bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of adjuvant endocrine therapy with CDK 4/6 inhibitor, ribociclib, for localized ER+/HER2- breast cancer (LEADER).
Authors: Spring Laura , Griffin Colleen , Isakoff Steven J. , Moy Beverly , Wander Seth Andrew , Shin Jennifer , Abraham Elizabeth , Habin Karleen , Patel Jaymin M. , Comander Amy H. , Mulvey Therese Marie , Bardia Aditya
Published: May 2020

531

Background: Given the success of CDK 4/6 inhibitors for ER+/HER2- metastatic breast cancer, there is much interest in exploring these agents in early breast cancer to potentially reduce recurrence risk. However, tolerability and adherence are important considerations in the adjuvant setting. We evaluated the tolerability and adherence of adjuvant endocrine therapy with the CDK 4/6 inhibitor, ribociclib, in two different schedules, in a prospective phase II clinical trial. Methods: Eligible patients were those with localized stage I-III ER+ (≥ 10%), HER2- breast cancer who had completed surgery and were on adjuvant endocrine therapy with at least one year or more of treatment remaining. Patients were randomized to receive continuous ribociclib (400 mg daily of 28-day cycle; arm 1) or intermittent ribociclib (600 mg daily on days 1-21 of 28-day cycle; arm 2) for one year, in addition to an aromatase inhibitor (plus GnRH agonist if premenopausal). Toxicities were evaluated using CTCAE version 4.03. Adherence was monitored by review of patient diaries and pill count. Results: Of the 81 patients enrolled, 24 discontinued early. The table shows the current status of the patients based on treatment arm (data cut-off as of 1/31/20; updated results will be presented at meeting). A total of 8 serious adverse events (AEs) have occurred thus far: grade 3 transaminitis (1), grade 4 transaminitis (3), grade 3 colitis (1), grade 3 infection (2), and grade 4 lymphopenia (1). The most common grade 3 or greater AEs leading to study discontinuation thus far were transaminitis (8.6%), neutropenia (2.5%), and fatigue (2.5%). No patients discontinued early due to prolonged QTc. Adherence results will be reported at the meeting. Conclusions: Interim results demonstrate that while serious AEs with one year of adjuvant ribociclib are low, a number of patients discontinued adjuvant CDK 4/6 inhibitor. Tolerability and adherence patterns will need to be carefully considered with CDK 4/6 inhibitors in the adjuvant setting. Clinical trial information: NCT03285412 . [Table: see text]
Real-world analysis of clinical and economic impact of 21-gene recurrence score (RS) testing in early-stage breast cancer (ESBC) in Ireland.
Authors: McSorley Lynda M , Al Rahbi Fathiya , Tharmabala Mehala , Evoy Denis , Geraghty James G. , Prichard Ruth , Rothwell Jane , McCartan Damian , McDermott Enda , Keane Maccon M. , Kennedy John , O'Reilly Seamus , Millen Steve , Crown John , Smyth Lillian Mary , Kelly Catherine Margaret , Quinn Cecily , Walshe Janice Maria
Published: May 2020

540

Background: Treatment of hormone receptor positive (HR+) ESBC is evolving. The use of chemotherapy (CT) is declining with use of the 21-gene RS assay. This validated tool predicts the likelihood of adjuvant CT benefit in HR+ ESBC. Results from the TAILOR-x study suggest up to 70% of HR+ node negative ESBC patients (pts) may avoid CT with RS ≤25. Our objectives were to assess the clinical and economic impact of RS testing on treatment decisions using real-world data. Methods: From October 2011 to February 2019, a retrospective, cross-sectional observational study was conducted of HR+ node negative ESBC pts who had RS testing in Ireland. A survey of Irish breast medical oncologists provided the assumption for the decision impact analysis that grade (G) 1 pts would not receive CT pre RS testing and G2/3 pts would receive CT. Using TAILOR-x results, pts were classified low risk (RS ≤ 25) and high risk (RS > 25). Data was collected via electronic patient records. Descriptive statistics were used. Cost data was obtained via the National Healthcare Pricing Regulatory Authority. The economic analysis was adjusted for changing treatment and assay costs over the study period. Results: 963pts were identified. Mean age 56 years. Mean tumour size 1.87cm. 114 (11.8%), 636(66%), 211(22%), 2(0.2%) pts had G1, G2, G3 and unknown G respectively (resp). 797pts (82.8%) had low RS, 159 (16.5%) had high RS, and 7pts(0.7%) unknown RS. 251pts(26%) were aged < 51 at diagnosis. Of these, 45(17.9%), 145(57.8%), 58(23%), 3(1.2) had G1, G2, G3 and unknown G resp. 208pts(82.9%) had RS ≤ 25, 39pts(15.5%) had RS > 25 and 4pts(1.6%) unknown RS. In the RS ≤ 25 group, 111pts(44%) had RS 0-15, 59(23.5%) had RS16-20, and 38(15.1%) had RS21-25. Post RS testing 595pts(61.8%) had a change in CT decision; 586 changed to hormone therapy (HT) alone, and 9 from HT to CT. In total, 227pts(23.5%) received CT, and 3pts(0.3%) declined. Of pts treated with CT; 9(4%) had RS 0-15, 89(39.2%) had RS16-25, 129(56.8%) had RS > 25. The most common CT regimen was docetaxel and cyclophosphamide(TC), administered to 121pts(53%). RS assay use achieved a 69% change in treatment decision among G2/3 pts and a net 61% reduction in CT use. This resulted in savings of over €4 million in treatment costs. Deducting the assay cost, net savings of over one million euro was achieved. Conclusions: Ireland was the first public healthcare system to approve reimbursement for RS testing. Over the 8 year period of the study, a net 61% reduction in CT use in Irish pts with HR+ ESBC was achieved with conservative net savings of over €1,000,000.
The comprehensive methylation landscape of metastatic castration-resistant prostate cancer (mCRPC) identifies new phenotypic subtypes: Results from the West Coast Prostate Cancer Dream Team (WCDT).
Authors: Small Eric Jay , Zhao Shuang , Chen William S. , Li Haolong , Foye Adam , Sjöström Martin , Hua Jun Jie , Aggarwal Rahul Raj , Alumkal Joshi J. , Beer Tomasz M. , Gleave Martin , Rettig Matthew , Witte Owen , Lara Primo , Chinnaiyan Arul , Maher Chris , Quigley David A. , Feng Felix Y
Published: May 2020

5507

Background: While recent studies have delineated the genomic landscape of mCRPC, its epigenomic landscape has not been as well characterized. The goal of this study was to define the comprehensive methylation landscape of mCRPC. Methods: mCRPC patients (pts) underwent a metastasis biopsy as part of a multi-institutional study (NCT02432001). Deep whole-genome bisulfite sequencing (mean depth 46x) was performed on fresh frozen tissue from 100 mCRPC patients; data was paired with deep whole-genome and transcriptome sequencing from the same samples. Unbiased hierarchical clustering of the mCRPC methylome was undertaken, and the survival of patients in each cluster was calculated using the Kaplan Meier method. Results: Unbiased hierarchical clustering revealed several distinct subtypes. 22% of mCRPC samples exhibited a novel epigenomic subtype associated with hyper-methylation. This hypermethylated (HM) cluster was significantly associated with somatic mutations in genes known to be involved in methylation, eg TET2 and DNMT3B, as well as in genes in which mutations have been associated with hyper-methylation in other cancer types ( IDH1 in glioblastoma and BRAF in colon cancer). mCRPC survival was 56.1 mos in pts with HM cancers compared to 35.6 mos in non-HM (p = .055). Methylome clustering also identified a unique cluster comprised of all patients with treatment-induced small cell/neuroendocrine cancer, a subtype previously associated with poor survival. Conclusions: This integrated study of whole-genome, whole methylome and whole-transcriptome sequencing provides the first comprehensive overview of the important regulatory role of methylation in metastatic castration-resistant prostate cancer, and has identified at least two distinct subtypes. The clinical and therapeutic implications of methylation subtypes should be explored in future studies. Clinical trial information: NCT02432001 .
Prostate cancer relative survival by stage and race/ethnicity, United States, 2001 to 2015.
Authors: Siegel David A , O'Neil Mary Elizabeth , Richards Thomas B , Dowling Nicole F , Weir Hannah K
Published: May 2020

5509

Background: Prostate cancer is the most common cancer diagnosed and the second leading cause of cancer-related deaths among U.S. men. Incidence rates for distant stage cancer increased during 2010–2014, and survival at all stages was lower for black men than white men. We examined temporal changes in survival by race/ethnicity. Methods: Five-year relative survival (RS) (cancer survival in the absence of other causes of death) was calculated for men with prostate cancer aged ≥40 years using National Program of Cancer Registries data (93% U.S. population coverage). Cancers were diagnosed during 2001–2015 with follow-up through 2015. RS was estimated by race/ethnicity (non-Hispanic white, non-Hispanic black, and Hispanic), stage, and year (2001–2007 and 2008–2015). Differences were determined by non-overlapping 95% confidence intervals (CI). Results: During 2001–2015, 2,234,233 cases were recorded. Five-year RS was 100% for localized disease in all race/ethnicities and time periods. Overall, RS improved from 29.0% (95% CI, 28.5–29.5) to 31.3% (30.8–31.9) for distant stage and 83.4% (83.0–83.8) to 84.7% (84.2–85.1) for unknown stage. For regional stage, RS improved for white men (table). For distant stage, RS was highest for black and Hispanic men. For unknown stage, RS was highest for white and Hispanic men. Conclusions: RS improved for regional, distant, and unknown stage, but disparities by race/ethnicity persist. The disparity between black and white men for distant stage reversed compared to past studies. Further investigation of diagnosis patterns and clinical characteristics of men with distant and unknown stage cancer could inform interventions to address disparities in outcomes. [Table: see text]
Overall survival (OS) results of phase III ARAMIS study of darolutamide (DARO) added to androgen deprivation therapy (ADT) for nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Fizazi Karim , Shore Neal D. , Tammela Teuvo , Ulys Albertas , Vjaters Egils , Polyakov Sergey , Jievaltas Mindaugas , Luz Murilo , Alekseev Boris , Kuss Iris , Le Berre Marie-Aude , Petrenciuc Oana , Snapir Amir , Sarapohja Toni , Smith Matthew Raymond
Published: May 2020

5514

Background: DARO is a structurally distinct androgen receptor inhibitor with a favorable safety profile, approved for treating men with nmCRPC after demonstrating significantly prolonged metastasis-free survival, compared with placebo (PBO), in the phase III ARAMIS trial: median 40.4 vs 18.4 months, respectively (HR 0.41; 95% CI 0.34–0.50; P<0.0001). We report final analyses of OS and prospectively collected, patient-relevant secondary endpoints, and updated safety results. Methods: 1509 patients (pts) with nmCRPC were randomized 2:1 to DARO 600 mg twice daily (n=955) or PBO (n=554) while continuing ADT. Secondary endpoints included OS, and times to pain progression, first cytotoxic chemotherapy, and first symptomatic skeletal event. The OS analysis was planned to occur after approximately 240 deaths. Secondary endpoints were evaluated in a hierarchical order. Results: Final analysis was conducted after 254 deaths were observed (15.5% of DARO and 19.1% of PBO patients). After unblinding at the primary analysis, 170 pts crossed over from PBO to DARO. DARO showed a statistically significant OS benefit corresponding to a 31% reduction in the risk of death compared with placebo. All other secondary endpoints were significantly prolonged by DARO (Table), regardless of the effect of crossover and subsequent therapies on survival benefit. Incidences of treatment-emergent adverse events (AEs) with ≥5% frequency were generally comparable between DARO and PBO, similar to the safety profile observed at the primary analysis. Incidences of AEs of interest (including falls, CNS effects, and hypertension) were not increased with DARO compared with PBO when adjusted for treatment exposure. AEs in the crossover group were consistent with those for the DARO treatment arm. Conclusions: DARO showed a statistically significant OS benefit for men with nmCRPC. In addition, DARO delayed onset of cancer-related symptoms and subsequent chemotherapy, compared with PBO. With extended follow-up, safety and tolerability were favorable and consistent with the primary ARAMIS analysis (Fizazi et al, N Engl J Med 2019;380:1235-46). Clinical trial information: NCT02200614 .[Table: see text]
Final survival results from SPARTAN, a phase III study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Small Eric Jay , Saad Fred , Chowdhury Simon , Oudard Stephane , Hadaschik Boris A. , Graff Julie N , Olmos David , Mainwaring Paul N. , Lee Ji Youl , Uemura Hiroji , De Porre Peter , Smith Andressa , Brookman-May Sabine Doris , Li Susan , Zhang Ke , Rooney Oliver Brendan , Lopez-Gitlitz Angela , Smith Matthew Raymond
Published: May 2020

5516

Background: SPARTAN evaluated APA vs PBO in pts with nmCRPC and a prostate-specific antigen doubling time of ≤ 10 mo receiving androgen deprivation therapy (ADT). At primary end point analysis of metastasis-free survival (MFS), APA significantly improved median MFS by 2 yrs, as well as time to metastasis, progression-free survival, and time to symptomatic progression vs PBO (Smith, et al. NEJM 2018); overall survival (OS) results were immature. SPARTAN was unblinded upon meeting the primary end point; pts still on PBO were allowed to cross over to APA. Final survival results are reported herein. Methods: 1207 nmCRPC pts were randomized 2:1 to APA (240 mg QD) or PBO plus ongoing ADT. At progression, pts could receive open-label sponsor-provided abiraterone acetate + prednisone. After the primary efficacy end point (MFS) was met, 76 PBO pts (19%) crossed over to APA. OS and time to cytotoxic chemotherapy (TTCx) were tested by group sequential testing procedure with O’Brien-Fleming (OBF)-type alpha spending function. Time-to-event end points were analyzed by Kaplan-Meier method and Cox model. A sensitivity analysis for OS, accounting for crossover using a naïve censoring approach, was conducted. Results: With follow-up of 52.0 mo, 428 (of 427 required) OS events had occurred. Median treatment duration: APA, 32.9 mo; PBO, 11.5 mo. Median OS was significantly longer with APA + ADT vs PBO + ADT (73.9 vs 59.9 mo), (hazard ratio [HR], 0.784, Table). APA significantly lengthened TTCx (HR, 0.629). Discontinuation rates (APA vs PBO) due to progressive disease were 42.7% vs 73.9%, and due to adverse events (AE) 15.2% vs 8.4%. Safety was consistent with previous reports; grade 3/4 treatment-emergent (TE) AEs of special interest were rash 5.2%, fractures 4.9%, falls 2.7%, ischemic heart disease 2.6%, hypothyroidism 0%, and seizures 0%. 1 TEAE leading to death (myocardial infarction) was considered potentially APA related. Conclusions: In pts with nmCRPC, APA + ADT significantly improved OS compared with PBO + ADT, with median OS > 6 yr in the APA + ADT group and 14 mo improvement over PBO + ADT. Benefit from APA was observed despite a 19% crossover from PBO. The safety profile of APA was consistent with prior interim analyses. Clinical trial information: NCT01946204 . [Table: see text]
A phase I, open-label, multicenter study to assess the safety, pharmacokinetics, and preliminary antitumor activity of AZD4635 both as monotherapy and in combination in patients with advanced solid malignancies: Results from prostate cancer patients (NCT02740985).
Authors: Lim Emerson A. , Bauer Todd Michael , Patel Manish R. , Falchook Gerald Steven , Karlix Janet L. , Choe Jennifer Hsing , George Daniel J. , Mugundu Ganesh M. , Pilling Elizabeth , Chen Huifang , Linghu Bolan , McGrath Lara , Shao Wenlin , Merchant Melinda S. , Sidders Ben , Sachsenmeier Kris F. , Pouliot Gayle Pageau , Drake Charles G. , Bendell Johanna C.
Published: May 2020

5518

Background: AZD4635 inhibits adenosine 2a receptor (A2aR) signaling and improves immune activation and anti-tumor activity in preclinical models. This phase I study assessed the safety, pharmacokinetics, pharmacodynamics and efficacy of AZD4635 monotherapy (mono) and in combination (combo) with durvalumab (durva) in patients (pts) with refractory solid tumors. Here we present data for immune checkpoint-naïve pts with metastatic castrate-resistant prostate cancer (mCRPC). Methods: Pts with refractory mCRPC received AZD4635 mono (75 mg or 100 mg QD oral nanosuspension [(RP2D]) or in combination (75 mg or 100mg QD) with durva 1.5g IV q4wk. Results: Between 30Aug16 and 20Jun19 (data cutoff [DCO]) 94 mCRPC pts were treated with mono (n = 49) or combo (n = 45): median age 70.5 yrs; ECOG 0-1 = 99%. The median number of prior treatment regimens was 5 (range = 1-10); 61% of pts (57/94) had prior chemotherapy, 90% had prior new hormonal therapy. PK data suggest AZD4635 concentrations at 75-100 mg QD are above the in vitro IC50 for A2aR inhibition throughout the dosing interval. Modeling predicts 80-90% A2aR occupancy at steady state for doses at ≥75 mg QD. Most common treatment-related AEs ( > 10%) were nausea, vomiting, fatigue, decreased appetite, dizziness, and diarrhea. At the DCO in this ongoing study, 70 pts were evaluable for response by RECIST v1.1 (mono = 33, combo = 37). Confirmed response occurred in 8 pts: mono = ORR 6.1% (2PRs) and combo = 16.2% (2CRs, 4PRs). The duration of response across cohorts ranged from 1-18.5 mo (5 pts ongoing). PSA response (defined as ≥50% decrease from baseline of ≥1ng/ml) was observed in 6.4% (3/47 pts; 95% CI, 1.3-17.5) of mono-treated patients and 20% (9/45 pts; 95% CI, 9.6-34.6) of combo-treated patients. Patients with high adenosine (ADO) gene expression signature (N = 46) in peripheral blood, showed a median PFS of 21 weeks v. 8.7 weeks in ADO signature low patients (N = 46) (HR 0.5, CI 0.3-0.9) (DCO 20Jun19). In addition, baseline TCR clonality and diversity were linked with response. Conclusions: In mCRPC pts, AZD4635 alone or in combination with durva was tolerable and associated with clinical benefit. A mCRPC phase II trial is ongoing with continued exploration of predictors of response to treatment. Clinical trial information: NCT02740985 .
Ability of cell-cycle progression score to predict risk for progression to metastatic disease and disease-specific mortality in prostate cancer patients after prostatectomy.
Authors: Swanson Gregory P. , Stone Steven , Lenz Lauren , Cohen Todd
Published: May 2020

5524

Background: Prostate cancer treatment aims to prevent metastatic disease (METS) and disease-specific mortality (DSM). A major challenge is to identify those at highest risk so additional intervention can be initiated earlier when it has a better chance of success. Pathologic parameters alone have limited ability to predict METS and DSM, but data suggests biomarkers can improve risk discrimination. Methods: Eligible patients had: (1) prostate cancer treated with radical prostatectomy (RP; 1988-1995); (2) available tissue for cell-cycle progression (CCP) testing that resulted in a valid score; (3) preoperative prostate-specific antigen (PSA); (4) no neoadjuvant therapy; and (5) clinical follow-up (N = 360). Cancer of the prostate risk assessment post-surgical (CAPRA-S) was combined with CCP into a combined cell-cycle risk score (CCR = 0.38 × CAPRA-S + 0.57 × CCP). Results: Median follow-up was 23.5 years for patients alive at last follow-up. Overall, 11% (41/360) developed METS and 9% (33/360) had DSM. CCP score added significant information to CAPRA-S when predicting METS (p = 0.001) and DSM (p = 0.001). CCR score was also a significant predictor of METS and DSM (p-values < 1×10−8). CCP and CCR scores were prognostic of METS in patients with rising post-RP PSA. Of patients with biochemical recurrence (BCR), 25% (41/163) developed METS. CAPRA-S alone was predictive of these events (p = 0.01) but was significantly improved with the addition of CCP (Hazard Ratio [HR] = 1.69 [95% Confidence Interval (CI) 1.13, 2.52], p = 0.014). CCR was also highly prognostic (HR = 1.56 [95% CI 1.20, 2.03], p = 0.001). CCR score discriminated risk of METS both post-RP and after post-RP BCR (Table). Conclusions: Overall, the CCR score significantly predicted METS and DSM in prostate cancer post-RP and was also highly prognostic in those with a post-RP rising PSA. It is therefore a useful tool for determining who is at greatest risk of treatment failure and may benefit from earlier intervention. [Table: see text]
Association of polymorphisms in androgen production, uptake, and conversion chain (APUC) genes with mortality of prostate cancer patients.
Authors: McSweeney Sean Thomas , Prizment Anna , Pankratz Nathan , Joshu Corinne E , Platz Elizabeth A. , Ryan Charles J.
Published: May 2020

5528

Background: Genes involved in APUC may affect prognosis in PC. We tested the association of four SNPs involved in the APUC pathway: hydroxy-delta-5-steroid dehydrogenase, 3 beta-and steroid delta-isomerase 1 ( HSD3B1), 5α reductase enzyme ( SRD5A), and solute carrier organic ion ( SLCO2B1) with all-cause and PC mortality 596 in the Atherosclerosis Risk in Communities (ARIC) study. Methods: Between 1987 & 2015 596 men were diagnosed with PC. Median age at diagnosis was 70 (range 53-86) years; 21% of all PC patients were African American. After diagnosis, follow-up was median 8.4 years (max 26.7 years) until PrC death (N = 60), death from any cause (N = 253), or end of 2015. SNPs were genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0 and imputed to the 1000 Genomes Phase 3 reference panel. To examine survival, we used Kaplan-Meier curves and Cox proportional hazards regression. Hazard ratios (HR) and 95% confidence intervals (CI) were adjusted for age, field center, stage and grade at diagnosis. We also controlled for confounding by ancestry by adjusting for genetic principal components. The analyses were conducted in all PrCa patients and in Whites PrCa patients only. Polymorphisms tested included rs1047303 (A = > C, also called 1245C); rs523349 (C = > G); and rs1789693 (A = > T) and rs12422149 (G = > A), located in the aforementioned genes. Results: The A allele for SLCO2B1 rs1789693 (A = > T) was significantly associated with an increased risk of PC mortality (versus T): multivariable-adjusted HRs (95%CI) were (2.06, 1.14-3.74; p = 0.02) and all-cause mortality (1.29, 1.00-1.66; p = 0.05) among Whites. The associations were similar when Whites and African-Americans were combined and when accounting for ancestry. The C allele for HSD3B1 rs1047303 (C = > A) was not statistically significantly associated with either PC or all-cause mortality in the whole cohort (which included localized disease), although HRs were increased for men diagnosed with stage 4 disease (n = 35) in both additive and dominant models. For carriers of the C allele (gain of function) versus AA, HRs were 5.32 (1.16-24.33; p = 0.03) and 6.13 (1.51-24.86; p = 0.01) for PC and all-cause mortality, respectively. All associations with SRDA2 (rs12422149) and SLCO2B1 (rs12422149) were not significant. Conclusions: The gain of function allele in HSD3B1 rs1047303 (1245C) was associated with increased PC and all-cause mortality in men diagnosed with metastatic PC, paralleling prior findings. Associations with SLCO2B1 SNP rs1789693 require validation in larger studies.
Prevalence and tissue concordance of BRCA2 copy number loss evaluated by single-cell, shallow whole genome sequencing of circulating tumor cells (CTCs) in castration-resistant prostate cancer (CRPC).
Authors: Barnett Ethan , Schonhoft Joseph , Schultz Nikolaus D. , Lee Jerry , Zaidi Samir , Abida Wassim , Carmichael Taylor , Dago Angel E. , Solit David B. , Wenstrup Rick , Scher Howard I.
Published: May 2020

5531

Background: Genomic studies have shown that up to 25% of prostate cancer tissue specimens harbor alterations in DNA Damage Repair (DDR) genes, which may sensitize the tumor to poly ADP-ribose polymerase inhibitors (PARPi). Trials evaluating PARPi in patients with DDR deficiencies have shown varied response rates and differences regarding which genomic alterations predict for sensitivity to these agents, with the majority of objective responses seen in BRCA2-altered tumors. These results highlight the need to develop biomarker assays which can predict benefit from PARPi therapy. Tissue and cell-free DNA (cfDNA) have been the most utilized sources of tumor material for analysis in this setting, but success rates of obtaining sufficient tumor for analysis from bone are low and detecting tumor-derived copy number variants (CNVs) in cfDNA is challenging. Circulating tumor cells (CTCs) represent an alternate source of genetic information, for which assays are available to isolate and sequence individual cells in a manner that eliminates background noise from stroma and healthy cells, while capturing inter-cellular heterogeneity. Methods: Blood samples, collected from 138 progressing metastatic CRPC patients within 30 days of a pre-treatment biopsy intended for sequencing using MSK-IMPACT, were sent to EPIC Sciences for CTC analysis. Detected CTCs underwent single cell, low pass whole genome sequencing. Prevalence and concordance of BRCA2 copy-loss, regardless of whether single copy or homozygous, was compared in matched tissue and CTC samples. Results: BRCA2 copy-loss was identified in 21% (23/108) and 50% (58/115) of successfully sequenced tissue and CTC samples, respectively. In the 58 patients with CTC-detected BRCA2 loss, BRCA2 loss was detected in 36% (220/565) of the sequenced CTCs, representing a median of 46% (range 4-100%) of CTCs found in each individual sample. When both sequencing assays were successful, BRCA2 loss was detected in CTCs in 84% (16/19) of the tissue-positive cases, whereas tissue sequencing detected BRCA2 loss in 35% (16/46) of CTC-positive cases. Conclusions: Data from this study supports the notion that single-cell CTC sequencing can detect BRCA2 copy-loss at a high frequency, including cases that were negative in tissue, while also characterizing inter-cellular heterogeneity. Further studies will investigate whether CTC BRCA2 copy-loss can predict the likelihood of response to PARPi.
Molecular determinants of outcome for metastatic castration-sensitive prostate cancer (mCSPC) with addition of apalutamide (APA) or placebo (PBO) to androgen deprivation therapy (ADT) in TITAN.
Authors: Feng Felix Y , Thomas Shibu , Aguilar-Bonavides Clemente , Gormley Michael , Agarwal Neeraj , Attard Gerhardt , Wyatt Alexander William , Davicioni Elai , Ricci Deborah S. , Lopez-Gitlitz Angela , Larsen Julie S. , Chowdhury Simon , Chi Kim N.
Published: May 2020

5535

Background: In TITAN, addition of APA to ADT improved radiographic progression-free survival (rPFS) and overall survival (OS) versus PBO plus ADT in patients (pts) with mCSPC. In this post hoc analysis, we performed transcriptome-wide profiling of tumor samples and assessed association of molecular subtypes with rPFS. Methods: The DECIPHER platform (Decipher Biosciences, Inc.) was used to assess gene expression in archival primary prostate tumors from TITAN. Samples were classified into high versus low to average risk of metastases (DECIPHER genomic classifier [GC] > 0.6 and ≤ 0.6, respectively), basal and luminal A/B (PAM50 classifier), and androgen receptor activity (AR-A) signature high and low. Associations between subtypes with rPFS were assessed with Cox proportional hazards model. Results: The biomarker population included 222 pts (APA, 110; PBO, 112). Benefit in rPFS from APA in the biomarker population (HR [95% CI]; p value; 0.49 [0.31-0.78]; 0.002) resembled that in the overall study population (0.49 [0.40-0.61]; < 0.0001). The majority of TITAN pts had GC high scores (n = 166, 75%). GC high risk subtype in the PBO group had poorer prognosis for rPFS than GC low to average risk subtype (median rPFS 18.2 mos for GC high vs not reached [NR] for GC low to average, 0.28 [0.11-0.69]; 0.006), but there was no difference in prognosis between high and low to average GC risk subtypes in the APA group (GC high NR vs GC low to average NR; 0.81 [0.35-1.89]; 0.625). Pts were further stratified based on basal/luminal and AR-A signatures. Basal (n = 112, 50%) and AR-A low (n = 96, 43%) subtypes, known to be nonresponsive to ADT, both showed significant benefit from APA vs PBO (0.30 [0.16-0.57]; < 0.001 and 0.25 [0.12-0.52]; < 0.001, respectively). The majority of AR-A low subtype (74%, 71/96) overlapped with basal subtype. Further conclusions for risk of rPFS in GC low, luminal, and AR-A high subtypes and OS across all subtypes will be assessed as more events occur. Conclusions: In TITAN, addition of APA to ADT improved rPFS for all subtypes of pts with mCSPC. APA overcame the poor prognosis of GC high risk subtype and prolonged rPFS in ADT-resistant AR-A low and basal molecular subtypes, suggesting APA is beneficial especially for the highest risk molecular subtypes. Clinical trial information: NCT02489318 .
Prostate-specific antigen (PSA) kinetics in patients (pts) with advanced prostate cancer treated with apalutamide: Results from the TITAN and SPARTAN studies.
Authors: Chi Kim N. , Saad Fred , Chowdhury Simon , Graff Julie N , Agarwal Neeraj , Oudard Stephane , Li Gang , Lopez-Gitlitz Angela , Larsen Julie S. , McCarthy Sharon Anne , Mundle Suneel , Smith Matthew Raymond , Small Eric Jay
Published: May 2020

5541

Background: The phase III TITAN and SPARTAN studies demonstrated improved outcomes with the addition of apalutamide (APA) to androgen deprivation therapy (ADT); outcomes included prolonging overall survival and radiographic progression-free survival (rPFS) in metastatic castration-sensitive prostate cancer (mCSPC) in TITAN, and metastasis-free survival (MFS) in nonmetastatic castration-resistant PC (nmCRPC) in SPARTAN. A post hoc analysis of PSA kinetics in pts from both studies is reported. Methods: Baseline PSA at randomization, time to PSA nadir, and proportion of pts achieving a PSA decline of ≥ 90% (PSA90) and of pts achieving a PSA ≤ 0.2 ng/mL at 3 and 12 months and at any time after treatment in the APA arms of the TITAN and SPARTAN studies were evaluated. Within each study, rPFS/MFS were compared between pts achieving a PSA90 or PSA ≤ 0.2 ng/mL response vs not. Results: 525 TITAN pts and 806 SPARTAN pts treated with APA were included in the analysis. Median baseline PSA, time to PSA nadir, median PSA nadir, and maximum percentage changes from baseline PSA are shown in the table. PSA90 and confirmed PSA ≤ 0.2 ng/mL were evident as early as 3 months in both TITAN and SPARTAN, and percentage of confirmed response continued to increase at 12 months. Pts treated with APA who achieved PSA90 were at lower risk of rPFS events in TITAN and of MFS events in SPARTAN, with a hazard ratio (95% confidence interval) of 0.46 (0.321-0.653) and 0.36 (0.271-0.489) in each respective study (both p < 0.0001), compared with APA pts who did not achieve PSA90. Pts with confirmed PSA ≤ 0.2 ng/mL had similar rPFS and MFS benefits. Conclusions: Pts with advanced PC, whether mCSPC or nmCRPC, treated with APA + ADT demonstrated rapid PSA declines that continued over time. There was a high rate of pts with PSA90 and with PSA ≤ 0.2 ng/mL responses, with a majority of pts reaching PSA90 by 12 months. Pts achieving PSA90 and/or PSA nadir of ≤ 0.2 ng/mL had a prolonged rPFS and MFS in TITAN and SPARTAN, respectively. Clinical trial information: NCT02489318; NCT01946204 . [Table: see text]
Efficacy of enzalutamide (ENZA) + androgen deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC) by pattern of metastatic spread: ARCHES post hoc analyses.
Authors: Shore Neal D. , Armstrong Andrew J. , Szmulewitz Russell Zelig , Petrylak Daniel Peter , Holzbeierlein Jeffrey , Villers Arnauld , Azad Arun , Alcaraz Antonio , Alekseev Boris , Iguchi Taro , Gomez-Veiga Francisco , Rosbrook Brad , Lee Ho-Jin , Haas Gabriel P. , Stenzl Arnulf
Published: May 2020

5547

Background: ENZA + ADT significantly reduced the risk of radiographic progression or death in men with mHSPC (NCT02677896). Here, we assess how pattern of metastatic spread impacts the efficacy of ENZA + ADT in patients enrolled in ARCHES. Methods: Patients with mHSPC were randomized 1:1 to ENZA (160 mg/day) + ADT or placebo (PBO) + ADT, stratified by disease volume and prior docetaxel treatment. The primary endpoint was radiographic progression-free survival (rPFS). Secondary endpoints included time to prostate-specific antigen (PSA) progression, time to first symptomatic skeletal event (SSE), time to castration resistance, and time to initiation of new antineoplastic therapy. Post hoc analyses were performed by pattern of metastatic spread at study entry. Results: Of the overall population with known metastases at screening (n=1146), the largest patient subgroups were those with bone metastases only (n=513) and those with bone and soft-tissue metastases only (n=351); there were fewer M0 patients or patients with soft-tissue metastases only (n=154) and patients with visceral ± bone metastases (n=128). ENZA + ADT reduced the risk of rPFS and other secondary endpoint measures versus PBO + ADT across all subgroups, with greater relative efficacy observed in patients without visceral metastases (Table). Conclusions: ENZA + ADT provides improvements in rPFS and other secondary endpoints versus PBO + ADT in patients with mHSPC regardless of pattern of metastatic spread, particularly in patients without visceral metastases. These results highlight the importance of patient/physician discussion regarding the use of ENZA in the treatment of mHSPC. Clinical trial information: NCT02677896 . [Table: see text]
Pembrolizumab (pembro) plus docetaxel and prednisone in patients (pts) with abiraterone acetate (abi) or enzalutamide (enza)-pretreated metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-365 cohort B efficacy, safety and, biomarker results.
Authors: Sridhar Srikala S. , Kolinsky Michael Paul , Gravis Gwenaelle , Mourey Loic , Piulats Rodriguez Jose Maria M. , Romano Emanuela , Berry William R. , Gurney Howard , Retz Margitta , Appleman Leonard Joseph , Boegemann Martin , De Bono Johann S. , Joshua Anthony M. , Emmenegger Urban , Conter Henry Jacob , Laguerre Brigitte , Wu Haiyan , Qiu Ping , Schloss Charles , Yu Evan Y.
Published: May 2020

5550

Background: Pembro + docetaxel and prednisone (cohort B) has shown antitumor activity in pts with mCRPC in the phase I/II KEYNOTE-365 study (NCT02861573). Updated efficacy and safety and new biomarker data from cohort B are reported. Methods: Pts who received at least 4 wk of abi or enza in the prechemotherapy mCRPC setting and whose disease progressed within 6 mo of screening were eligible. Pts received pembro 200 mg IV + docetaxel 75 mg/m2 IV Q3W and prednisone 5 mg orally twice daily. Primary end points were PSA response rate (PSA decrease ≥50%; confirmed by a second value ≥3 weeks later), ORR per RECIST v1.1 by blinded independent central review, and safety. Key secondary end points were DCR per RECIST v1.1 (CR+PR+SD or non-CR/non-PD ≥6 mo), DOR per RECIST v1.1, radiographic PFS (rPFS) per PCWG-modified RECIST, and OS. Biospecimens (blood, tissue) were collected for biomarker analysis, including tissue PD-L1 expression, androgen receptor variant 7 (AR-v7) expression in circulating tumor cells, and a T-cell-inflamed gene expression profile (GEP). Results: Of 105 enrolled pts, 104 were treated, and 50% had measurable disease. Median (range) time from enrollment to data cutoff was 19.9 mo (1.4-27.8) for all pts and 21.8 mo (17.9-27.8) for pts with ≥27 wks follow-up (n=72). Confirmed PSA response rate was 28% in 103 pts with a baseline PSA assessment. Median time to PSA progression was 6.2 mo (95% CI, 3.7-7.4). In pts with measurable disease and ≥27 wks follow-up (n=39), ORR was 18% (7/39, all PRs) and DCR was 51%. Median DOR was 6.7 mo (range, 3.4-9.0+ [+ indicates ongoing responder]); 5 pts had a response for ≥6 mo. In all pts, median rPFS was 8.3 mo (95% CI, 7.6-10.1) and OS was 20.4 mo (16.9-NR). At 6 mo, the rPFS rate was 72.8% and OS rate was 95.3%. Treatment-related AEs (TRAEs) occurred in 96% of all pts; most frequent were alopecia (39%), diarrhea (38%), and fatigue (38%). Grade 3-5 TRAEs occurred in 40% of pts; 2 pts died of TRAEs (pneumonitis). Overall, 24% of pts were PD-L1+ (combined positive score ≥1). Of 57 pts with AR-v7 data, 17.5% were AR-v7+, 77% were AR-v7−, and 5% were undetermined. GEP was not significantly associated with ORR or PSA response. Conclusions: Pembro + docetaxel and prednisone showed activity in pts with abi or enza-pretreated mCRPC. Safety of the combination was consistent with the known profiles of the individual agents. A phase 3 study of this combination is ongoing (KEYNOTE-921, NCT03834506). Clinical trial information: NCT02861573 .
Updated results of a phase I/II prospective dose escalation trial evaluating safety and efficacy of combination 177Lu PSMA 617 and idronoxil in men with mCRPC post androgen signalling inhibition and taxane chemotherapy (LuPIN trial).
Authors: Emmett Louise , Pathmanandavel Sarennya , Crumbaker Megan , Rofe Christopher , Yam Andrew On Wah , Ho Bao , Chan Wai Ling , Sharma Shikha , Keane Joanne , Hickey Adam James , Fullard Karen , Kongrak Kamonwan , Ratnayake Lalith , Violet John A. , Azad Arun , Eu Peter , Nguyen Andrew , Joshua Anthony M.
Published: May 2020

5557

Background: There is no established standard of care post cabazitaxel in men with mCRPC. Ongoing trials in 177LuPSMA-617 have demonstrated good efficacy and safety, but synergistic combinations may further improve treatment responses. Idronoxil (NOX66) inhibits external NADH oxidase type 2 with downstream pro-apoptotic actions including radio-sensitization. Herein we present updated results and an additional cohort of a prospective single arm phase I/II dose escalation/expansion trial of LuPSMA-617 and NOX66 in mCRPC. Methods: Men with progressive mCRPC post androgen signalling inhibition (ASI) and 2 lines of taxane chemotherapy were considered eligible. Key inclusion criteria included PSMA PET/CT intensity SUV max > 15 with no discordant disease on FDG PET/CT, Hb >10, Platelets >100 and GFR >40mls/min. Enrolled patients received up to 6 doses of 177 Lu-PSMA 617 (7.5Gbq) day 1 every 6 weeks in combination with NOX66 days 1-10 each cycle. Cohort 1 (n=8) received 400mg NOX66. Cohorts 2 and 3 subsequently received 800mg and 1200mg of NOX66, respectively, following safety reviews. Data regarding safety, efficacy, pain scores, and QOL were collected. Results: 32 men were enrolled in cohorts 1&2 (November 2017 – June 2019) and 24 in cohort 3 (August 2019-February 2020). To date there have been no dose-limiting toxicities. Data for cohort 3 are immature. For cohorts 1 & 2: 31/32 men received ≥2 cycles, with 12/32 (47%) completing 6 cycles. Any PSA response was seen in 84% (27/32), with a PSA response > 50% in 62.5% (20/32). Median PSA PFS is 6.1 months Of men with increased baseline pain scores ≥3 (24/32), 50% (12/24) had a clinically significant reduction in pain indicators. Adverse events are summarized below. Updated results for cohorts 1 and 2 and preliminary results of cohort 3 will be presented. Conclusions: Combination LuPSMA-617 + NOX 66 appears safe and efficacious in men with heavily pre-treated end stage mCRPC. Clinical trial information: ACTRN12618001073291 .
Phase I dose-escalation study of PSMA-targeted alpha emitter 225Ac-J591 in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Tagawa Scott T. , Osborne Joseph , Fernandez Escarleth , Thomas Charlene , Niaz Muhammad Junaid , Ciriaco Amy , Vallabhajosula Shankar , Vlachostergios Panagiotis J. , Molina Ana M. , Sternberg Cora N. , Singh Sharon , Babich John , Nanus David M. , Ballman Karla V. , Bander Neil Harrison
Published: May 2020

5560

Background: Antibodies (Abs) or small molecules can target PSMA with different biodistribution. Certain sites of PSMA expression (e.g. salivary/lacrimal glands, kidneys, small bowel) are not accessible to Abs. Given radiosensitivity of PC and potency of alpha emitters plus the ability to minimize targeting off tumor PSMA+ sites with J591, we performed a 1st in human study of 225Ac-J591. Methods: Men with progressive mCRPC following at least 1 potent AR-pathway inhibitor (ARPI) and chemo (or unfit/refuse) without limit of # prior therapies (Ra-223 and 177Lu-PSMA allowed) with ECOG PS 0-2 and adequate organ function were eligible. Baseline 68Ga-PSMA11 PET was performed, but not used for eligibility. Initially 1-subject cohorts treated until transition to 3+3 at dose level 5 (predicted by dosimetry to have moderate toxicity) with a single infusion of 225Ac-J591 (13.3 KBq/kg with planned escalation up to 93.3 KBq/kg). Dose-limiting toxicity (DLT) defined as attributable grade (Gr) 4 heme toxicity or Gr 3/4 non-heme tox. Imaging, genomic, patient-reported outcomes (PRO), and immune correlates embedded. Results: 22 men treated on 7 dose levels; median age 72.5 (range 58-89), PSA 147 (5-7168); 82% with >2 prior ARPI, 64% chemo, 23% Ra-223, 55% 177Lu-PSMA. 1 (5%) CALGB (Halabi) good prognostic risk, 10 (45%) intermed, 11 (50%) poor risk. 1 of 6 in cohort 6 (80 KBq/kg) had DLT (Gr 4 anemia and platelets); no others had attributable Gr > 2 non-heme or Gr > 3 heme AE (including 0 of 6 at the highest dose level 93.3 KBq/Kg). Gr 1/2 AE’s: 17 (77%) fatigue, 11 (50%) pain flare, 10 (45%) anemia (+1 Gr 3), 10 (45%) platelets, 6 (27%) nausea, 6 (27%) xerostomia (5 of 6 with prior 177Lu-PSMA), 5 (23%) neutropenia, 4 (18%) AST elevation. Despite prior treatment including 177Lu-PSMA and no selection for PSMA expression, 14 (64%) with any PSA decline, 9 (41%) with > 50% PSA decline. 15 (68%) had initial PSA rise followed by decline from peak (delayed effect). 2 with response > 1 year despite prior 177Lu-PSMA. Of 15 with paired baseline and 12-wk CTC counts, 8 declined, 4 remained undetectable, 3 increased. In subset with complete PRO data (baseline to 12 wks), pain was improved or absent by BPI-SF in 63% and by FACT-P in 89%. Social and emotional well-being domains of FACT-P improved or stabilized in majority; physical well-being improved in most responders. Conclusions: Alpha-emitter 225Ac targeting PSMA via J591 Ab is tolerable with early evidence of clinical activity in a pre-treated population with favorable PRO’s. Enrollment to expansion cohort being completed. Clinical trial information: NCT03276572 .
Results of the randomized phase II study of sipuleucel-T (Sip-T) +/- Radium-223 (Ra-223) in men with bone-metastatic castration resistant prostate cancer.
Authors: Marshall Catherine Handy , Park Jong Chul , Fu Wei , Wang Hao , DeWeese Theodore L. , King Serina , Afful Michaella , Hurrelbrink Julia , Manogue Charlotte , Cotogno Patrick , Moldawer Nancy P. , Barata Pedro C. , Drake Charles G. , Posadas Edwin Melencio , Armstrong Andrew J. , Sartor A. Oliver , Antonarakis Emmanuel S.
Published: May 2020

5563

Background: It has been suggested that immune modulation can be augmented by radiation, possibly by enhancing tumor-antigen display. SipT-induced antigen-specific immune responses in mCRPC patients correlate with survival. We hypothesized that the combination of Ra223 and SipT would enhance SipT-related immune response and improve outcomes compared to SipT alone. Methods: Patients with asymptomatic, bone-predominant mCRPC, without visceral mets >1.0 cm, were randomized (1:1) to SipT alone or with 6 doses of Ra223 (NCT02463799). Men in the SipT+Ra223 arm started SipT between the 2nd and 3rd dose of Ra223. The primary immunologic endpoint was PA2024-specific T-cell proliferation 6 wks after the first SipT infusion. Secondary immune endpoints were PA2024-specific ELISPOT response, PAP-specific proliferation and ELISPOT, humoral responses against both antigens, and antigen spread. Clinical endpoints were radiographic PFS, PSA response (≥50% decline), AlkPhos response (≥30% decline), and safety. Results: 32 men were randomized, 16 per arm. Baseline characteristics in SipT+Ra223 and SipT arms were similar: age (median 71 vs. 70 yrs), Gleason (8-10: 69% vs. 69%), baseline PSA (med 25 vs. 33 ng/mL), AlkPhos (med 89 vs. 92 U/L) and ECOG score (≥1: 31% vs. 19%). There was no significant difference in prior use of abi/enza (38% vs. 44%), or chemo (0% vs. 25%). At 6 weeks, absolute PA2024-specific T-cell proliferation was 2.1-fold higher in the Sip-T arm compared to the SipT+Ra223 arm (35.6 vs. 16.6; P=0.03) and remained higher through week 26. Relative to baseline, the 6-week PA2024-specific T-cell proliferation change was 3.6 times greater in the Sip-T arm compared to the SipT+Ra223 arm ( P=0.007) and remained higher through week 14. There were no significant differences in antigen spread or humoral responses. Median radiographic PFS was longer in the SipT+Ra223 arm (9.3 vs. 3.2 months; HR 0.26, 95% CI 0.11–0.61; P=0.007). PSA and AlkPhos responses were better in the SipT+Ra223 arm (PSA50: 5/15=33% vs. 0/14=0%; P=0.04; AlkPhos30: 9/15=60% vs. 1/15=7%; P=0.01). There was no difference in SREs (13% vs. 7%). Conclusions: SipT+Ra223 was associated with improved clinical outcomes and a higher rate of PSA responses compared to SipT alone, although surprisingly, the SipT arm demonstrated higher peripheral PA2024-specific T-cell proliferation. Since neither agent reliably induces PSA responses alone, these data suggest a synergistic effect of the combination. Larger randomized studies of this combination are planned. Clinical trial information: NCT02463799 .