bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of prior docetaxel (DOC) treatment on efficacy and safety of apalutamide (APA) plus androgen deprivation therapy (ADT) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) from TITAN.
Authors: Chi Kim N. , Merseburger Axel S. , Ozguroglu Mustafa , Chowdhury Simon , Bjartell Anders , Chung Byung , Pereira de Santana Gomes Andrea Juliana , Given Robert , Juárez Álvaro , Uemura Hirotsugu , Ye Dingwei , Karsh Lawrence Ivan , Gartrell Benjamin Adam , Brookman-May Sabine D. , Mundle Suneel , McCarthy Sharon Anne , Lefresne Florence , Rooney Oliver Brendan , Bhaumik Amitabha , Agarwal Neeraj 
Published: February 2022

89 Background: Addition of androgen receptor signaling inhibitors to ADT + DOC has been shown to improve clinical outcomes in pts with mCSPC. TITAN, a placebo-controlled phase 3 study, showed that APA + ADT improved overall survival (OS) and other clinical outcomes in mCSPC (Chi, J Clin Oncol 2021). This post hoc analysis of TITAN evaluated outcomes in pts who had received DOC prior to treatment with APA + ADT versus those who did not. Methods: In TITAN, 1052 pts were randomized 1:1 to APA (240 mg QD) or placebo added to ongoing ADT. We assessed radiographic progression-free survival (rPFS), OS, and time to prostate-specific antigen (PSA) progression in pts receiving DOC and ADT prior to adding APA vs those receiving only ADT plus APA. Outcomes by prior DOC were also assessed in pts with high- or low-volume disease at randomization (baseline [BL]) per adapted CHAARTED criteria, or those with matched BL characteristics. A Cox proportional hazards model was used to derive hazard ratios (HRs) and p values. rPFS was assessed using the first interim analysis cutoff (23 mo median follow-up); OS and time to PSA progression were assessed using the final analysis cutoff (44 mo median follow-up). Results: A total of 58/525 (11%) pts from the APA + ADT group had received DOC prior to randomization: 76% (n = 44) had high-volume disease, 62% (n = 36) had bone-only metastases, 16% (n = 9) had visceral metastases, and 59% (n = 34) had > 10 bone lesions. In the overall APA-treated population and in the subset of pts with high-volume disease, OS, rPFS, and time to PSA progression were similar in those who received prior DOC and those who did not (Table). Pts with low-volume disease also had similar results, although the number of pts was small. Clinical outcomes in pts with matched BL characteristics (including PSA and time from initial diagnosis to randomization, among others) were similar regardless of prior use of DOC (Table). The safety profile of APA was not substantially different between pts with or without prior DOC. Limitations of this analysis include lack of data on tumor volume and other disease characteristics at the initiation of prior DOC treatment; interpretation was based on small number of pts with prior DOC (only 11% of TITAN pts), most notably in the rPFS analysis. Conclusions: Prior use of DOC in pts with mCSPC did not further improve clinical benefits of APA + ADT in TITAN. Clinical trial information: NCT02489318. [Table: see text]
Impact of concomitant cardiovascular therapies on efficacy and safety of relugolix verus leuprolide in men with advanced prostate cancer: Subgroup analysis from the phase 3 HERO study.
Authors: Shore Neal D. , George Daniel J. , Mehlhaff Bryan Allyn , Cookson Michael , Saltzstein Daniel , Tutrone Ronald F. , Brown Bruce , Lu Sophia , Lee Jina , Hanson Sarah , Saad Fred 
Published: February 2022

101 Background: Cardiovascular (CV) events are the leading cause of death in prostate cancer. Men with prostate cancer are likely to have CV risk factors and CV-related concomitant medications. In the phase 3 HERO study, a 54% lower incidence of major adverse cardiac events was reported in men treated with the oral GnRH receptor antagonist relugolix vs leuprolide. Herein, we characterize the impact of concomitant CV therapies on efficacy and safety in the HERO study. Methods: In HERO, 930 men with advanced prostate cancer were randomized 2:1 and treated with relugolix (120 mg orally once daily [after single 360 mg loading dose] or leuprolide (injections every 3 months) for 48 weeks. Subgroups analyzed included men who received antihypertensives, antithrombotics, or lipid-modifying therapies, as well as the most common drug classes (>10%) and single most common agent within each class. Assessments included sustained testosterone suppression to castrate levels (<50 ng/dL) through 48 weeks and safety parameters (adverse events). Results: Antihypertensives, antithrombotics, and lipid modifying agents were utilized by 52.7%, 39.1%, and 39.6% of men in the HERO trial, respectively (table). In the main subgroups, point estimates for sustained castration rates were consistent with the overall estimates of relugolix and leuprolide observed in the overall population (table). Sustained castration rates were also consistent for men taking the most common drug classes (table) and individual agents in each class (losartan [n=103]: relugolix, 95.4% vs. leuprolide, 80.6%; amlodipine [n=229]: 97.2% vs. 85.5%; metoprolol [n=88]: 95.7% vs. 86.9%; acetylsalicylic acid [n=259]: 97.0% vs. 92.1%; clopidogrel [n=43]: 96.4% vs. 86.7%; simvastatin [n=78]: 98.0% vs. 87.3%). Incidence and types of adverse events were similar among men who received antihypertensives, antithrombotics, and lipid modifying agents during the trial. Conclusions: In the HERO trial, relugolix suppressed testosterone and was generally well tolerated when given with concomitant CV agents, with results consistent with those of the overall population. Clinical trial information: NCT03085095. [Table: see text]
The immunocytokine M9241 in the treatment of prostate cancer (PCa): Clinical and immune data from a phase 1 study.
Authors: Meininger Luke , Madan Ravi Amrit , Toney Nicole , Donahue Renee Nicole , Gatti-Mays Margaret Elena , Strauss Julius , Karzai Fatima , Bilusic Marijo , Marte Jennifer L. , Cordes Lisa M. , Redman Jason , Floudas Charalampos S. , Pastor Danielle M. , Figg William Douglas , Dahut William L. , Schlom Jeffrey , Gulley James L. 
Published: February 2022

127 Background: Interleukin-12 (IL-12) is a proinflammatory cytokine that plays a critical role in regulating the transition from innate to adaptive immunity but has toxicity with systemic administration. M9241 is an immunocytokine composed of 2 IL-12 heterodimers, each fused to one of the H-chains of the NHS76 antibody, which has affinity for both single and double stranded DNA. Thus, M9241 targets delivery to regions of tumor necrosis where DNA has become exposed. NCT01417546, a phase I trial of M9241 at escalating doses, established safety and dosing (Strauss J et al, CCR 2019). This was the first use of M9241 in human subjects with solid tumors including PCa. Methods: Nine patients (pts) with PCa enrolled in the phase 1 study, not all of which were presented previously. M9241 was given subcutaneously every 4 weeks (0.1-21.8mcg/kg) or every 2 weeks (12-16.8mcg/kg). PSA declines and immune responses were evaluated including systemic cytokine levels and 30 markers on 158 circulating immune cell subsets. Results: Nine PCa pts were treated with NHS-IL12 and 8 were evaluable for response, including 6 pts with biochemical recurrence and 2 with metastatic castration resistant prostate cancer (one patient discontinued the study treatment after 1 dose due to grade 3 elevation in ALT). There were no adverse events (AEs) of grade >4. Additional grade 3 toxicities included one each of: leukopenia, neutropenia and lymphopenia. The most common AEs of any grade were lymphopenia (77.8%), fatigue (55.6%), and ALT elevation (55.6%). 5 of 8 (62.5%) had PSA declines ranging from 8-42%. After treatment with M9241, evaluable pts had increases in systemic IL-10, TNF and INFg. Additional immune changes included increases in activated subpopulation of natural killer (NK) cells, consistent with the phase 1 experience. Conclusions: M9241 was found to be safe and well tolerated in PCa pts. PSA declines occurred in 5 of 8 evaluable pts. As with the phase 1 study, increases in NK subpopulations were seen in the small number of evaluable pts. These preliminary findings of a necrosis-targeting immunocytokine will be evaluated further in combination studies with cytotoxic therapy. M9241 is currently being evaluated in combination with docetaxel in metastatic prostate cancer (NCT04633252). Clinical trial information: NCT01417546.
DNA damaging therapies in patients (pts) with prostate cancer (PC) and pathogenic alterations in homologous recombination repair (HRR) genes.
Authors: Graham Laura , Green Edward , Park Joseph J. , Kellezi Olesia , Hwang Clara , Barata Pedro C. , Bilen Mehmet Asim , Kilari Deepak , Clingerman Melissa , Tripathi Abhishek , Labriola Matthew , Rothstein Shoshana , Garje Rohan , Koshkin Vadim S , Patel Vaibhav G. , Dorff Tanya B. , Armstrong Andrew J. , McKay Rana R. , Alva Ajjai Shivaram , Schweizer Michael Thomas 
Published: February 2022

129 Background: Pathogenic HRR gene mutations may confer sensitivity to PARP inhibitors (PARPi) and/or platinum chemotherapy (chemo). While pts harboring mutations in BRCA1/2 appear to benefit from these DNA damaging therapeutics, outcomes data for those with non- BRCA1/2 mutations are less robust. We evaluated outcomes in men with HRR gene-mutated PC who received treatment with PARPi and/or platinum-based chemo stratified by type of HRR alteration. Methods: Retrospective data from the PROMISE Consortium was utilized (PMID: 34363009). PC pts with pathogenic HRR mutations who received PARPi and/or platinum-based chemo were included. Differences in PSA progression-free survival (PFS), clinical/radiographic PFS (rPFS), and overall survival (OS) between those with BRCA1/ 2 mutations (Cohort A) and those with mutations in HRR genes that do not directly interact with the BRCA complex (Cohort B: ATM, CDK12, CHEK1, CHEK2, FANCL) were evaluated. We also evaluated outcomes in pts with HRR gene mutations known to interact with the BRCA complex aside from BRCA1/2 (Cohort C: RAD51B/C/D, RAD54L2, BARD1, GEN1, PALB2, FANCA, BRIP1). Results: Of 361 pts identified with HRR gene alterations, 89 received PARPi and 70 received platinum-based chemo. Prior therapy and metastatic disease sites were similar between cohorts. PSA PFS, rPFS, and OS were significantly improved in Cohort A vs. Cohort B with PARPi but not platinum-based chemo (Table). Sample size in cohort C was too small to allow for statistical comparison, although PSA PFS, PFS and OS were reasonably long. Conclusions: PC pts with BRCA1/2 mutations had improved outcomes to PARPi compared to those with mutations in HRR genes not directly interacting with the BRCA complex. Platinum-based chemo appeared effective regardless of which HRR gene was affected. [Table: see text]
Evaluating the optimal sequence of immunotherapy and docetaxel in men with metastatic castration-sensitive prostate cancer.
Authors: Chandran Elias Bin Aris , Atiq Mohammad O. , Donahue Renee Nicole , Karzai Fatima , Bilusic Marijo , Marte Jennifer L. , Arlen Philip M. , Cordes Lisa M. , Owens Helen , Hankin Amy , Williams Monique , Figg William Douglas , Dahut William L. , Schlom Jeffrey , Gulley James L. , Madan Ravi Amrit 
Published: February 2022

130 Background: Docetaxel is a standard of care for metastatic castration-sensitive prostate cancer (mCSPC). PROSTVAC is a pox viral-based therapeutic cancer vaccine encoding for PSA and three T-cell co-stimulatory molecules. Pox viral-based vaccines had previously demonstrated potential immune synergy with docetaxel. This clinical trial evaluated the optimal sequence of immunotherapy and chemotherapy in mCSPC. Methods: Key eligibility criteria were mCSPC within 4 months of ADT and ECOG performance status 0-2. Patients were randomized between Arms A (6 cycles of docetaxel 75mg/m2 followed by 6 doses of PROSTVAC) and B (docetaxel concurrent with PROSTVAC). After rapid accrual to the first 2 arms, Arm C was added by protocol amendment (6 doses of PROSTVAC prior to 6 cycles of docetaxel). ADT was continued throughout the treatment period. The primary endpoint was to evaluate antigen-specific responses to the tumor antigens, PSA and MUC1, and brachyury, a transcription factor implicated in the metastatic process, after patients completed their respective sequence of docetaxel and PROSTVAC. This was done using intracellular cytokine staining of 4 established markers in both CD4+ and CD8+ T-cells, for a total of 8 measures of activation per antigen. Results: The study enrolled 73 patients with a median age of 63 years (range 41-86). Gleason scores for patients were 6 (4.1%), 7 (21.6%) and 8-10 (68.9%), with 5.4% being unknown. Median pre-ADT PSA was 34.75 ng/mL. Per CHAARTED criteria, disease volume was low in 41.1% and high in 58.9% of patients. Numbers of patients evaluable for immune responses in arms A, B, and C were 16, 12 and 18, respectively. Clinical responses have previously been presented (Atiq, MO et al., ASCO 2021), with 22% of all patients having PSA <0.2 at 2 years. Conclusions: This data provides some insights into the potential of immune activating therapies in relation to chemotherapy in patients with prostate cancer. This preliminary analysis suggests the greatest magnitude of immune activation is seen when immunotherapy is followed by chemotherapy. Additional analysis of the breadth of immune responses and associations with clinical outcomes is ongoing and will be presented. Clinical trial information: NCT02649855. [Table: see text]
Blood biomarkers and association with clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC): prespecified longitudinal analysis from the ACIS study of apalutamide (APA) or placebo combined with abiraterone acetate plus prednisone (AAP).
Authors: Efstathiou Eleni , Attard Gerhardt , Lucas Justin , Thomas Shibu , Gormley Michael , Aguilar-Bonavides Clemente , Flaig Thomas W. , Franke Fabio , Goodman Oscar B. , Oudard Stephane , Pieczonka Christopher Michael , Li Susan , Dibaj Shiva , Brookman-May Sabine D. , Yeruva Kesav , McCarthy Sharon Anne , Steuber Thomas , Suzuki Hiroyoshi , Rathkopf Dana E. , Saad Fred 
Published: February 2022

142 Background: In ACIS, APA + AAP improved radiographic progression-free survival in mCRPC vs AAP; difference in overall survival (OS) was not statistically significant. We report a prespecified analysis of androgen receptor (AR) or non-AR genomic/transcriptional aberrations, known to be associated with poor prognosis, and their associations with OS in patients (pts) with mCRPC. Methods: Circulating tumor (ct)DNA and aberrations in 17 PC-relevant genes were assessed using next-generation sequencing at baseline (BL; n = 197) and at end of study treatment (EOST; n = 140) (biomarker population). ctDNA was summarized qualitatively; genomic aberrations were normalized by ctDNA detection. AR splice variant version 7 (ARv7) was detected by quantitative RT-PCR. Cox proportional hazards model assessed association of OS with biomarkers in univariate/multivariate analyses overall and in pts receiving subsequent treatment (tx). Results: BL characteristics of biomarker and total study populations were similar. From BL to EOST: ctDNA detection did not differ (123/196 [63%] to 92/140 [66%], p=0.6); significant increases occurred in ARv7, AR mutations, and any AR aberration (Table). Prevalence of aberrations in PI3K and homologous recombination repair (HRR) pathways did not change from BL to EOST (40/123 [33%] to 34/92 [37%], p=0.5 and 18/123 [15%] to 14/92 [15%], p>0.9, respectively). Worse OS was associated with ctDNA detection or HRR pathway inactivation at BL (HR, 2.5 or 2.2; all p < 0.001) or presence of ctDNA, ARv7, AR amplification or inactivation of TP53, RB1, or RB1/TP35 pathway at EOST (2.2, p < 0.001; 2.1, p < 0.001; 2.6, p < 0.001; 1.5, p < 0.05; 1.7, p < 0.05; 2.1, p < 0.001, respectively) in univariate analyses. EOST ARv7, AR amplification, and inactivation of RB1, TP53, or RB1/TP53 pathway was associated with worse OS in pts receiving subsequent tx. Detection of ctDNA and RB1 inactivation at BL and RB1/TP53 pathway inactivation at EOST was strongly associated with worse OS (2.1, 3.3, 2.9, respectively, all p < 0.01) in multivariate analyses. Conclusions: In ACIS, AAP or APA + AAP tx was associated with increased AR mutations and ARv7 expression. Detection of ctDNA and select AR/non-AR aberrations may predict poor survival in mCRPC. These markers may be used to improve tx selection following confirmation of their predictive value. Clinical trial information: NCT02257736. [Table: see text]
Changes in bone turnover markers (BTM) and association with outcomes in patients with metastatic hormone-sensitive prostate cancer (mHSPC) treated with androgen deprivation therapy (ADT) +/- docetaxel (D) in CHAARTED (ECOG-ACRIN E3805).
Authors: McGregor Bradley Alexander , Wang Xin Victoria , Hamnvik Ole-Petter R , Cheung, Yee Ming , Wei Xiao X. , Ravi Praful , Fichorova Raina N. , Sweeney Christopher 
Published: February 2022

145 Background: In the phase 3 CHAARTED trial pts with mHSPC treated with ADT + D had an improved overall survival (OS) and longer time to castrate resistant prostate cancer (TTCRPC) than pts treated with ADT alone. We aimed to define the association of BTM levels with pt outcomes recognizing both ADT and bone metastases impact bone turnover. Methods: Serum samples were collected at baseline (BL) (within 28 days of starting ADT) in 233 (116 in ADT, 117 in ADT+D) pts and at week 24 in 423 (224 ADT+D, 199 ADT) pts. Samples were analyzed for osteocalcin (OC), osteoprotegrin (OPG), sclerostin (SL), RANKL and bone alkaline phosphatase (BALP). Cox proportional hazards models were used to assess the prognostic and predictive effects of the BTM in terms of OS and TTCPRC. Results: Whereas BALP baseline (BL) level < BL median was associated with longer OS independent of therapy (HR 0.44 95% CI 0.31-0.63, p<0.001); BL OPG > BL median and BL RANKL < BL median were associated with longer OS in the ADT+D arm (HR 0.54 95% CI 0.32-0.9, p=0.015 and HR 1.69 95% CI 1,03-2.79, p=0.037) but not in the ADT alone arm (HR 0.75, 95% CI 0.45 − 1.25, p=0.271 and HR 1.06 95% CI 0.65 − 1.73 p=0.827). Changes in markers from BL to week 24 varied based on treatment and volume of disease with statistically significant changes noted (Table). A rise in OC or BALP on therapy from BL to week 24 was associated with improved TTCRPC and OS (OC: HR(TTCRPC) 0.792, p=0.033, HR(OS) 0.78 p=0.047; BALP: HR(TTCRPC) 0.82, p=0.03, HR (OS) 0.79, p=0.013) controlling for week 24 levels. However higher absolute OC and BALP levels at week 24 were associated with worse outcomes. (OC: HR(TTCRPC) 1.37, p=0.003, HR(OS)1.38, p=0.006; BALP: HR(TTCRPC) 1.54, p=0.007, HR(OS) 1.77, p=0.001). Conclusions: The BL finding with BALP are consistent with higher BALP being a poor prognostic marker. The BL OPG and RANKL findings suggest these markers might identify men who benefit from addingf D to ADT. The paradoxical improved survival with a rise in OC and BALP on therapy but worse outcomes with absolute higher levels at week 24 highlights complex dynamics of bone turnover related to varied impact from ADT, bone healing when responding to therapy versus active cancer. Clinical trial information: NCT00309985. [Table: see text]
Genomic classification of clinically advanced major genito-urinary cancers (GUca) based on methylthioadenosine phosphorylase (MTAP) genomic loss.
Authors: Spiess Philippe E. , Necchi Andrea , Grivas Petros , Bratslavsky Gennady , Jacob Joseph M , Kravtsov Oleksandr , Huang Richard S.P. , Parini Vamsi , Decker Brennan , Lin Douglas I. , Pavlick Dean C. , Danziger Natalie , Ross Jeffrey S. 
Published: February 2022

164 Background: Novel treatments for clinically advanced GUca including castrate resistant prostate ca (PC), bladder urothelial ca (BUC) and clear cell renal ca (ccRCC) are widely needed. Recently, the targeting of cancer cells with arginine accumulation caused by MTAP loss has emerged as a new synthetic lethality-based anti-cancer program. Methods: 8,436 mCRPC, 2,683 BUC and 841 ccRCC underwent hybrid-capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. PD-L1 tumor cell expression was determined by IHC (Dako 22C3). Results: 1.3% of PC, 24.2% of BUC and 5.5% of ccRCC featured MTAP loss. There were no significant age or gender differences associated with MTAP loss. CDKN2A/B loss ranged from 94% in ccRCC to > 99% in PC and BUC. The GA/tumor frequencies were similar when CDKN2A/B GA are excluded. In PC, GA in TP53, PTEN and BRCA1 were more frequent, while GA in AR, CDK12, RB1 and BRCA2 were less frequent in cases with MTAP loss. In BUC, GA in TSC1 and FGFR3 were more frequent and GA in RB1and TP53 were less frequent in cases with MTAP loss. In ccRCC, GA in NF2 were more frequent in cases with MTAP loss, while GA in VHL and PBRM1 were less frequent in cases with MTAP loss. “Targetable” kinase GA were rare in all groups, except for FGFR3 GA in MTAP loss BUC. Immunotherapy (IO) putative biomarkers varied among tumors, with MSI-high status less frequent and TMB ≥ 10 mut/Mb more frequent in BUC MTAP-intact than BUC with MTAP loss. PD-L1 expression was similar except for high PD-L1 expression more frequent in MTAP-intact BUC. Conclusions: When compared with PC and ccRCC, the clinical development of novel drugs, such as PRMT5 and MTA2 inhibitors in GUca will likely be focused on BUC given the 24% frequency of MTAP loss in that tumor type. CGP of PC, BUC and ccRCC reveal significant differences in GA in MTAP-intact and tumors with MTAP loss, which may impact future combinatorial clinical trial designs.[Table: see text]