bluuebunny/crossref_metadata_2025 huggingface dataset:
First-line avelumab + axitinib therapy in patients (pts) with advanced renal cell carcinoma (aRCC): Results from a phase Ib trial.
Authors: Choueiri Toni K. , Larkin James M. G. , Oya Mototsugu , Thistlethwaite Fiona C. , Martignoni Marcella , Nathan Paul D. , Powles Thomas , McDermott David F. , Robbins Paul B. , Chism David D. , Cho Daniel C. , Atkins Michael B. , Gordon Michael S. , Gupta Sumati , Uemura Hirotsugu , Tomita Yoshihiko , Compagnoni Anna , di Pietro Alessandra , Rini Brian I.
Published: September 2018

4504

Background: Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for treatment of aRCC. Avelumab is a fully human anti–PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib, a VEGF receptor inhibitor, is approved for second-line treatment of aRCC. JAVELIN Renal 100 (NCT02493751) is a phase Ib study evaluating safety and clinical activity of avelumab + axitinib in treatment-naïve pts with aRCC; updated results are reported here. Methods: Eligible pts had confirmed clear-cell aRCC, ≥1 measurable lesion, fresh or archival tumor specimen, ECOG PS ≤1, and no prior systemic therapy. Pts received avelumab 10 mg/kg IV Q2W + axitinib 5 mg orally BID until progression, unacceptable toxicity, or withdrawal. Endpoints included safety (NCI CTCAE v4.03) and objective response (RECIST v1.1). Results: As of Dec 30, 2016, 55 pts (median age 60.0 yrs [range 42.0–76.0]; 76.4% male; 34.5% ECOG PS = 1) were enrolled. 54 pts were treated with avelumab for a median of 24.1 wks (range 2.0–62.0); 55 pts were treated with axitinib for a median of 25.3 wks (range 3.0-61.0). 51 pts (92.7%) had an avelumab-related adverse event (AE) with the therapy combination, the most common (≥30% any grade) were fatigue and diarrhea (30.9% each). 10 pts (18.2%) had a max grade 3 and 1 pt (1.8%) had a max grade 4 avelumab-related AE. 52 pts (94.5%) had an axitinib-related AE with the therapy combination; the most common (≥30% any grade) were diarrhea (52.7%), hypertension (45.5%), dysphonia (43.6%), and fatigue (43.6%). 24 pts (43.6%) had a max grade 3 and 5 pts (9.1%) had a max grade 4 axitinib-related AE. 2 deaths occurred in the study during the reporting period: 1 due to progression and 1 related to both treatments (myocarditis). An AE led to discontinuation of avelumab in 5 pts (9.1%) and axitinib in 4 pts (7.3%). Confirmed ORR was 54.5% (95% CI 40.6–68.0) based on 2 CR and 28 PR. Unconfirmed ORR was 60.0% (95% CI 45.9–73.0). Conclusions: The safety profile of the combination of avelumab + axitinib appears manageable and consistent with those agents administered as monotherapy, and early encouraging antitumor activity was observed. Follow-up is ongoing. Clinical trial information: NCT02493751.
IMmotion150: A phase II trial in untreated metastatic renal cell carcinoma (mRCC) patients (pts) of atezolizumab (atezo) and bevacizumab (bev) vs and following atezo or sunitinib (sun).
Authors: Atkins Michael B. , McDermott David F. , Powles Thomas , Motzer Robert J. , Rini Brian I. , Fong Lawrence , Joseph Richard Wayne , Pal Sumanta K. , Sznol Mario , Hainsworth John D. , Stadler Walter Michael , Hutson Thomas E. , Ravaud Alain , Bracarda Sergio , Suarez Cristina , Choueiri Toni K. , Qiu Jiaheng , Huseni Mahrukh A. , Schiff Christina , Escudier Bernard J.
Published: September 2018

4505

Background: While inhibiting VEGF improves outcomes in mRCC pts, most develop resistance, often within a year. Here, we report results from a Ph II study of atezo (anti–PD-L1) and bev (anti-VEGF) vs and following atezo or sun (TKI) in mRCC pts. Methods: Pts with untreated mRCC were enrolled in the hypothesis generating IMmotion150 study (NCT01984242) and randomized to atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w, atezo alone or sun 50 mg PO QD 4 wk on/2 wk off. After progression on atezo or sun, crossover to atezo + bev was allowed. PD-L1 status was scored on tumor-infiltrating immune cells (IC, SP142 IHC assay). The primary analysis was modified prior to final analysis to reflect the coprimary endpoints of IRF-assessed PFS (RECIST v1.1) in ITT pts and pts with PD-L1 expression on ≥ 1% of IC (PD-L1+). Results: 54% of pts were PD-L1+. In PD-L1+ pts 1L treatment resulted in a PFS hazard ratio (HR) of 0.64 for atezo + bev vs sun (table). After 1L treatment, 78% of sun and 60% of atezo pts who progressed subsequently received atezo + bev and achieved ORRs of 28% and 24%, respectively (table). Safety was comparable to the known individual profiles of atezo and bev. Additional clinical, safety and biomarker data will be presented. Conclusions: Atezo + bev resulted in encouraging antitumor activity in 1L pts with PD-L1+ mRCC. Preliminary activity in the 2L setting was demonstrated in pts who crossed over to atezo + bev, regardless of prior therapy. 1L atezo + bev vs sun is being evaluated in the ongoing Ph III study IMmotion151 (NCT02420821). Clinical trial information: NCT01984242. [Table: see text]
A phase I/II study to assess the safety and efficacy of pazopanib (PAZ) and pembrolizumab (PEM) in patients (pts) with advanced renal cell carcinoma (aRCC).
Authors: Chowdhury Simon , McDermott David F. , Voss Martin Henner , Hawkins Robert E. , Aimone Paola , Voi Maurizio , Isabelle Naëije , Wu Yi , Infante Jeffrey R.
Published: September 2018

4506

Background: PAZ is indicated for the treatment of aRCC. The combination of an anti-angiogenic agent and immunotherapy may improve anti-tumor activity. We report preliminary safety and efficacy results of the phase I part of the study. Methods: Twenty pts were originally enrolled in cohorts A and B assessing PAZ 800 mg and 600 mg, respectively, both with 2mg/kg (Q2W and then Q3W) PEM to determine the maximum tolerated dose. Due to dose limiting liver toxicity, cohort C was opened to assess if the sequential schedule of 9 weeks PAZ run-in followed by PAZ+PEM would improve safety. Strict safety criteria for initiating PAZ+PEM were set. The data from this ongoing study are presented given the limited information available on the combination of TKI + PD-1 inhibitors in RCC. Results: Overall, 35 pts were treated; 5 out of 15 pts in cohort C received PAZ+PEM at the data cut-off. Three dose-limiting toxicities (DLT) occurred in cohort C in pts receiving PAZ+PEM; updated DLTs in all cohorts are reported in Table. G3/4 AEs were observed in 90% of pts in cohorts A and B and in 80% of pts in cohort C receiving PAZ+PEM. No G3/4 ALT/AST elevation was reported in cohort C PAZ+PEM while they were observed in 70% and 60% in cohorts A and B, respectively. Best overall response (CR+PR) was reported in 6, 2 and 1 pts receiving PAZ+PEM in cohorts A, B and C, respectively. Conclusions: Results from cohorts A and B showed significant hepatotoxicity. The sequential schedule PAZ → PAZ+PEM has shown reduced hepatotoxicity and preliminary signs of efficacy but overall limited tolerability. PAZ+PEM is not suitable to test in a larger cohort. Clinical trial information: 2013-003785-14. [Table: see text]
Epacadostat plus pembrolizumab in patients with advanced RCC: Preliminary phase I/II results from ECHO-202/KEYNOTE-037.
Authors: Lara Primo , Bauer Todd Michael , Hamid Omid , Smith David C. , Gajewski Thomas , Gangadhar Tara C. , Somer Bradley G. , Schmidt Emmett V. , Zhao Yufan , Gowda Hema , Olszanski Anthony J.
Published: September 2018

4515

Background: Epacadostat (E) is a potent oral inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan-catabolizing enzyme that induces immune tolerance by T-cell suppression. Preclinical and clinical data suggest that epacadostat has antitumor activity when combined with checkpoint inhibitors, including the PD-1 inhibitor pembrolizumab (P). ECHO-202/KEYNOTE-037 is an ongoing open-label, phase 1/2 (P1/2) study evaluating E + P in multiple tumor types. We report preliminary P1/2 efficacy and safety data for the advanced renal cell carcinoma (RCC) cohort as of a 29OCT2016 data cutoff. Methods: Eligible patients (pts) had advanced clear-cell RCC, prior antiangiogenic therapy (tx), and no prior checkpoint inhibitor tx. In P1 dose escalation (3+3+3), pts received E (25, 50, 100, or 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) dosing was selected for P2 cohort expansion. Response was assessed in RECIST 1.1 evaluable pts. Safety/tolerability was assessed in pts receiving ≥1 E + P dose. Results: 33 pts (P1, n = 11; P2, n = 22) were enrolled (median age, 63 years; 70% men; 97% white; MSKCC criteria of favorable, intermediate, and poor in 6%, 64%, and 12% of pts, respectively). Of 30 efficacy-evaluable pts, 63% (n = 19) had 0–1 prior tx and 37% (n = 11) had ≥2 prior tx for advanced disease. ORR (CR+PR) and DCR (CR+PR+SD) for pts with 0–1 prior tx was 47% (9/19; 1 CR, 8 PR) and 58% (11/19; 1 CR, 8 PR, 2 SD), respectively; for pts with ≥2 prior tx, ORR and DCR were 0% and 36% (4/11; all SD). At data cutoff, 9/9 responses were ongoing (range, 1+ to 372+ days). PFS and biomarker analyses are ongoing. TRAEs occurring in ≥10% of the 33 pts included fatigue and rash (36% each); and arthralgia, diarrhea, pruritus, and pyrexia (12% each). Grade ≥3 TRAEs occurred in 15% of pts (none in > 1 pt). Two pts discontinued due to TRAEs (grade 3 autoimmune hepatitis, n = 1; grade 3 aseptic meningitis/headache/nausea/vomiting/anxiety, n = 1). Conclusions: E + P was generally well tolerated and associated with encouraging response outcomes in advanced RCC pts with 0–1 prior line of tx. E + P represents a novel immunotherapeutic strategy. A phase 3 RCC study is planned. Clinical trial information: NCT02178722.
Updated efficacy and safety of avelumab in metastatic urothelial carcinoma (mUC): Pooled analysis from 2 cohorts of the phase 1b Javelin solid tumor study.
Authors: Apolo Andrea B. , Ellerton John Allan , Infante Jeffrey R. , Agrawal Manish , Gordon Michael S. , Aljumaily Raid , Britten Carolyn D. , Dirix Luc Yves , Lee Keun-Wook , Taylor Matthew H. , Schöffski Patrick , Wang Ding , Ravaud Alain , Gelb Arnold , Xiong Junyuan , Rosen Galit , Patel Manish R.
Published: September 2018

4528

Background: Avelumab, a fully human anti‒PD-L1 IgG1 antibody, has shown promising efficacy and safety in 2 cohorts of patients (pts) with mUC. We now report updated data from a pooled analysis of these pts with mUC from JAVELIN Solid Tumor (NCT01772004) and further characterize the clinical activity of avelumab in this disease. Methods: Pts with mUC progressed after platinum-based therapy or cisplatin ineligible received avelumab 10 mg/kg 1-hour IV Q2W. Tumors were assessed every 6 weeks by independent review (RECIST v1.1). Endpoints included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety (NCI CTCAE v4.0), and tumor PD-L1 expression. Results: As of Jun 9, 2016, 249 pts had received avelumab for a median of 12 weeks (range 2-92) and were followed up for a minimum of 6 weeks. Primary tumor site was upper tract (renal pelvis/ureter) in 23.3% and lower tract (bladder/urethra) in 76.7%. 242 pts (97.2%) had progressed on prior platinum therapy and 7 pts (2.8%) were platinum naive. In 161 post-platinum pts with ≥6 months of follow-up, confirmed ORR was 17.4% (95% CI 11.9-24.1; complete response in 6.2%) with a disease control rate of 39.8%. Response was ongoing in 23/28 responders at data cut (82.1%; median DOR not reached), and the 24-week durable response rate was 92.3% (95% CI 72.6-98.0). Responses occurred across PD-L1 expression levels tested (≥5% and < 5% tumor cell‒staining [25.4% and 13.2%]). In all post-platinum pts (n = 242), median PFS was 6.6 weeks (95% CI 6.1-11.6), median OS was 7.4 months (95% CI 5.7-10.3) and 6-month OS rate was 54.9 (95% CI 47.7-61.7). Treatment-related adverse events (TRAE) of any grade occurred in 166/249 pts (66.7%); most common (≥10%) were infusion-related reaction (22.9%, all grade ≤2) and fatigue (16.1%). 21 pts (8.4%) had a grade ≥3 TRAE (fatigue [1.6%] and asthenia [0.8%] in > 1 pt). 34 pts (13.7%) had an immune-related AE (grade ≥3 in 2.4%). There was 1 treatment-related death (pneumonitis). Conclusions: Avelumab was well tolerated and showed durable responses in heavily pretreated pts with mUC, irrespective of tumor PD-L1 expression status. Clinical trial information: NCT01772004.
Health-related quality of life (HRQoL) of pembrolizumab (pembro) vs chemotherapy (chemo) for previously treated advanced urothelial cancer (UC) in KEYNOTE-045.
Authors: De Wit Ronald , Bajorin Dean F. , Bellmunt Joaquim , Fradet Yves , Lee Jae-Lyun , Fong Lawrence , Vogelzang Nicholas J. , Climent Miguel Ángel , Petrylak Daniel Peter , Choueiri Toni K. , Necchi Andrea , Gerritsen Winald R. , Gurney Howard , Quinn David I. , Culine Stephane , Sternberg Cora N. , Mai Yabing , Li Haojie , Perini Rodolfo F. , Vaughn David J.
Published: September 2018

4530

Background: In KEYNOTE-045 (NCT02256436) (N = 542), pembro 200 mg Q3W significantly improved OS over investigator’s choice of paclitaxel, docetaxel, or vinflunine as second-line therapy for advanced UC following platinum-based chemo (HR 0.73; P = 0.0022). Fewer treatment-related AEs were reported with pembro. We present results of the prespecified HRQoL analysis of KEYNOTE-045. Methods: The EORTC QLQ-C30 HRQoL instrument was administered electronically at cycles 1–4, then every 2 cycles for up to 1 y and 30 d after discontinuation. The key HRQoL end points were 1) change from baseline to wk 15 and 2) time to deterioration (TTD) (defined as ≥10-point decrease from baseline) in the QLQ-C30 global health status/QoL score. HRQoL was assessed in patients (pts) who received ≥1 dose of assigned study treatment and completed ≥1 HRQoL instrument (N = 520). Score change from baseline was compared using a constrained longitudinal data analysis model. TTD was compared using a stratified log-rank test and Cox proportional hazards model. Results: Baseline global health status/QoL scores were similar between arms. HRQoL compliance at wk 15 was 88% for both arms. From baseline to wk 15, scores were stable for pembro (n = 266) (least squares [LS] mean +0.75 [95% CI –2.34 to +3.83]) but worsened for chemo (n = 254) (LS mean –8.30 [95% CI –11.76 to –4.83]); the difference in LS means between arms was 9.05 (95% CI 4.61-13.48; nominal 2-sided P < 0.001). At wk 15, pts without PD had improved scores with pembro but worsened scores with chemo (LS mean +5.97 vs –4.31), while pts with PD had less worsening with pembro (LS mean –3.54 vs –13.95). TTD was prolonged with pembro (HR 0.70; 95% CI 0.55-0.90; nominal 1-sided P = 0.002; median 3.5 mo vs 2.2 mo). Rates of improvement (defined as ≥10-point increase from baseline) at wk 15 were 31.2% with pembro and 22.0% with chemo; rates of deterioration were 28.9% and 40.6%, respectively. Conclusions: Pembro was associated with substantially better HRQoL for a longer duration than investigator-choice chemo in pts with previously treated advanced UC. Along with superior OS, these data support pembro as a new standard-of-care in this population. Clinical trial information: NCT02256436.
Predictors of urinary diversion choice in patients with bladder cancer in integrated care settings.
Authors: Kwan Marilyn L. , Leo Michael C , Lee Valerie S. , Danforth Kim N. , Weinmann Sheila , O'Keeffe-Rosetti Maureen Cecelia , Yi David , Wendel Christopher S. , Bulkley Joanna E. , Hornbrook Mark C. , Krouse Robert S. , Gilbert Scott Michael , McMullen Carmit K.
Published: September 2018

4543

Background: Annually over 10,000 people with bladder cancer in the US have cystectomy surgery with urinary diversion (UD). While ileal conduit (IC) is most common, neobladder (NB) and continent pouch (CP) are options to retain urinary continence. Few studies in community settings have examined patient and clinician factors associated with UD choice. Methods: Eligible patients were age ≥21 with a cystectomy and UD for bladder cancer from 1/2010 to 6/2015 in 3 West coast Kaiser Permanente regions. Data were obtained from the EHR and chart review.We useda mixed effects logistic regression model with surgeon as a random effect, and region as a fixed effect, to identify patient factors associated with UD choice (IC vs NB/CP). We also examined whether surgeon factors were associated with UD choice above and beyond patient factors. Results: Among 1063 patients, 80% had an IC. IC patients were older (mean age 72 vs. 62), more likely female (24% vs. 16%), more likely diagnosed with AJCC stage III/IV (41% vs. 28%), and had higher Charlson comorbidity score (median 4 vs. 3) than NB/CP patients. Surgeons accounted for a sizable portion of the variability in UD choice (ICC = .26). The model with patient factors showed good fit (AUC = .93, Hosmer-Lemeshow test p = .22). Including surgeon factors (annual cystectomy volume, specialty training, clinical tenure) did not improve model fit (p = .32). Female sex, eGFR < 45, 4+ comorbidities, and stage III/IV tumors were associated with higher odds of receiving an IC vs. NB/CP (Table). Conclusions: Patient factors predict much of the variability in UD choice. The high ICC indicates that surgeons also contribute to this process, but surgeon factors we examined were not uniquely associated with IC. Future studies should explore more nuanced surgeon factors, such as how UD choice is shaped by personal beliefs about UD and likely outcomes. [Table: see text]
Inter and intra-tumor heterogeneity of PD-L1 and MET expression in metastatic renal cell carcinoma (mRCC).
Authors: Derosa Lisa , Le Teuff Gwenael , Khordahi Manal , Chanez Brice , Zalcman Emanuelle , Gravis Gwenaelle , Negrier Sylvie , Radulescu Camelia , Albiges Laurence , Merabet Zahira , Escudier Bernard J.
Published: September 2018

4569

Background: Although inhibition of PD-1/PD-L1 and MET receptors have clinical efficacy in mRCC, their expression is not a predictive biomarker. Heterogeneity between the sites of disease might be one explanation. The aim of our study was to evaluate PD-L1 and MET expression in primary and metastases (brain (BM)/pancreas (PM)) RCC lesions and their correlation with clinicopathologic characteristics. Methods: RCC specimen from different institutions were collected. Clinicopathologic characteristics were assessed by revision of samples. PD-L1 and MET expression in tumor cells (TC) and immune cells (IC) ( > 1%) were assessed by immunohistochemistry. Results: 180resected RCC specimen were successful collected (42 primary tumors and 138 metastases (87 BM/51 PM)). Overall, 22%, 51% and 23% of patients had at least one specimen expressing PD-L1 TC, IC and MET, respectively. In primary tumours, the proportion was 12%, 50% and 0%, respectively. In metastasis, the proportion of PD-L1 TC was 22% (23% in BM vs 19% in PM, p = 0.631), PD-L1 IC was 48% (47% in BM vs 49% in PM, p = 0.821) and MET was 24% (35% in BM vs 2% in PM, p < 0.001). Comparing paired samples (primary tumour and metastasis) there was discordances of PD-L1 in TC or IC and of MET expression in 30%, 27% and 24% of samples, respectively. These two first disagreements seem varied over time. The discordance in PD-L1 TC or IC and MET between primary tumor and PM (BM) was 15% (40%), 33% (22%) and 0% (67%), respectively. Some correlations were observed between MET and PD-L1 and clinicopathologic characteristics. Conclusions: In this largest analysis, evaluating heterogeneity between primary tumor and metastases (brain/pancreatic lesions) in mRCC, PD-L1 and MET expression suggests that the assessment as predictive biomarkers may require analysis of metastatic lesions. [Table: see text]
Nivolumab treatment for patients with non-clear cell renal cell carcinoma: A multicenter retrospective analysis.
Authors: Koshkin Vadim S. , Barata Pedro C. , Vogelzang Nicholas J. , Pal Sumanta K. , Hsu Joann , Allman Kimberly D , Gilligan Timothy D. , Rini Brian I.
Published: September 2018

4586

Background: Nivolumab (Nivo) is approved for metastatic renal cell carcinoma (mRCC) refractory to prior antiangiogenic therapy. However, the clinical activity of Nivo in non-clear cell RCC subtypes remains unknown as these patients were not part of the trial population. Methods: Patients (pts) from 3 centers who received at least one dose of Nivo as monotherapy for mRCC between 12/2015 and 01/2017 were identified. All patients had histologically-confirmed non-clear cell histology. A retrospective analysis focusing on patient and treatment characteristics, objective response according to RECIST v1.1 and adverse events (AEs) was undertaken. Results: Twenty-three patients were identified. Median age was 59 years (33-82), 78% were male, 61% were white, 30% black and 9% Hispanic. MSKCC risk groups were 19% favorable, 67% intermediate, 14% poor. Most common histologies were Unclassified (48%) and Papillary (44%), followed by Collecting duct and Mucinous tubular and spindle cell carcinoma (MTSCC) (4% each). The majority of pts had ECOG PS 0 (57%) or 1 (33%). At diagnosis, 65% had metastatic disease; most common sites were lung (57%), retroperitoneal lymph nodes (35%), and liver or bone (26% each). Most pts (74%) had prior nephrectomy and had received one (74%) or > 1 (26%) prior systemic therapy, most commonly sunitinib (65%), pazopanib (30%) or axitinib (17%). No pts had prior IL-2, but one pt had atezolizumab on trial. After a median follow-up of 6.5 months (mos) and 8 Nivo doses, median PFS was 4.2 mos and median OS was not reached. Among 21 pts evaluable for best response, 6 (29%) had PR and 4 (19%) had SD. Median time to best response was 5.1 mos. At the time of analysis, 9 pts were still on Nivo, 2 were on treatment break, 8 pts had subsequent treatment after PD on Nivo, and 2 were lost to follow-up. Two of 23 pts died. Most common AEs ( > 10%, any grade) were fever (13%) and fatigue (13%). Nivo treatments were postponed in 6 pts due to intolerance and stopped in3 pts. There were no treatment-related deaths. Conclusions: Nivolumab monotherapy demonstrated a substantial objective response rate and was well tolerated in a heterogeneous population of treatment-refractory patients who had mRCC with non-clear cell histology.
Development and validation of a novel clinical-genomic risk group classification for prostate cancer incorporating genomic and clinicopathologic risk.
Authors: Spratt Daniel Eidelberg , Zhang Jingbin , Santiago-Jimenez Maria , Davis John W. , Den Robert Benjamin , Dicker Adam , Kane Christopher J. , Pollack Alan , Ross Ashley , du Plessis Marguerite , Choeurng Voleak , Yousefi Kasra , Haddad Zaid , Davicioni Elai , Weinmann Sheila , Schaeffer Edward M. , Klein Eric A. , Karnes R. Jeffrey , Feng Felix Yi-Chung , Nguyen Paul L.
Published: September 2018

5000

Background: It is clinically challenging to integrate genomic classifier results that report a continuous numerical risk of recurrence into treatment decisions for prostate cancer (PCa). We aimed to develop a novel clinical-genomic risk system that can readily be incorporated into treatment guidelines for localized PCa. Methods: Four multi-center cohorts (n = 6928 men; 5937 prospective samples and 991 retrospective samples with long-term follow-up) were utilized to identify and validate our clinical-genomic risk system in radical prostatectomy (RP) samples and subsequently in pre-treatment biopsy samples. All patients’ FFPE tissue underwent microarray analysis, and the expression values for 22 prespecified biomarkers that constitute Decipher were extracted. Cumulative incidence curves were constructed to estimate metastasis risk. C-indices were calculated to compare NCCN and CAPRA score to our clinical-genomic system. Results: With a median follow-up of 8 years for men in our RP cohort, the 10-year distant metastasis rates for NCCN low, favorable-intermediate, unfavorable-intermediate, and high-risk were 7.8%, 9.4%, 40.1%, and 41.4%, respectively. Our 3-tier clinical-genomic risk groups had 10-year distant metastasis rates of 3.7%, 30.7%, and 57.7%, for low, intermediate, and high-risk, which were validated in our pre-treatment biopsy cohort with 10-year rate of distant metastasis of 0%, 30.3%, and 63.2%, respectively. C-indices for the clinical-genomic system (0.84, 95%CI 0.62-0.92) were significantly improved over NCCN (0.71, 95%CI 0.59-0.84) and CAPRA (0.71, 95%CI 0.60-0.81) score. A total of 33.4% of men would be reclassified by the clinical-genomic system, and specifically 17.1%, 41.3%, and 19.4% of men in NCCN low, intermediate and high risk groups would be reclassified by our new system. Conclusions: The use of a readily available genomic classifier in combination with clinicopathologic variables can generate a simple to use 3-tier clinical-genomic risk system that is highly prognostic for distant metastasis, is more accurate than clinical risk, and can be easily incorporated into NCCN guidelines to inform treatment decisions.
Abiraterone + prednisone (Abi) +/- veliparib (Vel) for patients (pts) with metastatic castration-resistant prostate cancer (CRPC): NCI 9012 updated clinical and genomics data.
Authors: Hussain Maha , Daignault Stephanie , Twardowski Przemyslaw , Albany Costantine , Stein Mark N. , Kunju Lakshmi Priya , Robinson Dan R. , Cooney Kathleen A. , Montgomery Robert B. , Antonarakis Emmanuel S. , Shevrin Daniel H. , Corn Paul Gettys , Whang Young E. , Smith David C. , Caram Megan Veresh , Tomlins Scott A. , Knudsen Karen E. , Stadler Walter Michael , Feng Felix Yi-Chung , Chinnaiyan Arul M.
Published: September 2018

5001

Background: In preclinical CRPC models, PARP1 inhibition synergizes with AR targeted therapy, especially in ETS fusion-positive tumors. We hypothesized: 1. Co-targeting PARP-1 + AR is superior to AR inhibition and 2. ETS +ve predicts response. Methods: Pts had metastatic (mets) disease biopsy (bx), stratified by IHC-ETS status and randomized to Abi (Arm A) or Abi + Vel (Arm B). Primary endpoint: PSA response rate (RR > = 50% decline). Secondary endpoints: safety, objective RR (ORR), progression free survival (PFS), and molecular analysis including if DNA repair gene deficiency (DRD: BRCA 1, BRCA 2, ATM, FANCA, PALB2, RAD51B, RAD51C) predicts response. 148 pts stratified by IHC-ETS status were randomized to detect a 20% PSA RR improvement assuming a 5% 1-sided type I error and 80% power. An elastic net multivariable Cox model was used to analyze PFS. Mets bx underwent targeted exon sequencing and capture transcriptome analysis. Results: 72 pts were randomly assigned to Arm A and 76 to Arm B. PSA RR: Arm A 63.9%, Arm B 72.4% (p = 0.27). ORR: Arm A 45%, Arm B 52.2%, p = 0.51. Median PFS: Arm A 10.1 months (m), Arm B 11.3 m, p = 0.95. More Arm-B pts were on therapy for 12+ (45% vs 38%) and 18+ cycles (22% vs 17%). ETS status had no impact. Mets tissue sequencing (N = 80): 42 pts (53%) were ETS +ve, 19 (25%) had DRD, 47 (59%) had AR amplification/copy gain, 32 (40%) had PTEN mutation (mut), 33 (41%) had TP53 mut, 37 (46%) had PIK3CA activation (a) and 12 (15%) had WNT-a. Irrespective of arm pts with DRD had a higher PSA and ORR ( > = 87%) vs wild type (58%, 39%; p = 0.013, p = 0.002, respectively), higher PSA decline rate of > = 90% (74% vs 26%, p = 0.0004) and longer median PFS (95% CI): DRD 16.6 m (11 - NR) vs wild type: 8 m (5.4 – 13.3); p = 0.02. PFS was longer in pts with normal PTEN (13.5 vs 6.2 m, p = 0.02), TP53 (13.3 vs 7.8 m, p = 0.04) and PIK3CA (10.3 vs 8.3 m, p = 0.03). Controlling for clinical factors, DRD, PTEN, TP53 and PIK3CA are associated with PFS in this order of importance. Conclusions: There was a modest trend in favor of Abi + Vel but no difference by ETS. Pts with DRD, normal PTEN,TP53 and PIK3CA had better PFS raising new hypotheses regarding the importance of integrating molecular analysis in therapeutic trials. Clinical trial information: NCT01576172.
The benefit of combining docetaxel to androgen deprivation therapy in localized and metastatic castration-sensitive prostate cancer as predicted by ERG status: An analysis of two GETUG phase III trials.
Authors: Rajpar Shanna , Carmel Alexandra , Merabet Zahira , Vielh Philippe , Foulon StÃ©phanie , Lesaunier Francois , Delva Remy , Rolland Frederic , Priou Frank , Ferrero Jean-Marc , Houede Nadine , Mourey Loic , Theodore Christine , Krakowski Ivan , Faivre Laura , Habibian Muriel , Culine Stephane , Chauchereau Anne , Gravis Gwenaelle , Fizazi Karim
Published: September 2018

5012

Background: Combining docetaxel to androgen deprivation therapy (ADT) improves survival in metastatic castration-sensitive prostate cancer (CSPC) (Vale C, Lancet Oncol 2016; 17: 243-56) and it also improves relapse-free survival (RFS) in high-risk localized CSPC (Fizazi K, Lancet Oncol 2015; 16: 787-94). However it is unlikely that all patients (pts) derive a benefit from docetaxel treatment and identifying predictive biomarkers remains a major unmet need. A subset of prostate cancers contains TMPRSS2-ERG gene fusions leading to ERG overexpression. Methods: Pre-treatment prostate core biopsies were collected from 255/413 pts and 79/385 pts enrolled respectively in the GETUG 12 and GETUG 15 (Gravis G, Eur Urol 2016; 70: 256-62) phase 3 trials testing early docetaxel in high-risk localized and metastatic CSPC. ERG, PTEN, Ki67 and Rb expression was assessed using immunohistochemistry. RFS curves were compared using the Logrank test. Results: The median age was 63 years (46-77) and 62 years (49-76) in GETUG 12 and GETUG 15. ERG staining was positive in 88/191 (46%) and 33/79 (42%) pts with available tissue, respectively. In GETUG 12, docetaxel-based chemotherapy was associated with improved RFS in pts with ERG+ expression (HR = 0.55 [0.29-1.03]; 6-year RFS : 80% ADT+docetaxel vs 68% ADT alone), but not in pts with ERG- (HR = 1.10 [0.66-1.85]; 6-year RFS 55% ADT+docetaxel vs 60% ADT alone), interaction test: p = 0.02. Similar findings were observed in GETUG 15, which was used as a validation set: the median RFS was 10.7 (6.5-14.3) and 18.8 (9.8-41) months in pts with ERG+ cancers receiving ADT alone and ADT+docetaxel, and 10.6 (4.8-25.3) and 13.2 (9.4-24) months in pts with ERG- cancers. In contrast, no difference in patient outcome by docetaxel treatment was observed by PTEN, Ki67 and Rb expression. Conclusions: Docetaxel-related benefit in men with CSPC is predicted by ERG expression. This biomarker may help better select pts for docetaxel treatment.
SOLE (Study of Letrozole Extension): A phase III randomized clinical trial of continuous vs intermittent letrozole in postmenopausal women who have received 4-6 years of adjuvant endocrine therapy for lymph node-positive, early breast cancer (BC).
Authors: Colleoni Marco , Luo Weixiu , Karlsson Per , Chirgwin Jacqueline H. , Aebi Stefan Paul , Jerusalem Guy Heinrich Maria , Neven Patrick , Hitre Erika , Graas Marie-Pascale , Simoncini Edda , Kamby Claus , Thompson Alastair Mark , Loibl Sibylle , Gavilá Joaquín , Kuroi Katsumasa , Gnant Michael , Rabaglio-Poretti Manuela , Regan Meredith M. , Coates Alan S. , Goldhirsch Aron
Published: September 2018

503

Background: In animal models of hormone receptor positive (HR+) breast cancer, acquired resistance to continued letrozole was shown to be reversed by estrogen-induced apoptosis. Sensitization to reintroduction of estrogen withdrawal by letrozole was hypothesized to improve treatment outcome. SOLE tested the hypothesis that 3 mos treatment-free intervals during extended adjuvant therapy will improve disease-free survival (DFS). Methods: SOLE enrolled 4884 postmenopausal women with HR+ lymph node-positive BC who had completed 4-6 yrs of adjuvant endocrine therapy (19% SERM, 43% AI, 38% both; stratification factor). Pts were randomly assigned to an additional 5 yrs continuous letrozole (2.5 mg daily; n = 2441) vs 5 yrs intermittent letrozole (taken for the first 9 mos of yrs 1-4, and 12 mos in yr 5; n = 2443). The primary endpoint was DFS (randomization until invasive local, regional, distant recurrence or contralateral BC; 2nd malignancy; death). Final analysis was at 665 DFS events, after 2 interim analyses. SOLE required 4800 pts for 80% power to detect a 20% DFS hazard reduction with 2-sided α = 0.05 using a stratified log rank test. Analysis is by intention-to-treat. Results: At 60 mos median follow-up, 5 yr DFS from randomization was 85.8% vs 87.5% for patients assigned intermittent vs continuous letrozole (HR = 1.08; 95% CI 0.93-1.26; P = 0.31). Similar outcome was observed for breast cancer-free interval (HR = 0.98; 95% CI 0.81-1.19), distant recurrence-free interval (HR = 0.88; 95% CI 0.71-1.09), and overall survival (HR = 0.85; 95% CI 0.68-1.07). AEs of grade > 3 were reported for 43.5% vs 41.6% of pts assigned intermittent vs continuous letrozole. Overall 24% pts discontinued letrozole early in both groups. Conclusions: Among postmenopausal women with HR+ BC, extended intermittent letrozole did not improve DFS vs continuous letrozole. The similar observed outcomes and incidence of AEs provides clinically relevant information on the intermittent administration of extended letrozole for patients who could benefit from temporary treatment breaks. Clinical trial information: NCT00553410.
Patient (pt) characteristics and treatment patterns in the radium (Ra)-223 REASSURE observational study.
Authors: Higano Celestia S. , Zimberg Shawn H. , Dizdarevic Sabina , Harshman Lauren Christine , Logue John , Baldari Sergio , Richardson Timothy , Bottomley David M. , Schostak Martin , Tombal Bertrand F. , Sade Juan Pablo , Miller Kurt , Logothetis Christopher , Bellmunt Joaquim , Smith Matthew Raymond , Saad Fred , Muenz-Wollny Renate , De Sanctis Yoriko , Sartor A. Oliver , Sternberg Cora N.
Published: September 2018

5042

Background: Ra-223, a targeted alpha therapy, prolonged survival with good safety in metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 ALSYMPCA trial. REASSURE will evaluate Ra-223 short- and long-term safety in routine clinical practice settings. This is the first planned interim analysis (median 7 mo observation). Methods: This global, prospective, single-arm, observational study enrolled pts with mCRPC with bone metastases (mets) for whom Ra-223 therapy was planned. Follow-up will continue up to 7 years after last Ra-223 dose. Results: 1106 pts (437 N. America, 665 Europe, 4 not recorded) enrolled from 2 Sep 2014 to 22 Sep 2016. Baseline data are available from 583 pts receiving 1st- (1L), 2nd- (2L), or ≥3rd-line (≥3L) Ra-223 for mCRPC(Table). The majority of pts (n=369, 63%) completed 5–6 doses (1L, 70%; 2L, 64%; ≥3L, 49%); median 6 doses (1L,6; 2L, 6; ≥3L, 4). Treatment-emergent drug-related AEs occurred in 215 pts (37%). Post-treatment grade 3/4 thrombocytopenia occurred in 14 pts (2.4%) and anemia in 45 (7.7%). Conclusions: In routine clinical practice, Ra-223 was associated with no short-term safety concerns and appeared to be used in pts with less advanced mCRPC than in ALSYMPCA. The majority of pts on 1L/2L Ra-223 therapy received 5–6 doses. Ra-223 was often used with abiraterone or enzalutamide, but not chemotherapy. The next interim analysis in 2019 will report long-term safety and outcomes on all pts. Clinical trial information: NCT02141438. [Table: see text]
Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): Results from I-SPY 2.
Authors: Nanda Rita , Liu Minetta C. , Yau Christina , Asare Smita , Hylton Nola , Veer Laura Van't , Perlmutter Jane , Wallace Anne M. , Chien Amy Jo , Forero-Torres Andres , Ellis Erin , Han Heather , Sanders Clark Amy , Albain Kathy S. , Caroline Boughey Judy , Elias Anthony D. , Berry Donald A. , Yee Douglas , DeMichele Angela , Esserman Laura
Published: September 2018

506

Background: Pembro is an anti-PD-1 antibody with single agent activity in HER2– metastatic BC. I-SPY 2 is a multicenter, phase 2 platform trial which evaluates novel neoadjuvant therapies; the primary endpoint is pathological complete response (pCR, ypT0/Tis ypN0). We report current efficacy results, with final results at ASCO. Methods: Patients (pts) with invasive BC ≥2.5 cm by exam or ≥2 cm by imaging are assigned weekly paclitaxel x 12 (control) +/- an experimental agent, followed by doxorubicin/cyclophosphamide x 4. Combinations of hormone-receptor (HR), HER2, & MammaPrint (MP) status define the 8 signatures studied. MP low HR+ BC is excluded. Adaptive randomization is based on each arm’s Bayesian probability of superiority over control. Graduation by signature is based on an arm’s Bayesian predictive probability of a successful 1:1 randomized phase 3 trial with a pCR endpoint. We provide raw & Bayesian estimated pCR rates adjusted for covariates, time effects over the course of the trial, & serial MRI modeling for pts not yet assessed for pCR surgically. Results: 69 pts were randomized to pembro (HER2- subsets only) from Dec 2015 until it graduated in Nov 2016. 46 pts have undergone surgery (table); the other 23 have on-therapy MRI assessments. In 29 HR–/HER2– (TNBC) pts, pembro increased raw & estimated pCR rates by >50% & 40%, respectively; in 40 HR+/HER– pts, it did so by 13% and 21%. 5 pts had immune-related grade 3 adverse events (AEs); 1 hypophysitis & 4 adrenal insufficiency. 4 pts presented after completion of AC (149-179 d after starting pembro); 1 presented prior to AC (37 d after starting pembro). 7 pts had grade 1-2 thyroid abnormalities. Conclusion: Pembro added to standard therapy improved pCR rates in all HER2- BCs that meet I-SPY 2 eligibility, especially in TNBC. Immune-mediated AEs were observed; pt follow up is ongoing. Clinical trial information: NCT01042379. [Table: see text]
Changes in CTC burden and prevalence of specific CTC subtypes in mCRPC patients (pts) receiving alpharadin (Ra-223) as single agent or in combination with other therapuetics (Tx).
Authors: Dittamore Ryan Vance , Jendrisak Adam , Schreiber Nicole A. , McLaughlin Brigit , Graf Ryon , Rodriguez Angel , Fleisher Martin , Lee Jerry , Kelvin James , Wang Yipeng , Landers Mark Andrew , Scher Howard I.
Published: September 2018

5076

Background: Ra-223 prolongs life in mCRPC pts with symptomatic osseous metastasis with inconsistent effects on PSA. Survival times are prolonged further when combined with Abi/Enza. Data from preclinical studies suggest that Ra-223 may sensitize tumors to DDR agents and/or biologic therapies. But predictive biomarkers of benefit to each or both combinationso are lacking. We studied CTC counts and the prevelance of specific CTC subtypes in patients before and following Ra-223 therapy, both as a single agent and in combination, to identify biomarkers of sensitivity and treatement efficacy, and effects of Ra-223 on tumor biology. Methods: Pre and ~4 week post RA-223 therapy blood samples were collected from 35 pts (2 samples each) given as a single agent (n = 20 pts) or in combination with other therapies (n = 15 pts, 9 w/ Enza, 5 w/ Abi, 1 w/ Taxane). Samples were processed and CTCs analyzed using the Epic Sciences platform. Total CTC count and the prevalence of specific CTC phenotypes present pre and post Rx were identified utilizing high content digital pathology and associated with therapy type and post-treatment change. Results: CTC declines were observed in 55% (11/20) and 60% (9/15) of pts treated with single agent and combination respectively. In Ra-223 alone pts, a novel CTC subtype (high N/C ratio, high nuclear area) was identified at baseline 11/20 samples (med = 33% of CTCs). Which was no longer detected in 10 (90%) of the pts treated. This contrasts with a second novel CTC subtype present at baseline in 4 pts (med CTC = 9%) that increased to 9 cases (med CTC = 18%) at follow-up. Conclusions: A subset of pts demonstrate post-therapy CTC declines following Ra-223 alone or in combination. A novel CTC subtype resolved by RA-223 in conjunction with total CTC kinetics may indicate pt benefit from Ra-223. A novel emergent CTC subtype has also been identified in pts already receiving Ra-223. Single CTC sequencing and protein analysys of these CTC subtypes are ongoing, and may help describe tumor evolution and sensitization to novel therapuetics.
A randomised phase III trial comparing two dose-dense, dose-intensified approaches (EPC and PM(Cb)) for neoadjuvant treatment of patients with high-risk early breast cancer (GeparOcto).
Authors: Schneeweiss Andreas , Moebus Volker , Tesch Hans , Hanusch Claus , Denkert Carsten , Luebbe Kristina , Huober Jens Bodo , Klare Peter , Kummel Sherko , Untch Michael , Kast Karin , Jackisch Christian , Thomalla Jörg , Ingold Heppner Barbara , Blohmer Jens U. , Rezai Mahdi , Frank Matthias , Nekljudova Valentina , Von Minckwitz Gunter , Loibl Sibylle
Published: September 2018

518

Background: The sequential use of intense does-dense (idd) epirubicin, paclitaxel, cyclophosphamide (EPC) and weekly paclitaxel/liposomal doxorubicin (+/- carboplatin (Cb) in triple negative breast cancer (TNBC) (PM(Cb)) are considered highly efficient regimens for high-risk early stage breast cancer (BC). Methods: GeparOcto (NCT02125344) patients (pts) received 18 weeks (wks) either EPC (3x E 150mg/m² q2w followed by 3x P225 mg/m² q2w followed by 3x C 2000mg/m² q2) or PM(Cb) (12x P 80mg/m² plus M 20 mg/m² q1w, plus Cb AUC 1.5 q1w in TNBC). For HER2+ BC trastuzumab 6 (8) mg/kg q3w and pertuzumab 420 (840) mg q3w cycles were given concomitantly with P and C. Pts with histologically confirmed, cT1c - cT4a-d BC and central receptor assessment were included. Pts with HER2+ or TNBC were eligible irrespective of nodal status, luminal B-like tumours only if pN+. Primary objective compared pathologic complete response (pCR) rates (ypT0/is ypN0). Sample size calculations assumed a pCR rate of 50% for EPC and 60% for PM(Cb), requiring 950 pts to show superiority of PM(Cb). Secondary objectives compared pCR rates within the stratified subgroups (BC subtype, HER2+ vs HER2- HR+ vs HER2- HR-), amongst others. Results: 961 pts were recruited between 12/2014 and 05/2016, 945 started treatment. Median age was 48 years, 4% T3, 2% T4d, 46% N+, 82% ductal invasive, 66% G3 tumors; 40% were HER2+, 43% TNBC. 347 pts reported SAEs (176 EPC/171 PM(Cb)) and 2 pts died. 35 pneumonias (2 EPC vs 33 PM(Cb)) and 18 pneumonitis (3 EPC vs 15 PM(Cb)) were reported. 16.4% pts with EPC and 33.8% with PM(Cb) discontinued treatment (p<0.001), mainly due to AEs (47 EPC vs 113 PM(Cb)). Mean treatment duration was 17 wks with EPC and 16 wks with PM(Cb). pCR rate was 48.3% with EPC and 47.6% with PM(Cb)(OR 0.97 (95%CI 0.75-1.25), p=0.876). pCR rate in TNBC was 48.5% with EPC and 51.7% with PM(Cb); in HER2+ 62.0% vs 57.4% and in Luminal B 14.1% vs 14.6%. Conclusions: In high-risk early stage breast cancer pts pCR rates of idd EPC compared to weekly PM(Cb) were not significantly different. PM(Cb) appeared to be less feasible. Clinical trial information: NCT02125344.
Phase 3 study evaluating efficacy and safety of veliparib (V) plus carboplatin (Cb) or Cb in combination with standard neoadjuvant chemotherapy (NAC) in patients (pts) with early stage triple-negative breast cancer (TNBC).
Authors: Geyer Charles E. , O'Shaughnessy Joyce , Untch Michael , Sikov William , Rugo Hope S. , McKee Mark D. , Huober Jens Bodo , Golshan Mehra , Giranda Vincent L. , Von Minckwitz Gunter , Maag David , Sullivan Danielle Marie , Wolmark Norman , McIntyre Kristi , Ponce Lorenzo Jose Juan , Metzger Filho Otto , Rastogi Priya , Symmans William Fraser , Liu Xuan , Loibl Sibylle
Published: September 2018

520

Background: Clinical studies suggest that TNBC is sensitive to DNA-damaging agents, including Cb. V is a potent PARP inhibitor that may enhance the antitumor activity of such agents. We present primary response data from a phase 3 randomized, placebo-controlled study (NCT02032277) evaluating the addition of V + Cb or Cb to neoadjuvant paclitaxel (P) followed by doxorubicin + cyclophosphamide (AC). Methods: Pts with histologically confirmed, invasive TNBC (T2–T4 N0–2 or T1 N1–2) amenable to surgical resection were randomized 2:1:1 to (Arm A) P 80 mg/m2 weekly + Cb AUC 6 mg/mL/min q3 weeks + V 50 mg PO BID; (Arm B) P + Cb + PO placebo; or (Arm C) P + IV placebo + PO placebo, for 12 weeks followed by AC (60 mg/m2 or 600 mg/m2 q2 or 3 weeks) × 4. Primary endpoint was pathologic complete response (pCR) in breast and nodes with > 80% power at 2-sided α of 0.05 using pair-wise comparisons for A vs B and A vs C to detect significant treatment effects using Χ2 test; secondary endpoint was rate of conversion to eligibility for breast conservation surgery (BCS). Adverse events (AEs) were assessed with NCI CTCAE V4.0. Results: Six hundred thirty-four pts (median age 50 years; range 22–79) were randomized to Arms A (n = 316), B (n = 160), or C (n = 158). Baseline characteristics were well balanced. No pCR difference was observed between Arms A and B (53.2% vs 57.5% p = 0.36), but pCR in Arm A was higher than Arm C (53.2% vs 31.0% p < 0.001). In non-prespecified analysis, pCR in Arm B was also higher than Arm C (57.5% vs 31.0% p < 0.001). Among pts ineligible for BCS at screening (n = 141), 62% were eligible after NAC in Arm A vs 44% each in Arms B (p = 0.13) and C (p = 0.14). Grade 3–4 AEs (Arms A/B/C, 86%/85%/45%) and serious AEs (30%/27%/14%) neutropenia, thrombocytopenia, anemia, nausea, and vomiting were increased with the addition of Cb; V did not impact toxicity. Median cycles of NAC were not reduced with V + Cb + P or Cb + P vs P. Conclusions: Addition of V to neoadjuvant Cb + P followed by AC did not increase pCR rate in breast and nodes in stage II–III TNBC, while addition of V + Cb or Cb alone to P followed by AC did. Cb (+/– V) increased toxicity but did not impact delivery of NAC. Clinical trial information: NCT02032277.
A randomized phase III trial of cisplatin and tumor volume directed irradiation followed by carboplatin and paclitaxel vs. carboplatin and paclitaxel for optimally debulked, advanced endometrial carcinoma.
Authors: Matei Daniela , Filiaci Virginia L. , Randall Marcus , Steinhoff Margaret , DiSilvestro Paul , Moxley Katherine M. , Kim Byoung , Powell Matthew A. , O'Malley David M. , Spirtos Nicola M. , Tewari Krishnansu Sujata , Richards Wm Edward , Nakayama John , Mutch David Gardner , Miller David S.
Published: September 2018

5505

Background: Patients with stage III/IVA uterine cancer (UC) carry high risk of systemic and local recurrence. Chemotherapy was shown to reduce systemic recurrence, however the risk of local failure remains high. Methods: The primary endpoint of this open label, randomized phase III trial was to determine if treatment with cisplatin and volume-directed radiation followed by carboplatin and paclitaxel for 4 cycles (C-RT, experimental arm) reduces the rate of recurrence or death (i.e., increases recurrence-free survival, RFS) when compared to carboplatin and paclitaxel for 6 cycles (CT, control arm) in patients with stages III-IVA (<2 cm residual disease) or FIGO 2009 stage I/II serous or clear cell UC and positive cytology. Secondary objectives were assessment of overall survival (OS), acute and late toxicities, and quality of life. A 28.5% reduction in the rate of recurrence or death was considered significant. Treatment randomization and analysis were stratified by gross residual tumor and age. Results: Between 6/2009 and 7/2014, 813 patients were enrolled and randomized (407 C-RT and 406-CT). Of those, 733 were eligible (344 C-RT and 360 CT), and 680 received the trial intervention (333 C-RT and 347 CT). Median follow up is 47 months. Patients characteristics were balanced between arms. There were 201 (58%) > grd 3 toxicity events in the C-RT arm and 227 (63%) in the CT arm. The most common > grd 3 events were myelosupression (40% vs. 52%), gastrointestinal (13% vs. 4%), metabolic (15% vs. 19%), neurological (7% vs. 6%), infectious (4% vs. 5%). Treatment hazard ratio for RFS was 0.9 (C-RT vs. CT; CI 0.74 to 1.10). C-RT reduced the incidence of vaginal (3% vs. 7%, HR = 0.36, CI 0.16 to 0.82), pelvic and paraaortic recurrences (10% vs. 21%, HR=0.43, CI 02.8 to 0.66) compared to CT, but distant recurrences were more common with C-RT vs. CT (28% vs. 21%, HR 1.36, CI 1 to 1.86). The analysis is premature for OS comparison. Conclusions: Although C-RT reduced the rate of local recurrence compared to CT; the combined modality regimen did not increase RFS in optimally debulked, stage III/IVA UC. Clinical trial information: NCT00942357.