Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Abstract PD11-05: PD11-05 Gut microbiome signatures correlate with overall survival among patients receiving eribulin with or without pembrolizumab for hormone receptor-positive metastatic breast cancer

Abstract Background: The gut microbiome modulates response and resistance to immune checkpoint inhibitors (ICI) across different cancer types. The objective of this study was to explore the association between fecal microbiome profiles and clinical outcomes in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC) treated with eribulin (E) + pembrolizumab (P) or E alone as part of a randomized phase II study (NCT03051659). Patients and Methods: Metagenomic shotgun sequencing was performed on fecal samples collected prior to randomization from a subset of 26 participating patients (E+P, n = 15; E, n = 11) collected prior to randomization. Sequencing data were processed with MetaPhlAn3 to obtain diversity scores and taxonomic composition profiles. Associations between microbiome diversity, taxonomic composition, and clinical outcomes including survival metrics were assessed using Kaplan-Meier estimation methods and Cox proportional hazard models. Results: In this subset, median follow-up was 21.6 months and median overall survival (OS) was 17.9 months. OS was not statistically significant between two treatment arms as observed in the overall cohort. Metagenomic microbiome analysis revealed higher alpha diversity by inverse Simpson Index values associated with longer survival among all patients (p = 0.004), and in patients in the E + P arm (p = 0.006) but not in the E arm (p = 0.2). At the taxonomic level, longer OS among all patients was associated with a baseline lower relative abundance of Blautia wexlerae (≤0.2%vs &amp;gt;0.2%) (22.1 vs 16.6 months; p = 0.01) and a higher relative abundance of Odoribacter splanchnicus, a common short-chain fatty acid producing gut bacterium (&amp;gt;0.35% vs ≤0.35%) (22.3 vs 11.3 months; p &amp;lt; 0.0001). These associations remained significant after controlling for age, ECOG-PS status, and use or not of prior lines of chemotherapy in the metastatic setting. Conclusions: These results suggest high diversity and composition of the gut microbiome are associated with prolonged OS in HR+ MBC pts receiving eribulin with pembrolizumab. Additional and larger clinical studies are needed to validate these findings and preclinical models are needed to interrogate the mechanisms by which gut microbiome diversity and composition may impact therapeutic response and clinical outcomes in this patient population. Citation Format: Romualdo Barroso-Sousa, Tianyu Li, Ashish V. Damania, Molly K. DiLullo, Tanya Keenan, Gerburg M. Wulf, Laura M. Spring, Elizabeth A. Mittendorf, Jennifer A. Ligibel, Nadim J. Ajami, Jennifer Wargo, Nabihah Tayob, Sara Tolaney. PD11-05 Gut microbiome signatures correlate with overall survival among patients receiving eribulin with or without pembrolizumab for hormone receptor-positive metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-05.</jats:p

Abstract GS2-10: Nimbus: A phase 2 trial of nivolumab plus ipilimumab for patients with hypermutated her2-negative metastatic breast cancer (MBC)

Abstract Background: While high tumor mutational burden (TMB-H) has been used as a tissue-agnostic biomarker for approval of immune checkpoint inhibitors (ICI), there is a paucity of data regarding efficacy of ICI in TMB-H MBC. The aim of this study was to evaluate if patients with TMB-H HER2-negative MBC benefit from the combination of nivolumab plus ipilimumab. Methods: This is an open-label, single-arm, multicenter, phase 2 study assessing the efficacy of nivolumab 3 mg/kg intravenously (IV) every 14 days plus ipilimumab 1 mg/kg IV every 6 weeks in subjects with TMB-H HER2-negative MBC. Eligible patients were required to have measurable HER2-negative MBC, TMB ≥9 Mut/Mb assessed by a cancer-gene panel evaluating &amp;gt; 300 genes and performed in a CLIA-certified laboratory, and 0-3 prior lines of chemotherapy in the advanced setting. The primary objective was overall response rate (ORR) according to RECIST 1.1. Secondary objectives include safety and tolerability, progression-free survival (PFS), and overall survival (OS). The study followed a two-stage design. In the first stage, 14 patients were enrolled. The study required at least 1 objective response in order to continue to the second stage where an additional 16 patients were enrolled. At least 4 objective responses among the 30 patients would suggest the regimen is worthy of further study. If the true response rate is 25%, the chance that the regimen is declared worthy of further study is &amp;gt; 90%. Tumor biopsies, peripheral blood mononuclear cells, circulating tumor DNA, and stool collection were mandatory and were obtained at baseline and on treatment (end of cycle 1). Results: From February 2019 to June 2021, 31 patients were enrolled across 3 different academic institutions. Among 30 patients who initiated study treatment, the median age was 63 yo, 20 had hormone-receptor positive (HR+) breast cancer and 10 had triple-negative breast cancer (TNBC), and median number of prior lines of chemotherapy was 1.5 (0-3). Among the 10 patients with TNBC, PD-L1 status was known in 7 patients (3 positive and 4 negative). Median TMB was 10.9 Mut/Mb and 16.7% (n = 5) of patients had a TMB ≥14 mut/Mb. After a median follow-up of 9.7 (4.4 - 16.4) months, 4 (13.3%) patients achieved a confirmed objective response (all partial responses) meeting the primary endpoint of this study. The median duration of response has not been reached and 3 of these patients are still progression-free for at least 15 months. Two patients have short follow-up, and one has an unconfirmed partial response and the other has a stable disease at the time of the data cut. Median PFS and OS was respectively 1.4 (95% CI 1.3 - 9.5) months and 8.8 (95% CI 4.2 - not reached). Exploratory analysis did not show a difference in response rate according to HR status and PD-L1 status (data not shown) but tumors with TMB ≥14 mut/Mb had a response rate of 60% vs 4% in the group with TMB between ≥9 and &amp;lt;14 mut/Mb (p = 0.01). The treatment was associated with a favorable toxicity profile, with only three patients developing grade 3 immune-related adverse events (1 had adrenal insufficiency and cardiac troponin elevation, and two other had hepatitis). There were no reported grade 4-5 events. Data regarding TIL, PD-L1 and CD8 immunohistochemistry will be presented at the symposium. Conclusion: This study of nivolumab plus ipilimumab in TMB-H MBC achieved the primary endpoint and demonstrated a confirmed ORR of 13.3%. While patients with TMB ≥ 14 Mut/Mb were minority in this study, the 60% of ORR in this subgroup highlights the need to better evaluate the optimal TMB cutoff to predict benefit to immunotherapy in MBC. Citation Format: Romualdo Barroso-Sousa, Tianyu Li, Sangeetha Reddy, Leisha A. Emens, Beth Overmoyer, Paulina Lange, Molly K Dilullo, Victoria Attaya, Jeffrey Kimmel, Eric P. Winer, Elizabeth A. Mittendorf, Nabihah Tayob, Sara M. Tolaney. Nimbus: A phase 2 trial of nivolumab plus ipilimumab for patients with hypermutated her2-negative metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS2-10.</jats:p

Abstract PD18-02: Adjuvant Paclitaxel and Trastuzumab Trial (APT) for Node-Negative, Human Epidermal Growth Factor Receptor 2–Positive (HER2+) Breast Cancer: final 10-year analysis

Abstract Background: The APT trial evaluated the activity of adjuvant paclitaxel and trastuzumab (TH) among patients with small, node negative HER2+ breast cancer. This regimen showed a 7-year invasive disease-free survival (iDFS) of 93%, a recurrence-free interval (RFI) of 97.5% with only four (1.0%) distant recurrences, and a 7-year overall survival (OS) of 95%. In this end-of-study analysis, we report the survival outcomes at 10 years and assess the role of HER2DX testing in predicting long-term outcomes with adjuvant TH. Methods: APT was a single-arm multicenter investigator-initiated phase II study in which patients with HER2+ breast cancer with tumors ≤3 cm and negative nodes (one single micrometastatic node allowed) received IV weekly paclitaxel (80 mg/m2) with IV weekly trastuzumab for 12 weeks, followed by IV trastuzumab for 9 months. The primary endpoint was 3-year iDFS. Here we report 10-year iDFS, RFI, breast cancer–specific survival (BCSS) and OS. In an exploratory analysis, the risk of recurrence was evaluated with the HER2DX genomic assay. Results: A total of 410 patients were enrolled from October 2007 to September 2010, of which 406 started the study treatment and were included in the intent to treat analysis. Median age at enrollment was 55 years (range, 24 to 85 years), and most patients (67%) had hormone receptor (HR)-positive disease. Fifty percent of patients had tumors 1.0 cm or smaller and only 9% of patients had tumors between 2 cm to 3 cm. Mean tumor size was 1.1 cm. After a median follow-up of 10.2 years (122 months), 36 iDFS events were observed, consistent with a 10-year iDFS of 89.7% (95% CI, 86.3%-93.1%). Ten-year iDFS was 90.2% (95% CI, 86.3%-94.3%) and 88.5% (95% CI, 82.4%-95.1%) for patients with HR-positive and HR-negative tumors at baseline, respectively. 10-year RFI was 96.8% (95% CI, 95.0%-98.7%), 10-year OS was 94.2% (95% CI, 91.6%-96.8%) and 10-year BCSS was 99.1% (95% CI, 98.1%-100.0%). Of the iDFS events observed in the trial, 6 were non-breast cancer related deaths and 9 were contralateral tumors, all but one locally found to be HER2-negative upon biopsy (Table 1). Among patients experiencing an iDFS event, 7 patients (1.7%) had distant recurrences, including 1 with a T2 tumor, 3 with a T1c tumor and 3 with a T1b tumor. At baseline, 6 of them had HR-positive disease, 1 had HR-negative disease, and 6 had high-grade disease. Upon biopsy of metastatic lesions, 5 of the 7 distant recurrences were locally found to be HER2+, 1 was HER2-negative and 1 had unknown HER2 status. HER2DX testing was conducted on available baseline archival tumor tissue and analyses of patients’ survival outcomes based on the HER2DX score will be presented. Conclusion: After 10 years of follow-up, adjuvant TH confirmed excellent long-term outcomes for small, node-negative HER2+ breast cancer, with a 10-year RFI of 96.8% and a 10-year BCSS of 99.1%. Table 1: iDFS events with adjuvant paclitaxel plus trastuzumab after 10.2 years of follow up Citation Format: Sara Tolaney, Paolo Tarantino, Noah Graham, Nabihah Tayob, Chau T Dang, Denise Yardley, Beverly Moy, Paul K. Marcom, Kathy S. Albain, Hope Rugo, Matthew Ellis, Iuliana Shapira, Antonio C. Wolff, Lisa Carey, Romualdo Barroso-Sousa, Michelle K. DeMeo, Molly K. DiLullo, Ann Partridge, Adrienne Waks, Clifford Hudis, Ian Krop, Harold Burstein, Aleix Prat, Eric Winer. Adjuvant Paclitaxel and Trastuzumab Trial (APT) for Node-Negative, Human Epidermal Growth Factor Receptor 2–Positive (HER2+) Breast Cancer: final 10-year analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-02.</jats:p

Nivolumab plus low-dose ipilimumab in hypermutated HER2-negative metastatic breast cancer: a phase II trial (NIMBUS)

Abstract In the phase II NIMBUS trial, patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) and high tumor mutational burden (TMB ≥ 9 mut/Mb) received nivolumab (3 mg/kg biweekly) and low-dose ipilimumab (1 mg/kg every 6 weeks) for 2 years or until progression. The primary endpoint was objective response rate (ORR) per RECIST 1.1 criteria. Among 30 patients enrolled, the median TMB was 10.9 mut/Mb (range: 9–110) and the confirmed objective response rate was 20%. Secondary endpoints included progression-free survival, overall survival, clinical benefit rate, and safety and tolerability, including immune-related adverse events (irAEs). A prespecified correlative outcome was to evaluate the ORR in patients with a TMB ≥ 14 mut/Mb. Patients with TMB ≥ 14 mut/Mb (n = 6) experienced higher response rates (60% vs 12%; p = 0.041) and showed a trend towards improved progression-free survival and overall survival compared to patients with TMB < 14 mut/Mb. Exploratory genomic analyses suggested that ESR1 and PTEN mutations may be associated with poor response, while clinical benefit was associated with a decrease or no change in tumor fraction by serial circulating tumor DNA during treatment. Stool microbiome analysis revealed that baseline blood TMB, PD-L1 positivity, and immune-related diarrhea are associated with distinct taxonomic profiles. In summary, some patients with hypermutated HER2-negative MBC experience extended clinical benefit with a dual immunotherapy regimen; a higher TMB, and additional genomic and microbiome biomarkers may optimize patient selection for therapy with nivolumab plus low-dose ipilimumab. (Funded by Bristol Myers Squibb; ClinicalTrials.gov identifier, NCT03789110)

Abstract PD18-01: Adjuvant Trastuzumab Emtansine Versus Paclitaxel plus Trastuzumab for Stage I HER2+ Breast Cancer: 5-year results and correlative analyses from ATEMPT (TBCRC033)

Abstract Background: The ATEMPT trial primary analysis found that one year of adjuvant trastuzumab emtansine (T-DM1) achieved a 3-year iDFS of 97.8% for patients with stage I HER2+ breast cancer, but was not associated with fewer clinically relevant toxicities (CRTs) compared with paclitaxel and trastuzumab (TH). In this end-of-study analysis, we report 5-year survival outcomes and correlative analyses from the trial. Methods: Patients with stage I centrally confirmed HER2+ breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for one year or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or paclitaxel 80 mg/m2 IV with weekly trastuzumab IV followed by trastuzumab for 9 months. The co-primary objectives were to compare the incidence of CRTs between the 2 arms and to evaluate iDFS in patients receiving T-DM1. To investigate proteomic correlates of recurrence, spatial proteomic analyses were performed on samples from 13 patients experiencing iDFS events (cases) and 24 matched controls using the NanoString GeoMx Digital Spatial Profiler. The impact of HER2 heterogeneity on outcomes was investigated among 17 cases and 51 matched controls by fluorescence in-situ hybridization (FISH). HER2 genetic heterogeneity was assessed by scrutinizing the whole tumor area and defined as the occurrence of HER2 gene amplification in &amp;gt;5% but &amp;lt; 50% invasive tumor cells. The risk of recurrence was evaluated centrally with the HER2DX genomic assay from 225 primary tumor samples. Germline whole genome sequencing (WGS) was conducted among 55 patients experiencing T-DM1-induced thrombocytopenia and/or bleeding and 55 matched controls to identify genomic correlates for this side effect. Results: A total of 497 patients who initiated protocol therapy were included in this analysis (383 T-DM1 and 114 TH). After a median follow up 5.8 years, among patients receiving T-DM1 there were a total of 11 iDFS events, with 3 distant recurrences. The 5-year iDFS for T-DM1 was 97.0% (95% CI, 95.3-98.8%), the 5-year recurrence-free interval (RFI) was 98.6% (95% CI: 97.4-99.8%) and the 5-year overall survival (OS) for T-DM1 was 97.8 % (95% CI, 96.3-99.3%). Although the study was not powered to evaluate the efficacy of TH, among the 114 patients receiving TH, a total of 9 iDFS events were observed, including 2 distant events; the 5-year iDFS with TH was 91.3% (95% CI: 86.0-96.9%), 5-year RFI was 93.3% (95% CI: 88.6-98.2%) and 5-year OS was 97.9% (95% CI: 95.2-100%). A total of 56 samples were evaluable for heterogeneity analyses, among which 14% (n=8) harbored HER2 genetic heterogeneity. Spatial proteomic analyses found that NF1 (adjusted p=0.72 × 10-6) and CTLA-4 (adjusted p=0.15 × 10-3) were significantly upregulated in primary samples from cases, while cleaved caspase 9, CD25, GITR, ICOS, p53 and PD-L2 were significantly upregulated in controls (all with adjusted p&amp;lt; 0.05). Germline WGS found that the top gene associations with thrombocytopenia and thrombocytopenia or bleeding were ALMS1 (p=0,19 × 10-3) and APBA3 (p=0,23 × 10-3), respectively, although none reaching the threshold for genome wide significance. rs62143195 and rs114169776 were the top single nucleotide polymorphisms associated with thrombocytopenia and thrombocytopenia or bleeding, respectively. Data on the impact of HER2 heterogeneity and of HER2DX score on survival outcomes will be presented. Conclusion: With longer follow-up, adjuvant T-DM1 confirmed outstanding long-term outcomes among patients with stage I HER2+ breast cancer, demonstrating a 5-year RFI of 98.6%. Spatial proteomic analyses identified a potential association between NF1 and CTLA-4 expression with recurrence. Details on the impact of HER2 heterogeneity and HER2DX assay on prognosis will be presented. Citation Format: Paolo Tarantino, Nabihah Tayob, Chau T Dang, Denise Yardley, Steven J. Isakoff, Vicente Valero, Meredith Faggen, Therese Mulvey, Ron Bose, Douglas Weckstein, Antonio C. Wolff, Katherine Reeder-Hayes, Hope Rugo, Bhuvaneswari Ramaswamy, Dan Zuckerman, Lowell Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit Cheng, Audrey Merrill Garrett, Paul K. Marcom, Kathy S. Albain, Patricia DeFusco, Nadine Tung, Blair Ardman, Rita Nanda, Rachel C. Jankowitz, Mothaffar Rimawi, Vandana Abramson, Paula R. Pohlmann, Catherine Van Poznak, Andres Forero-Torres, Minetta C. Liu, Kathryn Ruddy, Yue Zheng, Romualdo Barroso-Sousa, Adrienne Waks, Michelle K. DeMeo, Molly K. DiLullo, Giuseppe Curigliano, Harold Burstein, Ann Partridge, Eric Winer, Giuseppe Viale, Winnie Hui, Elizabeth A. Mittendorf, Bryan P. Schneider, Aleix Prat, Ian Krop, Sara Tolaney. Adjuvant Trastuzumab Emtansine Versus Paclitaxel plus Trastuzumab for Stage I HER2+ Breast Cancer: 5-year results and correlative analyses from ATEMPT (TBCRC033) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-01.</jats:p