There are no biomarkers predicting radiation outcomes, limiting the opportunity to best personalize prostate radiation therapy. Methods: A prospectively enrolled single arm trial for locally advanced prostate cancer patients (T1-T4N0-N1M0) treated with definitive RT (74Gy IMRT) plus ADT was studied. Biologic samples were available in 108 of 138 patients. Toxicity was recorded using the RTOG morbidity grading system. We applied a panel of microRNA-based germline mutations shown to predict cancer therapy endpoints. Machine learning techniques were used to simultaneously identify prognostic features and perform classification of the biomarkers. Upsampling nested LOO-CV was used to assess performance and generality. Independent Fisher’s exact tests were performed to identify statistically significant marginal associations. Three classifiers were studied: logistic regression with elastic net regularization (EN-LR), classification trees (CT), and random forests (RF), with corresponding hyper-parameters of regularization weights (EN-LR), minimum split and bucket level sample size (CT), number of trees and mtry (RF). Normalized on the simplex, feature importance was defined as absolute value of regression weights for EN-LR, and cumulative decrease in Gini impurity for primary and surrogate splits at each node/splits for CT and RF. Results: Grade 2 or higher toxicity included acute GI (11%), acute GU (34%), late GI (3%) and late GU (16%). GI and GU toxicity and acute and late toxicity had unique predictive biomarkers. The top three marginal genetic associations for late GU toxicity were microRNA site variants in CD6 and CD274 (PDL1)(p.val < 0.01) and BRCA2 (p.val = 0.014). Using RF, CT and EN_LR we could predict late GU toxicity with up to 70% sensitivity, 96% specificity, and 90% accuracy. Conclusions: We have identified microRNA-based biomarkers that can predict late GU toxicity. Work incorporating patient reported outcomes and to identify biomarkers for additional endpoints is ongoing.
Impact of DNA damage repair (DDR) mutations on treatment outcomes in men receiving conventional therapy for metastatic castration resistant prostate cancer (mCRPC).
Authors: Carlson Alex S. , Acevedo Rigo , Lim Daniel M. , Gulati Roman , Yu Evan Y. , Schweizer Michael Thomas
Published: February 2020

172

Background: Nearly 25% of patients with mCRPC harbor DDR alterations, with some of these mutations associating with increased tumor susceptibility to PARP inhibitors and platinum-based chemotherapies. While, mutations in some DDR genes (e.g. BRCA1/2) have been associated with a more aggressive clinical course, prior studies correlating DDR mutational status with treatment response to androgen receptor (AR) signaling inhibitors (ASIs) or taxane-based chemotherapy have yielded conflicting results. Methods: We conducted a single center retrospective analysis to assess clinical outcomes to standard therapies in mCRPC patients with/without DDR mutations as determined on clinical grade next-generation sequencing assays. The primary endpoint was PSA50 response (i.e. ≥50% PSA reduction from baseline), estimated using Bayesian logical regression; secondary endpoints included PSA progression-free survival (PFS), estimated using Kaplan-Meier methods. Results: A total of 93 patients were included in this analysis, with DDR mutations identified in 40/93 (43%). No significant correlations were found between DDR status and PSA50 response within treatment modalities even after adjusting for receipt of prior therapies within the same class (Table). DDR status was not associated with PSA PFS in patients treated with ASIs. There was evidence of decreased PFS in patients with BRCA1/2 and PALB2 mutations treated with Docetaxel (p = 0.008) and Cabazitaxel (p = 0.005), but limited patient numbers precluded significant pairwise analysis with Cabazitaxel. Conclusions: DDR gene mutational status was not associated with inferior clinical outcomes following treatment with ASIs or taxane-based chemotherapy. Additional prospective studies are needed to confirm these findings.[Table: see text]
Association of circulating tumor cell chromosomal instability with worse outcomes in men with mCRPC treated with abiraterone or enzalutamide.
Authors: Brown Landon Carter , Halabi Susan , Schonhoft Joseph , Luo Jun , Nanus David M. , Giannakakou Paraskevi , Szmulewitz Russell Zelig , Danila Daniel Costin , Healy Patrick , Anand Monika , Somarelli Jason , Scher Howard I. , Wenstrup Rick , Berry William R. , Tagawa Scott T. , Antonarakis Emmanuel S. , George Daniel J. , Armstrong Andrew J.
Published: February 2020

183

Background: While AR-V7 is a known driver of hormonal resistance, most men with mCRPC lack AR-V7 detection and commonly experience cross-resistance to abiraterone and enzalutamide (abi/enza). Loss of AR dependence through neuroendocrine (NE) differentiation or chromosomal instability (CIN) may explain AR therapy cross-resistance in additional men. Methods: PROPHECY was a multicenter prospective study of men with poor risk mCRPC starting abi/enza. We assessed Epic CTC AR-V7, CIN and NE phenotypes before abi/enza and at progression. Radiographic/clinical progression free survival (PFS) and overall survival (OS) were associated with CIN (>3 CTCs) and NE (>3 CTCs) CTC phenotypes using the proportional hazards model adjusting for Cellsearch CTC, AR-V7, and clinical risk score. Results: 118 men with mCRPC starting on abi/enza were enrolled; 106 had evaluable CTCs for AR-V7, CIN, and NE on the Epic platform. Of these, 22.6% and 9.4% of men exhibited high CTC CIN and NE scores, respectively. High pre-treatment CIN and NE phenotypic scores were observed in 63 and 27% of AR-V7 (+) and in 17 and 7% of AR-V7 (-) men. CTC CIN phenotype but not NE phenotype was associated with a lower confirmed PSA response rate and OS (TABLE) with abi/enza, adjusting for CTC number, AR-V7 and risk score. Conclusions: A high chromosomal instability CTC phenotype is associated with worse outcomes in men with mCRPC treated with abi/enza and warrants further study as a prognostic or predictive biomarker. Clinical trial information: NCT02269982. [Table: see text]
Assessment of inherited DNA repair defects in African-American and Caucasian men with prostate cancer.
Authors: Sartor A. Oliver , Yang Shan , Ledet Elisa Marie , Moses Marcus W. , Nicolosi Piper L.W.
Published: February 2020

185

Background: Pathogenic inherited DNA repair defects are well described in Caucasian American (CA) men with prostate cancer (PCa) but comparative data with large subsets of African-American (AA) men are limited. Methods: Herein we examine germline pathogenic/likely pathogenic defects (P/LP) in 14 well annotated genes involved in DNA repair pathways in a large Invitae Corporation (San Francisco) lab-derived dataset of men with PCa. Frequency of P/LP alteration were directly compared in AA men and CA men. Reliable data on metastatic rates, family history, and Gleason score are missing. These data are derived from “real-world” experiences using both academic and private practice sites in accordance with physician ordering practices. The number of men assessed for individual genes aberrations varied. The 14 genes were assessed in 148-213 AA men and 1760-2488 CA men. Results: Comparative data using Invitae assays have lower levels of P/LP DNA repair alterations (as a whole) in the assays from AA men as compared to CA men (7.5% vs 13.9%, P=0.008). The P/LP variants in AA men were BRCA2 (6/214, 2.8%), BRCA1 (3/213, 1.4%), PALB2 (2/182, 1.1%), ATM (2/206, 1.0%), RAD51C (1/148, 0.68%), CHEK2 (1/207, 0.48%), and PMS2 (1/212, 0.47%). No AA men in this data set had P/LP mutations in BARD1, BRIP1, MLH1, MSH2, MSH6, NBN, or RAD51D. Lower frequency of P/LP findings in non-BRCA alterations were notably different in AA men as compared to CA men (0.48% vs 3.11%, P=0.03). The frequency of BRCA P/LP variants was not distinct between the AA and CA men. Additional comparisons show that Invitae CA data set is similar to a well cited previously published metastatic PCa data set. Conclusions: Taken together these data from comparable commercial assays indicate that AA men with PCa in this large dataset have lower rates of germline DNA repair P/LP alterations as compared to CA men. These findings are driven by lower rates of P/LP alterations in the non-BRCA genes.
Biomarker analysis (CTC and ctDNA/RNA) of GT0918 (Proxalutamide) new AR blocker in phase I mCRPC patients with dose escalation.
Authors: Zhou Karl , Zhang Phoebe , Tong Youzhi , Ma Liandong
Published: February 2020

186

Background: AR blockade is an important treatment option for mCRPC in clinic and GT0918 is a new chemical entity of AR blocker in 2nd generation. A phase I dose escalation study was planned in pts with mCRPC progressed on multiple lines of SoC and experimental therapies. Daily oral administration of GT0918 has shown better clinical outcomes in 400mg and 500mg cohorts with no comprised toxicities. To study the tumor biology in response to study drug in clinical setting, CTC and cfDNA/RNA based biomarkers were explored. Methods: Pts with histologically confirmed mCRPC who progressed on enza, abi, docetaxel, etc were enrolled and treated with GT0918 continuously until PD, intolerable toxicity or withdraw. Blood samples were collected at baseline, on study drug every 8 wks during the trial and pts with ≥ 3 blood test samples were qualified for various assays for CTCs and cfDNA/RNA via EPIC and PredicinePlus platforms. Results: Total 40 pts were orally administrated GT0918 with dose increasing 50, 100, 200, 300, 400, 500 and 600 mg daily and shown well tolerated with mild to moderate toxicities. Pts received GT0918 over 16 weeks were run biomarkers in Predicine and/or Epic platforms. ctDNA/RNA based variants and CTCs are all detectable in selected pts samples. AR splicing variants (AR-V3 and AR-V7), AR hotspot mutations (W742C, T878A and S889G) and amplifications were detected and shown interesting trends with the clinical outcomes. Both exploratory biomarkers and CTCs suggested higher doses of GT0918 resulted in better clinical outcomes. Conclusions: This is a preliminary study to explore genomic alterations and the CTC enumeration in late stage of mCRPC pts in response to GT0918 treatment with dose increase. As non-invasive assays, both CTC and ctDNA/RNA assays provided valuable molecular insights for monitoring treatment effects besides PSA and imaging scan. Early detection of possible drug sensitivity/resistance mechanisms will facilitate clinical development programs. More patients will be tested in phase II study GT0918 in mCRPC progressed on either abiraterone or enzalutamide. Clinical trial information: NCT02826772. [Table: see text]
Testosterone recovery as biomarker for overall and cause-specific survival in combined treated patients with high-risk and locally advanced prostate cancer.
Authors: Deek Mathew , Vaage Victoria , Hole Knut H. , DeWeese Theodore L. , Stensvold Andreas , Seierstad Therese , Tran Phuoc T. , Lilleby Wolfgang
Published: February 2020

188

Background: Androgen deprivation therapy (ADT) can cause considerable toxicity and may influence outcome. The study assessed the impact of testosterone recovery (TR) on survival after ADT and definitive radiotherapy in two independent cohorts. Methods: Two hundred and forty-four patients (high risk JHH cohort N=106, T1c-T3N0M0 [A], locally advanced OUH cohort N=138, T1c-T4N0-1M0 [B]) with adenocarcinoma of the prostate were included in this retrospective analysis. Short and long-term ADT was given (median 12 months A, 24 months B, respectively,) and along with conformal external beam radiation 76-80 Gy given to the prostate in cohort A, 74 Gy prescribed in cohort B and 46-50 Gy to the whole pelvis. Testosterone levels were measured at the end of ADT and at biochemical relapse. TR was defined as ≥ 9 nmol/L. Kaplan Meier plots were generated for overall survival (OS) and cause-specific survival (CSS) stratified by TR, in addition to patient characteristics median time to TR and FU were calculated. Results: The median age in the A cohort was 66.7 years and 64.7 years in the B group. FU was 6 years for A and 8 years in B. Patients in group A received median ADT of 12 months and 24 months in group B. The median time to TR was 1.6 yr in A and 2.5 yrs in B, respectively. Patients in group A stratified to TR showed no difference in overall survival (p=0.92)), on contrary, patients in group B showed improved overall survival depending on TR (Fig. 1, KM plot, 10 year OS 75.3% vs 59.9% p=0.034). CSS was seemed to trend towards improvement with TR for cohort A (p=0.19) and was improved in cohort B (p=0.022). The Univariate ADT length, age, and RT dose was associated with time to TR, but on multivariate analysis only longer ADT time (p = 0.03) was significantly associated with time to TR. Conclusions: TR was associated with improved OS in patients with unfavorable locally advanced disease a finding not seen in patients with high-risk disease.
Molecular underpinnings of RB status as a biomarker of poor outcome in advanced prostate cancer.
Authors: Mandigo Amy C. , McNair Christopher , Ku Kexin , Pang Angel , Guan Yi Fang , Holst Jeff , Brown Myles , Kelly William Kevin , Knudsen Karen E.
Published: February 2020

189

Background: There is emergent and compelling evidence to support RB status as a biomarker in advanced prostate cancer. RB loss is strongly associated with poor progression-free, disease-specific, and overall survival in prostate cancer (PCa). Preclinical studies in PCa have revealed RB positive tumors are more responsive to CDK4/6 inhibitors. An ongoing randomized Phase IB/II study of enzalutamide with and without ribociclib in patients with metastatic castration-resistant, chemotherapy naïve PCa has become a pioneer trial to include a positive RB status as inclusion criteria in a PCa study (NCT02555189). Beyond CDK4/6 inhibitors, therapeutic agents that target tumor metabolism have been introduced in the clinic. Current data suggests that RB status may be crucial to understand and predict therapeutic response to these agents within tumors. Methods: The biological significance of RB loss was studied utilizing isogenic model systems and human tumor xenografts of castration resistant prostate cancer (CRPC) with and without RB deletion. The mechanism that drives aggressive tumor phenotypes was identified through comprehensive transcriptomic, cistromic, and metabolomic analysis. Novel functions of RB were identified and the response to clinically-relevant therapeutics was examined. Results: Exclusively in CRPC, RB loss results in significant rewiring of cancer cell metabolism. Functional investigation revealed a causative link between RB loss and antioxidant production sufficient to alter responsiveness to genomic insult and selected chemotherapeutics. Observed changes in response to therapeutic intervention were attributed to RB-dependent modulation of intracellular reactive oxygen species. Conclusions: RB loss is strongly associated with poor outcome in advanced PCa. Molecular investigation identified RB-dependent rewiring of cancer cell metabolism as a significant consequence of RB loss, sufficient to alter response in model systems to therapeutic strategies of clinical relevance. These studies significantly advance understanding of the means by which RB loss enhances lethal tumor phenotypes, and are of relevance for development of RB status as a clinically actionable biomarker.
Impact of 18F-fluciclovine PET on salvage radiotherapy plans for men with post-radical prostatectomy recurrence of prostate cancer.
Authors: Payne Heather Ann ,   FALCON Study Group
Published: February 2020

19

Background: Imaging options to localize lesions in men with biochemical recurrence (BCR) of prostate cancer after radical prostatectomy (RP) are limited, especially at low PSA levels. Consequently, radiation oncologists typically target the prostate bed (PB) with or without pelvic lymph nodes (LN) based on clinical or pathologic features. The FALCON study (NCT02578940) evaluated the clinical benefit of 18F-fluciclovine PET through its impact on management plans for men with BCR. Here, we report the impact on salvage radiotherapy (RT) decisions in men post-RP. Methods: Men with a first BCR episode following curative-intent therapy who were being considered for salvage therapy underwent 18F-fluciclovine PET at one of 6 UK sites. Physicians documented patients’ treatment plans pre- and post-scan. Imaging results and management plans were stratified by prior treatment as determined from patient records. Results: Sixty-five (63%) of the 104 FALCON patients had undergone RP. Of these, 62 (median PSA, 0.32 ng/mL) had a pre-scan plan for salvage RT. Lesions were found in 21 (34%) patients (median PSA, 0.32 ng/mL), of whom 10 (16%; median PSA, 0.54 ng/mL) had extraprostatic findings (Table). Post-scan, 25 (40%) men had a management change, 17 (68%) due to a positive scan. Of the 25 post-scan revisions, 17 (68%) were changes to the treatment modality: 8 to systemic therapy, 8 to watchful waiting, 1 other. A further 8 (32%) men had RT fields modified: PB alone modified to include a boost to a 18F-fluciclovine-avid lesion (n = 7) or whole pelvis field refocused on a smaller area (n = 1). Conclusions: Two fifths of men scheduled to undergo salvage RT after RP had their management plan revised following 18F-fluciclovine PET. The majority of changes involved a completely new treatment modality. Future studies to evaluate the clinical outcomes of such changes are warranted. Clinical trial information: NCT02578940. [Table: see text]
Circulating tumor (ct) DNA-based comprehensive genomic profiling to identify microsatellite instability (MSI) and defective DNA damage repair (DDR) in prostate cancer (PCa) patients.
Authors: Drusbosky Leylah M. , Kiedrowski Lesli Ann , Johnson Kelsey , Nagy Rebecca , Saam Jennifer , Bilen Mehmet Asim , Gupta Niraj K. , Lilly Michael B.
Published: February 2020

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Background: Recent trials in PCa have shown efficacy of PARP inhibitors (PARPi) in patients (pts) with mutations in DDR genes such as BRCA1/2 (TOPARP-B, GALAHAD), as well as efficacy of immunotherapy (IO) in PCa pts with MSI. The combination of PARPi + IO is currently being evaluated in the KEYNOTE-365 trial. This analysis explored the utility of ctDNA in identifying PCa pts who may benefit from PARPi, IO, or a combination. Methods: ctDNA-based comprehensive genomic profiling (Guardant360) of 2,165 PCa pts was performed between 10/2018-08/2019. Frequency of pathogenic somatic BRCA1/ 2 mutations and MSI are reported. Results: Out of 2,165 PCa pts tested, Guardant360 identified 24 (1.1%) and 59 (2.7%) pts harboring pathogenic somatic BRCA1 or BRCA2 variants, respectively; MSI was detected in 40 (1.8%) PCa pts. Of the 40 MSI samples, 9 (22.5%) pts also had a somatic pathogenic BRCA1 and/or BRCA2 mutation . One pt harbored pathogenic somatic mutations in both BRCA1 and BRCA2. The variant allele frequency (VAF) for somatic pathogenic BRCA1 (N=2) ranged from 0.2-0.88%, and BRCA2 (N=8) ranged from 0.05-12.4%. There were no BRCA1/2 mutations at VAFs suspicious for germline in MSI PCa pts. A median of 19 genomic alterations (range 8-28) was identified among the 9 pts with pathogenic BRCA1/2 variants. The most frequent co-occurring aberrations were found in TP53, APC, AR, BRCA2, ARID1A, PTEN, RB1, and PIK3CA. An 82yo male with recurrent metastatic PCa underwent Guardant360 testing which identified BRCA2 T3085fs at 7.9% VAF and MSI. He was treated with pembrolizumab for 3 cycles and remains in remission. Another 51yo with MSI was treated with pembrolizumab for 4 cycles. He also remains in remission. Subsequent analysis shows clearance of ctDNA and MSI. Conclusions: ctDNA-based comprehensive genomic profiling can be used to detect PCa pts eligible to receive PARPi, IO, or a combination, improving clinical treatment decision making and pt outcomes, especially when a tissue biopsy is not feasible or sufficient for comprehensive genomic profiling. PSA and objective responses to IO have been observed in PCa pts with MSI detected by ctDNA.
Androgen receptor cfDNA longitudinal mutational analysis in metastatic castrate-resistant prostate cancer.
Authors: Ledet Elisa Marie , Cotogno Patrick , Hatton Whitley , Jaeger Ellen , Moses Marcus W. , Manogue Charlotte , Lewis Brian E. , Barata Pedro C. , Sartor A. Oliver , Layton Jodi Lyn
Published: February 2020

197

Background: Androgen receptor (AR) mutations commonly occur in metastatic castrate resistant prostate cancer (mCRPC). Methods: Circulating tumor DNA (ctDNA) data were obtained from Guardant 360 assays throughout the clinical course of mCRPC patients (pts). Retrospective analysis for any pt with ≥ 3 Guardant assays at least 4 weeks apart were reviewed. Patients must have at least 1 AR mutation or amplification to qualify for inclusion. Statistical analyses, including chi-sq and longitudinal analyses, were conducted. Results: Of the 259 patients with Guardant testing, a total of 88 patients had at least 3 Guardant tests; of these, 59 (67%) had at least one AR alteration. Patients had a median of 4 Guardant assays (range 3-10). Patients with AR amplification, AR mutation or both were identified (23, 20, 16 respectively). The most common and clinically relevant AR mutations found alone or in combination with amplification were T878A (22%), L702H(19%), W742C (19%), and H875Y (10%). These particular functional AR mutations occurred alone in 16 patients. Only 3 patients had neither amplification nor common AR mutation. 17/59 patients were found to have at least one common AR mutation and amplification at some point (on same or different Guardant). One patient had seven different AR mutations with no amplification and two other patients had 3 AR mutations. Remainder of patients had either AR amplification or ≤ 2 alternative mutations. Patients with an AR amplification were 0.1138x (95% Cl 0.0289 - 0.4491) significantly less likely of having a common known functional mutation (p <0.002) at any point. Conclusions: Patients with the most frequently identified known functional AR mutations are less likely to have AR amplification in pts with mCRPC; these common AR mutations have been shown to be associated with resistance to 2nd generation androgen deprivation. Further clinical correlation between treatment regimen and %cfDNA of these and other non-AR driver mutations is planned.
Biomarkers of prolonged time to treatment failure in metastatic castration-resistant prostate cancer patients treated with abiraterone or enzalutamide: A real life patients-based nomogram and web app.
Authors: Silveira Vilbert Maysa Tamara , Pandolfi Natasha Carvalho , Cesca Marcelle Goldner , Calsavara Vinicius Fernando , Corassa Marcelo , Rinck José Augusto , Dettino Aldo A. , Coelho Ricardo Lima , Xerfan Mariana , Oliveira Thiago Bueno
Published: February 2020

202

Background: Survival outcomes for metastatic castration resistant prostate cancer (mCRPC) patients (pts) have greatly improved following the approval of Docetaxel and abiraterone(Abi)/enzalutamide(Ez). However, it is not clear who is likely to benefit more from these therapies in real life clinical practice. Methods: A retrospective cohort study was performed with mCRPC pts treated with Abi/Ez in pre-Docetaxel setting. Primary endpoint: to identify predictive biomarkers of long time to treatment failure (TTF), develop a nomogram and convert it into a web app. Secondary endpoint: to correlate biomarkers with overall survival (OS). Kaplan Meier survival estimates and Cox Regression models were used for time-to-event analyses. Statistical analysis was made with R software. All statistical tests were two-sided and statistical significance was fixed at 0.05. Results: From May2012 to October2017, 117 pts were assessed, 81 received Abi and 36 Ez. Median follow-up of 21 months (mo), estimated median TTF was 12.8mo (95%CI 9.98-15.7) for the total population. Predictive biomarkers for TTF included in the first nomogram model were time from start of androgen deprivation therapy (tADT) to start of Abi/Ez, pain at baseline, Gleason score, baseline testosterone and lower PSA nadir in castration sensitive prostate cancer (CSPC). The second nomogram model included pain and Gleason plus neutrophil counts, tADT to CRPC and baseline PSA at CRPC. C-index: 0.726 and 0.731 respectively, providing a reliable prediction of long-term benefit with Abi/Ez in this setting. All these characteristics were significantly associated with OS. Conclusions: The two nomogram achieved a good internal validation and can work as a tool to the decision-making process of the best strategy to first-line therapy in mCRPC pts.[Table: see text]