bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic value of sequential 18F-FDG + Na18F PET/CT (NaF+FDG PET) in metastatic genitourinary (GU) cancer patients (pts) treated with cabozantinib/nivolumab +/- ipilimumab (CaboNivoIpi).
Authors: Verdini Nicholas Peter , Lim Ilhan , Mena Esther , Lindenberg Liza , Mortazavi Amir , Pal Sumanta K. , Lara Primo , Graap Katherine , Mallek Marissa , Keen Corrine , Thompson Ryan , Mayfield Christian , Turrell Corinne , Cadena Jacqueline , Saraiya Biren , Lilly Ray L , Knopp Michael V. , Wright Chadwick , Steinberg Seth M. , Apolo Andrea B.
Published: May 2019

4544

Background: NaF+FDG PET imaging are used to assess soft tissue and bone metastases. The prognostic value of NaF+FDG PET in GU cancer pts was assessed as a secondary endpoint within a phase I trial of combination CaboNivoIpi. Methods: NaF+FDG PET scans were collected at baseline and cycle (C)3 day (D)1 for 50pts. Up to 50 lesions/patient were analyzed at baseline, up to 10 lesions/organ in case of extensive disease. Lesion number and whole-body metabolic tumor volume (wMTV) were recorded at baseline, C3D1 and percent change for FDG and NaF scans. Whole-body total lesion glycolysis (wTLG) and its percent change was obtained for FDG scans. Parameters were evaluated with respect to OS using Kaplan-Meier and log-rank, with quartiles, then refined to show strongest distinction, adjusting p-values to account for this exploration. Parameters with strongest OS association were also analyzed for associations with OS in urothelial carcinoma (UC) pts. Results: 50 pts, (UC (n = 20); others (renal cell, prostate, urachal/adenocarcinoma, germ cell, penile, bladder squamous cell (n = 2-7 each)). Median (m) overall survival (OS) was 23.9 months (mo) (95% CI: 13.7mo – NE) with 29.7mo m potential follow up and mOS of 24.7mo (95% CI: 13.7mo-NE) for UC. For FDG in all pts, wMTV: baseline ≤ vs > 51.6, mOS (NR vs 10mo, p = .0006), C3D1 ≤ vs > 85 mOS (25.9mo vs 5.1mo, p = .0001), percent change (0/increase vs decrease, mOS 14mo vs 25.9mo, p = .015); wTLG: baseline ≤ vs > 178, mOS (NR vs 11.5mo, p = .011), C3D1 ≤ vs > 300, mOS (25.9mo vs 8.3mo, p < .0001), percent change decrease vs increase, mOS (25.9mo vs 14.0mo, p = .016); and lesion number: baseline ≤ vs > 13, mOS (25.9mo vs 9.9mo, p = .0090), C3D1 ≤ vs > 13 mOS (25.9mo vs 9.9mo, p < .0001) significantly predicted OS. In UC pts, wMTV percent change (0/increase vs decrease, mOS 14mo vs. 25.9mo, p = .057), wTLG percent change decrease vs increase, mOS (NR vs 8.4mo, p = .0015), and lesion number C3D1 ≤ vs > 13 mOS (25.9mo vs 2.8mo, p = .022) significantly predicted OS. NaF parameters failed to do so. Conclusions: FDG wMTV and wTLG at baseline, C3D1, and percent change and lesion number at baseline and C3D1, predicted OS in GU cancer pts on CaboNivoIpi. Clinical trial information: NCT02496208.
5-factor prognostic model for survival of patients with metastatic urothelial carcinoma receiving three different post-platinum PD-L1 inhibitors.
Authors: Sonpavde Guru , Manitz Juliane , Gao Chen , Hennessy Daniel , Makari Doris , Niegisch Guenter , Rosenberg Jonathan E. , Bajorin Dean F. , Grivas Petros , Apolo Andrea B. , Dreicer Robert , Hahn Noah M. , Galsky Matt D. , Necchi Andrea , Srinivas Sandy , Powles Thomas , Gupta Ashok Kumar , Abdullah Shaad Essa , Pond Gregory Russell
Published: May 2019

4552

Background: A prognostic model for overall survival (OS) of metastatic urothelial carcinoma (mUC) was previously reported in the setting of post-platinum atezolizumab (Pond GR, GU ASCO 2018). This model was limited by employing only atezolizumab treated patients (pts), small size of the validation dataset and unclear applicability to other PD-1/L1 inhibitors. Hence, we constructed a robust prognostic model utilizing the combined atezolizumab cohort as the discovery dataset and used 2 separate validation datasets comprised of post-platinum avelumab or durvalumab treated pts. Methods: The discovery dataset consisted of pt level data from 2 phase I/II trials (IMvigor210 and PCD4989g) evaluating atezolizumab (n = 405). Pts enrolled on 2 separate phase I/II trials, EMR 100070-001 that evaluated post-platinum avelumab (n = 242) and CD1108 that evaluated durvalumab (n = 189) comprised the validation datasets. Cox regression analyses evaluated the association of candidate prognostic factors with OS. Factors were dichotomized and laboratory values were normalized by logarithmic transformation. Stepwise selection was employed to propose an optimal model using the discovery dataset. Discrimination and calibration were assessed in the avelumab and durvalumab datasets following the validation procedure by Royston and Altman (2013). Results: The 5 factors included in the optimal prognostic model in the discovery dataset were ECOG-PS (1 vs. 0; HR 1.80; 95% CI [1.36-2.36]), presence/absence of liver metastasis (HR 1.55; 95% CI [1.20-2.00]), number of platelets (HR 2.22; 95% CI [1.54-3.18]), neutrophil-lymphocyte ratio (NLR; HR 1.94; 95% CI [1.57-2.40]) and lactate dehydrogenase (LDH; HR 1.60; 95% CI [1.28-1.99]). There was robust discrimination of survival between low, intermediate and high-risk groups based on 0-1, 2-3 and 4 factors. The concordance of survival was 0.692 in the discovery and 0.671 and 0.775 in the avelumab and durvalumab validation datasets, respectively. Acceptable or good calibration of expected 1-year survival rate was observed. Conclusions: A 5-factor prognostic model is prognostic for survival across 3 different PD-L1 inhibitors (atezolizumab, avelumab, durvalumab) in this large study totaling 836 pts overall in the setting of post-platinum therapy for mUC. This model may assist in prognostic stratification and interpreting nonrandomized trials of post-platinum PD1/L1 inhibitors.
Multi-omics profiling of upper-tract urothelial carcinomas.
Authors: Malouf Gabriel G. , Yao Hui , Mouawad Roger , Roupret Morgan , Kurtz Jean-Emannuel , Spano Jean-Philippe , KHAYAT INSTITUT CANCEROLOGIE Meyer , Comperat Eva , Su Xiaoping
Published: May 2019

4560

Background: Upper-tract urothelial carcinomas (UTUC) may harbor similar genetic profile as compared to bladder cancer, although frequencies of mutated genes have been shown to differ between them. However, to the best of our knowledge, the epigenetic landscapes of UTUC and their association with genetic alterations and clinico-pathological tumor features remain unknown. Methods: We collected 40 UTUC samples (20 non-muscle invasive (NMI) and 20 muscle-invasive (MI) and carried out whole-exome sequencing (n = 30), DNA methylation using Infinium EPIC arrays (n = 35) and RNA sequencing (n = 20). Validation was performed on TCGA bladder cancer dataset. Results: We identified 3232 putative somatic mutations with an average of 2.1+/-2.6 mutations per megabase. Significantly mutated genes were FGFR3 (50%), KDM6A (27%), MLL2 (27%) and ARID1A/B (23%). No difference in term of genetic alterations were identified between MI- and NMI- UTUC. Unsupervised hierarchical clustering using most variable DNA methylation probes uncovered two robust DNA methylation epi-clusters. Epi-cluster C1 (n = 23; 65.7%) displayed markedly higher DNA methylation relative to Epi-cluster C2 (n = 12; 34.3%). Notably, all muscle-invasive samples were enriched in C1 (16/17, 94.1%); conversely, C2 was enriched with non-muscle-invasive samples (p = 0.0009). Overall, 14.209 probes were significantly hypermethylated in C1 as compared to C2 epi-cluster; Gene Set Enrichment Analysis (GSEA) demonstrated that those were enriched for PRC2 targets (p = 6x10-65). Integrative analysis with tumor genetic landscape showed that C1 epi-cluster was enriched for mutations in SWI/SNF complex as compared to C2 (p = 0.02). We then applied our epi-signature to bladder TCGA cohort and obtained two similar epi-clusters associated with patients overall survival (p = 0.035). Conclusions: Our study demonstrate for the first time that difference between MI- and NM- invasive UTUC might be related to epigenetic rather than genetic alterations. This might pave the way for testing epigenetic therapies in non-muscle invasive tumors with the aim to prevent recurrence and distant metastasis.
Deferred cytoreductive nephrectomy among patients with newly diagnosed metastatic renal cell carcinoma treated initially with sunitinib.
Authors: Bhindi Bimal , Graham Jeffrey , Wells Connor , Donskov Frede , Pasini Felice , Lee Jae-Lyun , Basappa Naveen S. , Hansen Aaron Richard , Wood Lori , Kollmannsberger Christian K. , Kanesvaran Ravindran , Yuasa Takeshi , Ernst D. Scott , Srinivas Sandy , Rini Brian I. , Bowman I. Alex , Pal Sumanta K. , Choueiri Toni K. , Heng Daniel Yick Chin
Published: May 2019

4578

Background: While the CARMENA trial prompts more caution with upfront cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma (mRCC), 17% of patients in the sunitinib alone arm underwent deferred CN (dCN). Upfront systemic therapy has been proposed as a potential litmus test to identify patients suitable for CN, but data on outcomes are limited. We sought to characterize outcomes of dCN after upfront sunitinib relative to sunitinib alone. Methods: Patients with newly diagnosed mRCC receiving upfront sunitinib were identified from the International mRCC Database Consortium (IMDC) from 2006-2018. All CNs done after initial sunitinib were included, excluding CNs performed after sunitinib failure. The outcomes were overall survival (OS) and time to treatment failure (TTF). Kaplan Meier and multivariable Cox regression analyses were performed; dCN was analyzed as a time-varying covariate to account for immortal time bias. Results: The cohort included 708 patients of whom 53 (7.5%) underwent dCN at a median of 6.5 months (IQR 3.5,10.5) from diagnosis. Patients in the dCN group were more likely to have better Karnofsky performance status (KPS), intermediate IMDC risk, fewer metastatic sites, and response to upfront sunitinib (Table). There were 604 deaths during a median follow-up of 63 months. Median OS and TTF with dCN were 43.5 and 19.8 months vs. 9.4 and 4.3 months without, respectively. Upon multivariable analysis, dCN remained significantly associated with OS (HR 0.45, 95%CI 0.31-0.65; p < 0.001) but not TTF (HR 0.73, 95%CI 0.52-1.01; p = 0.056). Conclusions: Patients who received dCN were carefully selected and achieved long OS. With these benchmark outcomes, optimal selection criteria need to be identified and confirmation of the role of dCN in a clinical trial is warranted. [Table: see text]
Malignant pheochromocytoma (MP): A comprehensive genomic profiling (CGP) study.
Authors: Bratslavsky Gennady , Necchi Andrea , Shapiro Oleg , Jacob Joseph , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Jonathan Keith , Ngo Nhu , Ramkissoon Shakti , Severson Eric Allan , Hemmerich Amanda , Ali Siraj Mahamed , Chung Jon , Reddy Prasanth , Miller Vincent A. , Alexander Brian , Schrock Alexa Betzig , Liu Nick , Ross Jeffrey S.
Published: May 2019

4584

Background: We CGP to characterize the genomic alterations (GA) in MP and to enable the search for potential therapy targets. Methods: From a series of 201,766 consecutive clinical cases, 44 cases of clinically advanced MP underwent CGP using a hybrid-capture based commercial assay to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and reported as mutations/Mb and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (DAKO 22C3 antibody). Results: All patients had clinically advanced recurrent and/or metastatic disease. 23 patients were females and 21 patients were males. There were 34 (77%) of MP known to have originated in the adrenal gland and 10 (23%) of the MP were sequenced from metastatic site where the exact primary site was unknown. The primary tumor was used for sequencing in 14 (32%) of the MP cases and a non-primary tumor metastatic site (liver, lung, bone, soft tissue, lymph node, kidney, peritoneal cavity, and chest wall) in 30 (68%) of the MP cases. There were 2.3 GA/tumor. The most frequent un-targetable GA were ATRX (25%), TP53 (21%), SDHB (13%), CTNNB1 (7%), VHL (7%), and CDKN2A/2B, PIK3R2, NOTCH2 and MEN1 (all 5%). The most frequent potentially targetable GA included RET (9%), NF1 (9%) and FGFR1 (5%). PBRM1 GA were found in 2% of MAP. Germline mutations in known cancer predisposition genes were predicted in 8 (18%) of cases involving SDHB (5 cases) and BRCA1, MEN1, and MSH2 (1 case each). The genomic signatures of primary MP were not significantly different from that obtained from sequencing of metastatic site biopsies. 0 (0%) of 5 MP stained positively for PD-L1 expression. The mean TMB was 2.95 mutations/Mb, the median TMB was 2.4 mutations/Mb. There 2 (5%) of MP with TMB ≥ 10 mutations/MB and 0 (0%) with TMB ≥ 20 mutations/Mb. 0 (0%) of 33 MP evaluated for MSI had a MSI-High status. Conclusions: Although the GA/tumor is relatively low for MP, CGP can reveal important potential therapy targets including RET, NF1 and FGFR1. MP do not reveal strong potential for immunotherapies with low TMB, absence of MSI-High status and low (2%) PBRM1 mutation frequencies.
First results from TITAN: A phase III double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) receiving androgen deprivation therapy (ADT).
Authors: Chi Kim N. , Agarwal Neeraj , Bjartell Anders , Chung Byung Ha , Pereira de Santana Gomes Andrea Juliana , Given Robert W. , Juárez Soto Álvaro , Merseburger Axel Stuart , Ozguroglu Mustafa , Uemura Hirotsugu , Ye Dingwei , Deprince Kris , Naini Vahid , Li Jinhui , Cheng Shinta , Yu Margaret K. , Zhang Ke , Larsen Julie S. , McCarthy Sharon Anne , Chowdhury Simon
Published: May 2019

5006

Background: TITAN was designed to determine whether APA, a selective next-generation androgen receptor inhibitor, plus ADT improves radiographic progression-free survival (rPFS) and overall survival (OS) compared with PBO plus ADT in pts with mCSPC. Methods: In this randomized, double-blind phase 3 study, pts with mCSPC regardless of extent of disease were randomized (1:1) to APA (240 mg/d) or PBO, added to ADT, in 28-day cycles. Pts with prior treatment (tx) for localized disease or prior docetaxel for mCSPC were allowed. All pts received continuous ADT. Dual primary end points were rPFS and OS. Secondary end points were time to a) initiation of cytotoxic chemotherapy, b) pain progression, c) chronic opioid use, d) skeletal-related event. Time-to-event end points were estimated by Kaplan-Meier and Cox proportional hazards methods. This first planned OS interim analysis took place after ~50% of expected events. Results: 525 pts were randomized to APA and 527 to PBO. Median age was 68 y; 8% had prior tx for localized disease; 11% had prior docetaxel. 63% and 37% had high- or low-volume disease, respectively. At median 22.6 mo follow-up, 66% APA and 46% PBO pts remained on tx. APA significantly improved rPFS (HR, 0.48; 95% CI, 0.39-0.60; p < 0.0001), with a 52% reduction in risk of death or radiographic progression; benefit was observed across all subgroups analyzed. Median rPFS was not reached in the APA group and 22.1 mos in the PBO group. APA also significantly improved OS (HR, 0.67; 95% CI, 0.51-0.89; p = 0.0053), with a 33% reduction in risk of death. Median OS was not reached in the APA or PBO group. Time to initiation of cytotoxic chemotherapy was significantly improved with APA (HR, 0.39; 95% CI, 0.27-0.56; p < 0.0001). Based on these results, the independent data monitoring committee recommended unblinding to allow crossover of PBO pts to receive APA. Rates of grade 3/4 adverse events (AEs) (42% APA, 41% PBO) were similar, and discontinuations due to AEs (8% APA, 5% PBO) were low. Conclusions: In the TITAN study in pts with mCSPC, including pts with high- and low-volume disease and prior docetaxel, addition of APA to ADT significantly improved rPFS and OS, and the safety profile was tolerable. These results support the addition of APA to ADT for tx of pts with mCSPC. Clinical trial information: NCT02489318.
PSA decline and objective response rates in White (W), Black (B), and Asian men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Halabi Susan , Dutta Sandipan , Chi Kim N. , Tangen Catherine M. , Xuan Mengdi , Petrylak Daniel Peter , Araujo John C. , Fizazi Karim , Quinn David I. , Morris Michael J. , Higano Celestia S. , Tannock Ian , Small Eric Jay , Kelly William Kevin
Published: May 2019

5021

Background: We have shown previously in multivariable analysis that AA men had 19% lower risk of death than C men with metastatic castration resistant prostate cancer (mCRPC) treated with a docetaxel (D) and prednisone (P) based regimen. The primary goal of this analysis was to compare ≥50%PSA decline and objective response rate (ORR) in C men, AA men, and Asian men with mCRPC treated with a DP based regimen. Methods: Individual patient data from 8,151 mCRPC men randomized on eight phase III trials to a D containing regimen were combined. Race used in the analysis was based on self-report. The endpoints were ≥50% PSA decline from baseline defined by the PSA working group 2 and ORR (defined as complete or partial response). The logistic regression model was employed to assess the prognostic importance of race in predicting ≥50% PSA decline and ORR adjusting for treatment arm, performance status, and site of metastases. Results: Of 8,151, 7,687 (94%) patients had evaluable PSA data. Of 7,687 men, 6,535 (85%) were W, 445 (6%) were B, 395 (5%) were Asian and 312 (4%) had race unspecified. Men with race unspecified were excluded from the analysis, leaving 7,375 men. Percentage of patients who experienced PSA decline from baseline were: 64%, 58% and 62% in W, B and Asian men, respectively. In multivariable analysis adjusting for risk factors, the pooled odds ratios for PSA decline for AA vs. W were 0.9 (95% CI = 0.7-1.1, p = 0.16) and 1.0 (95% CI = 0.8-1.2, p = 0.92) for Asian vs. W. In 2,760 patients with measurable disease, the percentage of patients who had ORR were: 39%, 31% and 34% in W, B and Asian men, respectively. In multivariable analysis, the pooled odds ratios for ORR were 1.0 (95% CI = 0.7-1.4) for B vs. W and 0.9 (95% CI = 0.6-1.4) for Asian vs. W. Conclusions: There were no differences in PSA decline and ORR outcomes in W, B, or Asian men with mCRPC enrolled on these phase III clinical trials with DP. Clinical trial information: NCT00110214.
Pembrolizumab (pembro) plus olaparib in docetaxel-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC): Cohort A of the phase 1b/2 KEYNOTE-365 study.
Authors: Yu Evan Y. , Massard Christophe , Retz Margitta , Tafreshi Ali , Carles Joan , Hammerer Peter , Fong Peter C.C. , Shore Neal D. , Joshua Anthony M. , Linch Mark David , Gurney Howard , Romano Emanuela , Augustin Marinela , Piulats Josep M. , Wu Helen , Schloss Charles , Poehlein Christian Heinrich , De Bono Johann S.
Published: May 2019

5027

Background: Individual activity with pembro or olaparib has been observed in mCRPC pts who progressed on second-generation hormone therapy (HT) and chemotherapy. Data from cohort A (pembro+olaparib) of KEYNOTE-365 (NCT02861573), a phase 1b/2 umbrella study to test combinations in mCRPC, are presented. Methods: Pts with mCRPC who progressed within 6 mo before screening, were docetaxel-pretreated (up to 1 other chemotherapy permitted) for mCRPC and had ≤2 second-generation HTs were eligible. Pts received pembro 200 mg IV Q3W+olaparib 400 mg orally twice daily. Primary end points: safety and PSA response rate (confirmed PSA decrease ≥50%). Key secondary end points: ORR per RECIST v1.1 (investigator review), disease control rate (DCR: CR+PR+SD ≥6 mo), time to PSA progression, composite response rate, rPFS, and OS. Results: Median (95% CI) follow-up was 11 (6-15) mo. 41 pts initiated treatment (median age, 69 y; visceral disease, 42%; RECIST-measurable, 68%; homologous recombination deficient detected, 0%). Efficacy is outlined in the table. Treatment-related AEs occurred in 39 (95%) pts; most frequent (≥30%) were anemia (37%), fatigue (34%), and nausea (34%). Grade 3-5 treatment-related AEs occurred in 21 (51%) pts. There were 2 deaths; 1 was treatment-related (cause unknown). Conclusions: Pembro+olaparib had activity in pts with mCRPC who were molecularly unselected and were previously treated with docetaxel and second-generation HT. The observed safety profile for the combination is consistent with individual profiles of pembro and olaparib. Clinical trial information: NCT02861573. [Table: see text]
RESIST-PC phase 2 trial: 177Lu-PSMA-617 radionuclide therapy for metastatic castrate-resistant prostate cancer.
Authors: Calais Jeremie , Fendler Wolfgang P , Eiber Matthias , Lassmann MIchael , Dahlbom Magnus , Esfandiari Rouzbeh , Gartmann Jeannine , Nguyen Kathleen , Thin Pan , Lok Vincent , Herrmann Ken , Czernin Johannes , Delpassand Ebrahim
Published: May 2019

5028

Background: This is an investigator-initiated open-label prospective bi-centric single-arm phase 2 clinical trial (NCT03042312) of 177Lu-PSMA-617 radionuclide therapy in patients with progressive metastatic castrate-resistant prostate cancer (mCRPC). Methods: Patients with progressive mCRPC (biochemical, radiographic or clinical) after ≥1 novel androgen axis drug (NAAD), either chemotherapy (CTX) naïve or post-CTX, with sufficient bone marrow reserve and normal kidney function were eligible. All patients underwent a screening PSMA PET/CT to confirm target expression. Patients received up to 4 cycles of 177Lu-PSMA-617 every 8±1 weeks and were randomized into 2 treatment activities groups (6.0 or 7.4 GBq). Kidney dosimetry was performed for the first cycle. Efficacy was defined as serum PSA decline of ≥50% from baseline at 12 weeks and served as primary endpoint. Results: 64 patients (median PSA 75 ng/ml; range 0.5-2425) were included in the study. 20% were CTX naïve while 80% were post-CTX (1.9 CTX regimens on average, range 1-4). 45% completed 4 cycles of 177Lu-PSMA-617. Androgen deprivation therapy was given concomitantly in 83%, NAAD in 23% and immunotherapy in 6%. PSA decline of ≥50% was observed in 23% of patients at 12 weeks and in 38% of patients at any time (best PSA response). The median time to best PSA response was 22 weeks (range 6-49 weeks). 16% had a PSA decline of ≥90% and 59% had any PSA decline ( > 0%). Mild and transient (CTCAE grade 1-2) side effects included xerostomia (72%), nausea/vomiting (69%) and bowel movement disorders (45%). CTCAE grade 3 toxicity included nausea/vomiting (6%), anemia (8%), leukopenia (5%), kidney failure (3%), thrombocytopenia (3%), and neutropenia (3%). The mean kidney dose was 2.7 Gy for the first cycle (range 0.9-5.9) i.e. 0.4 Gy/GBq (range 0.15-0.9). There was no difference between the efficacy and toxicity for the 6.0 GBq (n = 23) and 7.4 GBq (n = 41) treatment arms. Conclusions: 177Lu-PSMA-617 radionuclide therapy is well tolerated in patients with progressive mCRPC. PSA declined by ≥50% in 38% of patients. The best PSA response rate occurred after 3 cycles. Updated data will be provided at the time of the conference. Clinical trial information: NCT03042312.
Pembrolizumab (pembro) plus docetaxel and prednisone in abiraterone (abi) or enzalutamide (enza)-pretreated patients (pts) with metastatic castrate resistant prostate cancer (mCRPC): Cohort B of the phase 1b/2 KEYNOTE-365 study.
Authors: Massard Christophe , Retz Margitta , Hammerer Peter , Quevedo Fernando , Fong Peter C.C. , Berry William R. , Gurney Howard , Piulats Josep M. , Joshua Anthony M. , Linch Mark David , Kolinsky Michael Paul , Romano Emanuela , Sridhar Srikala S. , Conter Henry Jacob , Augustin Marinela , Wu Helen , Schloss Charles , Poehlein Christian Heinrich , Yu Evan Y.
Published: May 2019

5029

Background: Pembro had activity as monotherapy in pretreated advanced mCRPC. Data are presented here from cohort B (pembro + docetaxel/prednisone) of KEYNOTE-365 (NCT02861573), a phase 1b/2 umbrella study to test combinations in mCRPC. Methods: Pts who progressed on or became intolerant to ≥4 wk of abi or enza in the prechemotherapy mCRPC state and progressed within 6 mo before screening were eligible. Pts received pembro 200 mg IV with docetaxel 75 mg/m2 IV Q3W plus prednisone 5 mg orally twice daily. The primary end points were safety and PSA response rate (confirmed PSA decrease ≥50%). Key secondary end points were investigator-determined ORR (RECIST v1.1), disease control rate (DCR: CR+PR+SD ≥6 mo), time to PSA progression, rPFS, and OS. Results: 72 pts (median age, 68 y; visceral disease, 36%; measurable disease, 50%) began pembro + docetaxel. Median (95% CI) follow-up was 10 (8-12) mo. Efficacy is outlined in the table. Treatment-related AEs occurred in 69 (96%) pts; most frequent (≥30%) were alopecia (43%), fatigue (40%), and diarrhea (39%). Grade 3-5 treatment-related AEs occurred in 27 (38%) pts, including 2 deaths from treatment-related AEs (pneumonitis). Most commonly reported immune-mediated AEs were infusion-related reactions (11%) and colitis (10%). Conclusions: Pembro + docetaxel/prednisone has activity in pts with mCRPC who previously progressed on second-generation hormone therapy. AEs were considered mild for the treatment combination. Clinical trial information: NCT02861573. [Table: see text]
Circulating tumor DNA fraction (ctDNA) as a surrogate predictive biomarker in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Conteduca Vincenza , Wetterskog Daniel , Scarpi Emanuela , Romanel Alessandro , Gurioli Giorgia , Jayaram Anuradha , Lolli Cristian , Schepisi Giuseppe , Casadei Chiara , Menna Cecilia , Wingate Anna , Demichelis Francesca , De Giorgi Ugo , Attard Gerhardt
Published: May 2019

5039

Background: Plasma ctDNA is a promising minimally invasive biomarker in mCRPC. Pre-treatment high levels of ctDNA reflect poor prognosis (Romanel et al, Sci Transl Med 2015; Annala et al, Cancer Discov 2018). However, the role of plasma ctDNA in prostate tumour monitoring is largely unexplored. We aimed to determine if monitoring tumour response by quantifying ctDNA levels in plasma could enable early assessment of therapy efficacy for mCRPC. Methods: Between January 2011 and June 2016, 132 sequential plasma samples from 54 mCRPC patients (pts) (30 pre- and 24 post-chemotherapy) treated with abiraterone (abi) were collected. Targeted next-generation sequencing was performed on the PGM Ion Torrent using a 316 or 318 Chip to account for 1000X expected coverage per target. We estimated the global tumour content for each sequential plasma sample from study patients by using the approach developed in (Carreira et al, Sci Trasl Med 2014; Romanel et al, Sci Transl Med 2015 ), which extends the CLONET framework (Prandi et al, Genome Biol 2014). Prostate Cancer Working Group -3 (PCWG3) criteria were used to assess clinical, biochemical (PSA) and radiographic (RAD) progression disease (PD). We considered ctDNA PD any increase of ctDNA from baseline value. Results: In our cohort of 54 pts (median age: 75 years, range 70-78), we observed 17 (31.5%) PD, 14 (25.9%) stable disease, and 23 (42.6%) partial/complete response after the first 3 months (mo) abi therapy. The odds ratio (OR) for PD having any increase in ctDNA and a PSA decline < 50% at ~3-mo therapy was 10.83, 95% CI 2.55-45.95, P = 0.001, and 3.27, 95% CI 0.89-12.3, P = 0.074, respectively. In addition, we assessed all 3 types of median PD time from starting abi treatment, suggesting the ability of ctDNA variation to predict overall PD [RAD PD = 6.8 mo, PSA PD = 4.4 mo, and ctDNA PD = 3.0 mo, P = 0.008). An increase of ctDNA levels during the first 3-mo abi treatment was significantly associated with a long-term androgen deprivation therapy (ADT) before plasma sample collection (previous ADT > 24 mo vs 12 > previous ADT ≤23 mo vs < 12 mo: P = 0.036). Conclusions: In mCRPC, an early change in ctDNA fraction may be considered as a predictive biomarker playing a key role in individualized disease monitoring. Prospective evaluation of treatment decisions based on ctDNA is now required.
Benefit from letrozole as extended adjuvant therapy after sequential endocrine therapy: A randomized, phase III study of Gruppo Italiano Mammella (GIM).
Authors: Del Mastro Lucia , Mansutti Mauro , Bisagni Giancarlo , Ponzone Riccardo , Durando Antonio , Amaducci Laura , Fabi Alessandra , Frassoldati Antonio , Michelotti Andrea , Pazzola Antonio , Valle Enrichetta , Sanna Giovanni , Gori Stefania , De Placido Sabino , Garrone Ornella , Donadio Michela , Bruzzi Paolo , Bighin Claudia , Lambertini Matteo , Poggio Francesca
Published: May 2019

504

Background: The effect of extended adjuvant endocrine therapy (ET) with aromatase inhibitors (AI) after sequential ET with tamoxifen (Tam) followed by AI for 5 years is still controversial. We conduct a clinical trial to assess different durations of ET of letrozole after tam. Methods: The GIM4 LEAD (Gruppo Italiano Mammella 4- Letrozole adjuvant therapy duration study, ClinicalTrials.gov:NCT01064635 ) was a prospective, randomized, Italian multicentric trial. Post-menopausal patients (pts) with hormone receptor positive early breast cancer free of recurrence after 2-3 years of adjuvant tam, were randomized in a 1:1 ratio to receive 3-2 years (short arm, S) or 5 years (long arm, L) of letrozole. The primary study end point was disease-free survival (DFS). Results: Between August 2005 and May 2010, 2056 pts were randomly assigned to receive 3-2 years (n=1030) or 5 years (n=1026) of letrozole. Main patients characteristics in the S and L arms were, respectively: median age 60 vs 61 years, node negative 56 vs 56%, (neo)adjuvant chemotherapy 53.4 vs 54.1%. The median follow-up was 10 years (IQR range: 8.6-11.4). The 8-year DFS was 80% (95% CI:77.3-82.7) and 85% (95% CI:82.9-87.6) in the S and L arm, respectively (hazard ratio, HR 0.82; 95% CI:0.68-0.98; p=0.031). This effect did not change in a multivariate Cox model that included nodal status, grading and age. No evidence of interaction between random assignment and nodal status, age and grading was observed. Among 1960 pts evaluable for toxicity, osteoporosis was diagnosed in 47 (4.8%) in S arm and 81 (8.3%) pts in L arm (chi-square=9.88; p=0.002). Bone fractures occurred in 5 (0.5%) and 9 (0.9%) pts in S and L arm, respectively ( p=0.29, Fisher exact test). Conclusions: After 2-3 years of adjuvant tam, extended treatment with 5 years of letrozole resulted in significant improvement in DFS compared to the standard duration of 2-3 years of letrozole. Clinical trial information: NCT01064635.
Health-related quality of life (HRQoL) and pain progression with enzalutamide (ENZ) in metastatic hormone-sensitive prostate cancer (mHSPC) from the ARCHES study.
Authors: Stenzl Arnulf , Dunshee Curtis , De Giorgi Ugo , Alekseev Boris , Iguchi Taro , Szmulewitz Russell Zelig , Flaig Thomas W. , Tombal Bertrand F. , Morlock Robert , Ivanescu Cristina , Ramaswamy Krishnan , Saad Fred , Armstrong Andrew J.
Published: May 2019

5044

Background: The Phase 3 ARCHES trial (NCT02677896) evaluated the efficacy and safety of ENZ + androgen deprivation therapy (ADT) vs placebo (PBO) + ADT in 1150 men with mHSPC. Here we report patient-reported outcome (PRO) data using Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Brief Pain Inventory Short Form (BPI-SF). Methods: FACT-P and BPI-SF were assessed at baseline (BL), week (wk) 13, and then every 12 wks until disease progression. Longitudinal changes were assessed using mean scores and mixed-model repeated measures; lower BPI-SF scores represent less pain/interference; higher FACT-P scores represent better HRQoL. Time from BL to first deterioration in PRO score was assessed by Kaplan-Meier estimates and Cox proportional hazards models. Clinically meaningful difference was defined by change from baseline ≥10 for FACT-P total and ≥2 for worst pain/severity. Results: PRO instrument completion rates were high (88−96%) up to wk 73. At BL, men in both arms were generally asymptomatic and reported good HRQoL (FACT-P total: ENZ + ADT, 113.9; PBO + ADT, 112.7) and low pain (worst pain [item 3]: ENZ + ADT, 1.80; PBO + ADT, 1.77). HRQoL and pain scores remained stable over time and there were no clinically meaningful differences between groups in change from BL to wk 73. The proportion of men with no change or improvement in PRO scores (67–88%) was similar in both groups at all time points up to wk 73. There was no significant difference between arms for time to deterioration in FACT-P total (HR 0.90 [95% CI] (0.74, 1.09); p = 0.2998). ENZ + ADT significantly delayed time to pain progression for worst pain (HR 0.82 [0.69, 0.98]; p = 0.0322) and pain severity (HR 0.79 [0.65, 0.97]; p = 0.0209) vs PBO + ADT. Conclusions: Men with mHSPC were generally asymptomatic and had high levels of HRQoL and low levels of pain at BL, likely due to most men initiating ADT several months prior to study entry. No clinically meaningful differences in HRQoL were observed between ENZ and PBO. The prolongation in radiographic progression-free survival observed with ENZ + ADT was accompanied by a significantly prolonged time to progression of worst pain and pain severity vs PBO + ADT. Clinical trial information: NCT02677896.
Abiraterone acetate plus prednisone (AA+P) without continuing LHRH-therapy in patients with metastatic chemotherapy: Naive castrations-resistant prostate cancer—Results from the SPARE-trial (NCT02077634).
Authors: Ohlmann Carsten Henning , Ruessel Christoph , Zillmann Roger , Hellmis Eva , Suttmann Henrik , Janssen Martin , Marin Jan , Dahm Johannes , Hübner Andreas , Gleissner Jochen , Scheffler Michael , Feyerabend Susan , Telle Jens , Jähnig Peter , Jäschke Michelle , Klier Joerg
Published: May 2019

5046

Background: The value of continuation of androgen deprivation therapy (ADT) in metastatic castration-resistant prostate cancer (CRPC) remains controversial and clear evidence is lacking. Especially upon treatment with the life-prolonging cytochrome P450 17-alpha-hydroxylase/C17,20 lyase (Cyp17)-inhibitor, abiraterone acetate (AA), which in combination with prednisone (P), has the ability to further suppress serum testosterone levels over ADT alone, continuation of ADT seems to be negligible. Methods: The exploratory phase II trial randomized CRPC patients to receive continued ADT plus AA+P versus AA+P alone (NCT02077634), funded by Jansen-Cilag GmbH, Germany. The primary endpoint was rate of rPFS at month 12, not powered for a direct comparison between treatment arms. Secondary endpoints included PSA response rate, objective response, time to PSA progression and safety. Results: Altogether, 67 patients were randomized between 08/2014 to 04/2017. Median testosterone-levels (T) remained far below castrate-levels throughout treatment in all patients. However, in 6 patients (18%) from Arm B, T-levels increased above castrate levels within 28 days after cessation of AA+P treatment. Median treatment duration is shorter in Arm A. Safety analysis is underway and results will be presented. Conclusions: Results of this exploratory study suggest that treatment with AA+P without ADT may be effective in patients with mCRPC and that ADT may not be necessary in patients receiving AA+P. In some patients, serum-testosterone levels may rise rapidly upon treatment discontinuation so that the levels should be monitored closely. Clinical trial information: NCT02077634. [Table: see text]
Plasma cell free DNA (cfDNA) based somatic aberrations detected in treatment naïve metastatic hormone sensitive prostate cancer (mHSPC), hormonally ablated mHSPC and metastatic castration resistant prostate cancer (mCRPC) states and their impact on survival.
Authors: Kohli Manish , Tan Winston , Zheng Tiantian , Wang Amy , Wong Calvin , Tan Meng-Yao , Jia Shidong , Yu Jianjun
Published: May 2019

5047

Background: We identified plasma cell free DNA (cfDNA) based copy number variations (CNV); single nucleotide variants (SNVs) & TMPRSS-ERG fusion in four sub states of metastatic prostate cancer (mPCa) and determined the impact on survival. Two mHSPC cohorts included treatment naïve, gp-1 and mHSPC patients (pts) responding to chronic androgen ablation (AA) (gp-2). Two mCRPC cohorts included mHSPC pts with PSA relapse on chronic AA (gp-3) and a clinically progressive mCRPC cohort post AA (gp-4). Methods: Enrollment of mPCa pts was performed from 2009-14 who were followed until 2018. Plasma from collected blood was used for extracting cfDNA. NGS was performed using Illumina HiSeq X for a preselected target panel of 129 genes including DNA damage repair genes. Statistical analyses of genomic aberrations were performed in R 3.5.1 and Cox proportional-hazard models were used for survival analyses. Results: A total of 255 pts were enrolled with 215 having adequate cfDNA that passed NGS QC. Median study follow up was 90.2 (Range:73;99) months. The table highlights pts in each gp with CNV, SNV, fusion events. ARamplification was higher in mCRPC gps3&4 (20/103 pts) compared to 3/106 pts in mHSPC gps1&2 (p < 0.001) and was prognostic for poor survival in mCRPC (p < 0.001;HR:3.34; 95%CI: 1.9-5.76). 54/103 pts in gp3&4 had SNVs in TP53 compared to 34/106 pts in mHSPC gps1&2 (P < 0.01). SNVs in APC, AR, CDK12 and BRIP1 were also increased in gps3&4 (p < 0.01). Gp1 mHSPC pts with SNVs in ATM/ CHEK2 had shorter response to AA (p < 0.001; HR:3.66; 95%: CI:1.81-7.39). Conclusions: Plasma cfDNA based somatic aberrations are detected with increased prevalence in mHSPC to mCRPC states. The ease of specimen collection and the need for molecular profiling in mPCa increases its potential for clinical applications in pt care. [Table: see text]
AR changes in circulating-tumor DNA (ctDNA) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with high-dose testosterone.
Authors: Moses Marcus W. , Ledet Elisa , Manogue Charlotte , Cotogno Patrick , Lewis Brian E. , Sartor A. Oliver , Barata Pedro C. , Layton Jodi Lyn
Published: May 2019

5058

Background: High-dose testosterone (HDT) is active in mCRPC pts and may allow successful re-sensitization to previously utilized androgen-axis targeted therapies. The relationship of genomic alterations in AR gene to HDT responsiveness is unclear. Methods: Analysis of consecutive pts treated with ≥1 dose of HDT (testosterone cypionate q 2-4 weeks n = 29; continuous gel n = 4). Baseline characteristics, ctDNA data (Guardant360), and clinical outcomes were assessed. Presence of genomic AR alterations included amplifications (amps) and mutations (muts); all muts had allele fraction ≥0.3%. PSA response rates included PSA declines of > 30% or ≥50%. PSA-progression-free survival (PSA-PFS) was defined as HDT start date to PSA ≥ 25% over baseline after a second confirmed PSA rise. Results: Between May 2016 and Feb 2018, 33 mCRPC pts had median age 73 (58-85), 39% Gleason 8-10, 100% bone mets, 24% nodes + bone, and median baseline PSA level 36.1 ng/mL (0.04-1290). HDT was given post-median of 2 (1-10) CRPC therapies. 73% (24/33) of pts previously received abiraterone (n = 14), enzalutamide (n = 4), or both sequentially (n = 6) prior to HDT for a median of 10.5 months (0.7-56.8). Baseline ctDNA showed 42% AR alterations (amps = 8, muts = 4, both = 2); 33% TP53, and 6% DNA repair (ATM n = 1; BRCA2 n = 1). With median follow-up 4.4 months, HDT given for median of 4.2 months (95% CI, 3.6-4.8); 29% had PSA ≥50% response and 45% PSA ≥30% response. Median PSA-PFS is immature at 5.5 months (95% CI, 1.5-9.5); 14 pts still on HDT treatment. Grade ≥3 AEs were observed in 6% of pts (G4 thrombocytopenia = 1; G4 asthenia = 1). For pts with baseline AR alterations and HDT treatment, repeated ctDNA assays (n = 7) showed that 100% had decreased AR alterations. No relationship between PSA response and baseline ctDNA AR characteristics are discerned at this time. Conclusions: HDT was safe and active in a subset of mCRPC. Responses were clearly noted for men receiving continuous daily testosterone gels, thus continuously high testosterone levels are active in addition to injection-induced bipolar changes. Further understanding of the genomic alterations predicting responsiveness to HDT in mCRPC is required.
Prevalence of pathogenic germline variants in DNA repair by race, age, and ethnicity in men with prostate cancer.
Authors: Mara Alexandria , Zhu Jason , Wu Yuan , Callis Tom , Yang Shan , Esplin Edward D. , Nussbaum Robert L. , Zhang Tian , McNamara Megan Ann , Harrison Michael Roger , George Daniel J. , Cooney Kathleen A. , Armstrong Andrew J.
Published: May 2019

5062

Background: Patients with advanced prostate cancer (PC) frequently harbor pathogenic or likely pathogenic (P/LP) germline variants (GVs) in mismatch repair (MMR) and homologous repair (HR) enzymes which have clinical and treatment implications. However, whether the prevalence of such GVs differ by race, ethnicity, family history, or age is unknown in men with PC. Methods: This is a retrospective analysis of germline DNA from men with PC in the United States, tested by Invitae. Baseline characteristics including self-identified race, ethnicity, family history (FH), and age were recorded. Race and ethnicity were analyzed by 3 cohorts: non-Ashkenazi Caucasian Americans (CA), non-Ashkenazi African Americans (AA), and Ashkenazi Jewish Americans (AJ). Chi-square testing was performed to identify significant differences across these categories between the three cohorts, with respect to combined and individual pathogenic MMR (MSH2/6, MLH1, PMS2, and MUTYH) and HR genes (BRCA1/2, ATM, CHEK2, RAD51D, and PALB2). Results: 3057 men were included in the final analysis: 2248 (74%) men were CA, 229 (7%) were AA, and 210 (7%) were AJ. Of these, 2665 (87%) men had a FH of PC and 463 (15%) had a P/LP GV. In addition, 1068 (35%) were found to have a variant of uncertain significance, and 35 (1.6%) had the HOXB13 G84E variant. There were no significant differences in the overall prevalence of MMR (CA 1.5% vs AA 0.9% vs AJ 1.4%, p = 0.89) or HR genes (CA 7.8% vs AA 7.9% vs AJ 10.5%, p = 0.37) by race/ethnicity. With respect to individual genes, AJ had a higher prevalence of pathogenic BRCA1 alterations (AJ 3.3% vs CA 0.8% vs AA 1.7%, p = 0.0034) and CHEK2 alterations (AJ 4.3% vs CA 2.8% vs AA 0.4%, p = 0.02). There were no significant differences in the prevalence of individual or specific classes of GVs between those with or without a self-reported FH of prostate or breast/ovarian cancers. There was also no association between prevalence of HR genes and age at germline testing (p = 0.40). Conclusions: This national study found that the overall prevalence of pathogenic GVs in MMR and HR genes do not differ by race, ethnicity, or age at the time of testing, and suggests that all men with advanced prostate cancer should be offered germline testing.
CALGB 90203 (Alliance): Radical prostatectomy (RP) with or without neoadjuvant chemohormonal therapy (CHT) in men with clinically localized, high-risk prostate cancer (CLHRPC).
Authors: Eastham James Andrew , Heller Glenn , Halabi Susan , Monk Paul , Clinton Steven K. , Szmulewitz Russell Zelig , Coleman Jonathan , Gleave Martin , Evans Christopher P. , Hillman David W. , Beltran Himisha , Taplin Mary-Ellen , Hahn Olwen Mary , Parsons J Kellogg , Small Eric Jay , Mohler James , Morris Michael J.
Published: May 2019

5079

Background: Neoadjuvant CHT followed by RP did not increase 3-year biochemical progression free-survival (bPFS) compared to RP alone in men with CLHRPC. However, there is evidence that bPFS and overall survival over time was improved. In the current analysis we assessed whether CHT followed by RP improved pathological specimen features compared to RP alone. Methods: CALGB 90203 (Alliance) is a Phase III study which randomly assigned, in a 1:1 fashion, men with CLHRPC [biopsy Gleason Grade Group (GGG) 4 or 5 or Kattan pre-op nomogram bPFS < 60%] to RP alone or RP plus neoadjuvant CHT [androgen deprivation plus docetaxel (75 mg/m2 every 3 weeks for 6 cycles)]. We conducted an exploratory analysis comparing histologic findings, determined at the treating center, in the RP specimens of men receiving CHT plus RP and men treated with RP alone. We used the Chi-square test, with P-values adjusted by the Holm method for multiple comparisons. Results: A total of 788 men (median age, 62; range: 32-83 years) were randomized, with 738 ultimately undergoing RP. There was no difference in pathologic GGG (Table). Men treated with neoadjuvant CHT had a lower pathologic T-stage and lower likelihood of having seminal vesicle invasion (SVI), positive pelvic lymph nodes, or positive surgical margins (SM) (Table). Conclusions: Most pathologic features in the RP specimen were improved in men receiving neoadjuvant CHT compared to RP alone. The relationship between pathologic changes and the development of metastasis and survival require further analysis. RP pathologic outcomes. Summary statistics are calculated for the number of patients with non-missing data for each characteristic. Clinical trial information: NCT00430183. [Table: see text]
Impact of the extent of resection on primary breast angiosarcoma survival.
Authors: Mitin Timur , McClelland Shearwood , Hatfield Jess , Degnin Catherine , Chen Yiyi
Published: May 2019

521

Background: The widely accepted standard of care in treating primary breast angiosarcoma involves surgical resection, often followed by adjuvant therapy (radiation and/or chemotherapy). The rarity of this disease has precluded large-scale analyses. The question regarding the impact of resection extent on survival has yet to be examined on a nationwide scale. Methods: The National Cancer Data Base (NCDB) from 2004-2014 identified primary breast angiosarcoma patients throughout the United States having undergone surgical resection. The extent of resection (mastectomy versus lumpectomy) was adjusted for several variables (including patient age, race, income, primary payer for care, tumor size, adjuvant therapies, and medical comorbidities) to assess its impact on breast angiosarcoma-related mortality. Results: Over this eleven-year span, 826 resected primary breast angiosarcoma patients were identified in the United States. Mastectomy was by far the most common surgical modality for primary breast angiosarcoma (86% of patients). Increasing tumor size was predictive for mastectomy over lumpectomy (p < 0.0001), and for involvement of adjuvant radiation therapy (p = 0.001). The extent of surgical resection was inversely predictive of radiation usage (p = 0.017). However, surgical modality was not significantly predictive of breast angiosarcoma-related mortality. Conclusions: Despite the frequent preference of mastectomy for primary breast angiosarcoma treatment (more than 6 of every 7 patients), there is no survival benefit of mastectomy versus lumpectomy. This lack of benefit should be discussed with patients, given the reduced operative morbidity of lumpectomy versus mastectomy. The Class IIB evidence provided from this analysis represents the highest level of evidence to-date governing management of this disease.