Addition Of Carboplatin Research Articles

Real world outcomes with cabazitaxel (cab) plus carboplatin (car) in metastatic castration-resistant prostate cancer (mCRPC).

e17052 Background: Taxane chemotherapies are a mainstay of treatment in mCRPC. The addition of carboplatin (car) to cabazitaxel (cab) has shown efficacy and toxicity within clinical trials. Although car/cab were initiated concurrently in trial, clinical efficacy of car addition in those with PSA progression on cab is unknown. Furthermore, little is known about outcomes in older patients treated with car/cab. Methods: We retrospectively reviewed 72 patients with mCRPC treated with car/cab combination therapy. Demographics, disease characteristics, and treatment history were collected via electronic medical record. Overall survival (OS), progression-free survival (PFS), best overall response (BOR) per RECIST 1.1 in those with measurable disease, PSA30 and PSA50, defined as a decrease in PSA by at least 30% or 50%, respectively, were assessed. Adverse events related to treatment were assessed. In patients ≥ 65 years old, baseline frailty was assessed with the G8 screening tool, which incorporates recent food intake, weight loss, mobility, neuropsychological conditions, BMI, polypharmacy, self-assessed health status, and age. A score of ≤ 14 suggests geriatric vulnerability. Univariate association between clinical variables and the G8 score was assessed by Fisher’s exact test and Chi-square analysis. Survival outcomes were assessed via Kaplan-Meier method. Results: Median age was 66.5 years, 45.8% were Black, and 84.5 % had high volume disease. 88.1% of patients had an impaired G8 score even though 83.7% of all patients included were classified as ECOG 0-1 by their oncologist. Initially, 32 patients (44.4%) started cab monotherapy with car added later and received a median of 4 cycles of cab prior. Median OS was 10.8 months (95% CI 8.8, 13.3) and median PFS was 6.2 months (95% CI 5.8, 8.3). PSA30 and PSA50 were 38.6% and 25.7%, respectively, with BOR of partial response (PR) in 5 patients (8.6%). In those in whom car was added due to a lack of response to cab, 32.3% and 16.1% of patients were able to recapture PSA30 and PSA50 with the combination, respectively; only 1 patient (3.8%) had a PR as BOR. 56.9% of patients did not receive further treatment after car/cab. 93.1% of patients experienced toxicity (90.6% of those in whom car was added) and 34.7% stopped treatment due to toxicity alone. Fatigue (64.8%), anemia (85.9%), leukopenia (36.6%), and thrombocytopenia (40.8%) were the most common. G-CSF support was required in 70.8% and those with an impaired G8 score were significantly more likely to require this support (p=.008). Conclusions: To our knowledge, this is the first study showing that the addition of car in those not responding to cab can recapture PSA response in roughly one third of patients. Since car/cab is toxic, this may represent a strategy to expose only those not responding to cab to the added toxicity of the doublet. More frail patients may experience increased toxicity with car/cab.

Abstract PS16-06: Tumor-infiltrating lymphocytes and pathologic response to neoadjuvant chemotherapy with the addition of platinum and pembrolizumab in TNBC: A single-center real-world study

Abstract Background Previous studies have presented compelling evidence suggesting that the inclusion of platinum agents alongside anthracyclines and taxanes could potentially enhance treatment outcomes in high-risk triple-negative breast cancer (TNBC). Moreover, pembrolizumab has been integrated into clinical practice as a part of standard-of-care for non-metastatic TNBC with high risk. In light of these findings, we undertook a real-world study to investigate the impact of incorporating platinum agents and pembrolizumab on achieving pathologic complete response (pCR) in TNBC patients undergoing neoadjuvant chemotherapy (NAC). Furthermore, we specifically examined the influence of tumor-infiltrating lymphocytes (TILs) on the treatment outcomes. Patients and Methods In this real-world study conducted at Gangnam Severance Hospital, Seoul, Republic of Korea, we analyzed a cohort of 398 patients with TNBC who underwent surgery following NAC between March 2007 and November 2022. Among them, 247 patients received an anthracycline-taxanes (A-T), 120 received a carboplatin regimen including A-T, and 31 received a pembrolizumab regimen including A-T-carboplatin as part of their neoadjuvant chemotherapy treatment. TIL was evaluated in biopsied samples prior to NAC according to the guideline of TIL international working group. The high TIL was defined with a cutoff of 50%. Results Among the 398 patients analyzed, 87 (21.9%) had high TIL tumors. The pCR rates were 32% in the anthracycline-taxane (A-T) regimen group, 57% in the A-T-carboplatin regimen group, and 68% in the pembrolizumab with A-T-carboplatin regimen group. Within the high TIL group, the pCR rate did not increase with the addition of carboplatin (51.8% in the A-T group and 41.7% in the A-T-carboplatin group), but reached 85.7% with the addition of pembrolizumab and carboplatin. Among the low TIL group, the pCR rate increased from 26.7% to 61.1% with the addition of carboplatin, but there was no difference in the pCR rate between the carboplatin and pembrolizumab groups (61.1% and 60.9%, respectively). In clinically node-positive patients, the pCR rate significantly increased with pembrolizumab in the high TIL group (40.9% versus 100%, p=0.035). However, in low TIL patients, the addition of carboplatin alone significantly increased the pCR rate to 62.3%, whereas the addition of pembrolizumab did not show the same effect. Conclusions Our real-world data consistently demonstrates an increased pCR rate with the addition of carboplatin and pembrolizumab. Among patients with high TIL, the addition of carboplatin did not result in an elevated pCR rate. However, the addition of pembrolizumab tended to maximize the pCR rate, surpassing 80%. On the other hand, among patients with low TIL, the addition of carboplatin significantly increased the pCR rate, while the addition of pembrolizumab did not have the same effect. Efforts should be made to improve the response to pembrolizumab-containing regimens for patients with low baseline TIL levels. Citation Format: Min Ji Kim, Yoonwon Kook, Seung Ho Baek, Junghyun Kim, Sohyun Moon, Seung Eun Lee, Jee Hung Kim, Soong June Bae, Sung Gwe Ahn, Joon Jeong. Tumor-infiltrating lymphocytes and pathologic response to neoadjuvant chemotherapy with the addition of platinum and pembrolizumab in TNBC: A single-center real-world study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS16-06.

A Modular Trial of Androgen Signaling Inhibitor Combinations Testing a Risk-Adapted Strategy in Patients with Metastatic Castration-Resistant Prostate Cancer.

To determine the efficacy and safety of risk-adapted combinations of androgen signaling inhibitors and inform disease classifiers for metastatic castration-resistant prostate cancers. In a modular, randomized phase II trial, 192 men were treated with 8 weeks of abiraterone acetate, prednisone, and apalutamide (AAPA; module 1) and then allocated to modules 2 or 3 based on satisfactory (≥50% PSA decline from baseline and <5 circulating tumor cell/7.5 mL) versus unsatisfactory status. Men in the former were randomly assigned to continue AAPA alone (module 2A) or with ipilimumab (module 2B). Men in the latter group had carboplatin + cabazitaxel added to AAPA (module 3). Optional baseline biopsies were subjected to correlative studies. Median overall survival (from allocation) was 46.4 [95% confidence interval (CI), 39.2-68.2], 41.4 (95% CI, 33.3-49.9), and 18.7 (95% CI, 14.3-26.3) months in modules 2A (n = 64), 2B (n = 64), and 3 (n = 59), respectively. Toxicities were within expectations. Of 192 eligible patients, 154 (80.2%) underwent pretreatment metastatic biopsies. The aggressive-variant prostate cancer molecular profile (defects in ≥2 of p53, RB1, and PTEN) was associated with unsatisfactory status. Exploratory analyses suggested that secreted phosphoprotein 1-positive and insulin-like growth factor-binding protein 2-positive macrophages, druggable myeloid cell markers, and germline pathogenic mutations were enriched in the unsatisfactory group. Adding ipilimumab to AAPA did not improve outcomes in men with androgen-responsive metastatic castration-resistant prostate cancer. Despite the addition of carboplatin + cabazitaxel, men in the unsatisfactory group had shortened survivals. Adaptive designs can enrich for biologically and clinically relevant disease subgroups to contribute to the development of marker-informed, risk-adapted therapy strategies in men with prostate cancer.

Abstract P6-01-09: Efficacy of platinum-based chemotherapy and germline mutational status in early-stage triple-negative breast cancer: a unicenter retrospective analysis with long-term follow-up

Abstract BACKGROUND: In early-stage triple negative breast cancer (TNBC), the addition of carboplatin (CBDCA) to neoadjuvant chemotherapy (CT) increases pathologic complete response (pCR) and relapsed-free survival. However, it is unclear whether CBDCA improves overall survival (OS). In addition, the prognostic and/or predictive role of pathogenic germline variants (PGV) in BRCA1/2 genes and other cancer risk in this setting is not fully understood. Here, we assessed the efficacy of (neo)adjuvant CBDCA and the prognostic and predictive role of a panel of 14 genes in patients (pts) with eTNBC. METHODS: This is a retrospective study on 117 pts diagnosed with early-stage TNBC between 2000-2021 at Hospital Clinic of Barcelona. Eighty-one pts (69%) were candidates for PGV testing. Overall, 14 genes (PGV) (BRCA1, BRCA2, PALB2, BRIP1, CHEK2, TP53, ATM, RAD51C, RAD51D, BARD1, MLH1, MSH2, MSH6 and PMS2) were assessed using the TruSight hereditary cancer panel (Illumina MySeq platform) according to local guidelines. Univariable and multivariable logistic regression and Cox regression analyses were performed to identify clinical and molecular predictors of pCR and relapse-free survival (RFS), respectively. Chi-squared or Fisher’s exact tests were used to assess characteristics’ distribution as appropriate. RESULTS: Of 117 pts, 83 (71%) received CT in the neoadjuvant setting and 28 (24%) in the adjuvant setting. CBDCA was added to standard CT in 68 pts (82%) in the neoadjuvant cohort and 7 pts (6%) in the adjuvant cohort. Among pts with germline testing, 32/81 (39%) harbored PGV. BRCA1 was the most frequently mutated gene (18/32, 56%), followed by BRCA2 (5/32, 16%), PALB2 (4/32, 13%), BRIP1 (2/32, 6%), CHEK2, TP53 and PMS2 (3/32, 6%). Percentages of pts receiving CBDCA were similar between patients with and without PGV (14/16,87% and wild type (53/67,79%)(p=0.120). In the neoadjuvant cohort (n=83), CBDCA was the only variable significantly associated with pCR at both univariate (pCR rates of 58.5% with CBCDA and 14.3% without CBCDA; odds ratio [OR]=8.2 [95% CIs 2.0-55.7], p=0.008) and remained statistically significant after adjusting for PGV, tumor size and nodal status (OR=6.9 [95% CIs 1.4-53.0], p=0.028). pCR rates according to PGV are reported in Table 1. In terms of RFS, addition of CBDCA to neoadjuvant therapy (hazard ratio [HR]=0.2 [0.1-0.45], p&amp;lt; 0.001), PGV (HR=0.2 [0.05-0.9], p=0.048), pCR (HR=0.2 [0.1-0.6], p=0.004) and nodal status (HR=5.1 [1.7-15.2], p&amp;lt; 0.003) were significantly associated with RFS in univariate analyses. In a multivariable model, CBDCA remained an independent predictor of improved RFS along with pCR. When the neoadjuvant and adjuvant cohort were pooled together (n=117), platinum-based CT remained significantly associated with better RFS (HR=0.2 [0.14-0.86], p=0.021) regardless of time of administration (i.e., neoadjuvant or adjuvant). With a median follow-up of 5 years, CBCDA use was not found associated with OS (HR=0.7 [0.3-1.8], p= 0.560). CONCLUSIONS: The addition of CBDCA to standard CT was significantly associated with pCR and RFS but not OS, consistent with the phase III data. The benefit in terms of RFS was independent of the presence and the type of pathogenic germline alterations. Table 1. pCR rates according to PGV Citation Format: Adela Rodríguez Hernández, Benedetta Conte, Laia Fernández, Fara Brasó-Maristany, Belén Pastor, Miriam Potrony, Lorena Moreno, Elia Grau, Joan Antón Puig-Butillé, Aurora Sánchez, Blanca González-Farré, Esther Sanfeliu, Olga Martínez-Sáez, Claudette Falato, Maria Vidal, Nuria Chic, Tomás Pascual, Francesco Schettini, Montserrat Muñoz, Francesc Balaguer, Aleix Prat, Barbara Adamo. Efficacy of platinum-based chemotherapy and germline mutational status in early-stage triple-negative breast cancer: a unicenter retrospective analysis with long-term follow-up [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 P6-01-09.

Adjuvant Transarterial Chemoembolization for Patients with Intrahepatic Cholangiocarcinoma after Surgical Resection: A Systematic Review and Meta-analysis

Aim: To investigate the efficacy of postoperative adjuvant transarterial chemoembolization (TACE) in patients with intrahepatic cholangiocarcinoma (ICC) after resection.&#x0D; Methods: Studies were systematically searched until August 2021 in the following databases: MEDLINE, EMBASE, PUBMED, Web of Science, Cochrane Library, Science Direct, and Springer Link. Overall survival (OS) and recurrence-free survival (RFS) were considered as the main outcomes. Pooled hazard ratio (HR) with 95% confidence interval (95%CI) was reported as results for the survival data. Subgroup analysis was conducted on the outcomes stratified by early-stage ICC and intra-arterial chemotherapeutic regimen.&#x0D; Results: Eleven studies with 2,757 patients were finally included in the study. The pooled HR of OS was 0.68 (95%CI: 0.50-0.87, I 2 =83.7%). The pooled HR of RFS was 1.00 (95%CI: 0.69-1.31, I 2 =88%). Receipt of postoperative adjuvant TACE improved the OS in the early-stage ICC subgroup (HR=0.68, 95%CI: 0.50-0.86, I 2 =54%). Addition of carboplatin could slightly improve the OS (HR=0.6, 95%CI: 0.35-0.85, I 2 =48%). But receipt of postoperative adjuvant TACE (HR=1.06, 95%CI: 0.83-1.29, I 2 =41.2%) or use of carboplatin (HR=1.30, 95%CI: 0.93-1.67, I 2 =0%) caused no significant improvement in the RFS in the early-stage ICC subgroup.&#x0D; Conclusions: Postoperative adjuvant TACE could improve the OS in ICC patients after hepatectomy but could not prevent late recurrence. Survival benefit was also found in early-stage ICC patients undergoing postoperative adjuvant TACE after hepatectomy. Addition or non-addition of carboplatin in chemoembolization showed a similar OS outcome.

Abstract P2-12-07: Fdg PET/CT early response prediction for triple negative breast cancer neoadjuvant chemotherapy with addition of carboplatin

Abstract Introduction. The addition of carboplatin to standard neoadjuvant chemotherapy (NAC) including dose-dense (dd) anthracycline-cyclophosphamide (AC) combination followed by taxanes in triple negative breast cancer (TNBC) is the most intense routinely used approach, not widely accepted and potentially of increased toxicity. Fluorodeoxyglucose PET/CT ealy response assessment may aid to decide about treatment intensification. The aim of our study was to define the optimal cut-off of SUVmax decrease for pathological complete response (pCR) prediction after one cycle of AC regimen, in patients who received further AC and taxane plus carboplatin. Material and Methods. 122 patients with TNBC were enrolled into neoadjuvant chemotherapy (NAC) within STRATEGMED 2/267398/4/NCBR/2015 research project in our center between Jan 2018 and Dec 2020, upon approval of Ethics Commitee. Among them 15 patients still continued neoadjuvant treatment at the time of data cut-off, 3 patients did not receive anthracyclines because of lifetime cumulative dose with previous treatments, in 2 patients treatment was interrupted during first cycles of anthracycline-based treatment and in one patient there was no evident (18)F-fluorodeoxyglucose uptake. Remaining 101 patients were enrolled into this study. Baseline PET/CT study before NAC was performed in all patients, 73 patients had baseline PET/CT as well as additional study performed after 1st cycle of chemotherapy. Majority of patients received ddAC followed by docetaxel plus every-three-week carboplatin or weekly paclitaxel plus weekly carboplatin. Patients with residual disease received 8 cycles of capecitabine treatment adjuvantly. Radiation therapy was performed according to guidelines, concurrently or before capecitabine treatment. Mann-Whitney U test was used to assess differences in variables, predictive value was evaluated by receiver-operating characteristic (ROC) curve analysis. Results. 54 patients (53,5%) achieved pCR after neoadjuvant chemotherapy. At baseline, median of SUVmax in breast was 10.2 (IQR 7.2-14.4), whereas median of SUVmax in lymph nodes was 3.7 (IQR 0-10.0). In 16 patients (16%) baseline SUVmax in lymph nodes was higher than in breast (ratio&amp;gt;1). Higher baseline value of SUVmax was associated with pCR achievement (p=0.037). Median SUVmax decrease in breast after one cycle of chemotherapy was 33% (IQR 11%-52%) and was predictive for pCR (p=0.000021). Median decrease of 18-FDG uptake in lymph nodes was more pronounced than in breast (53%; IQR 29%-84%) and was also associated with pCR achievement (p=0.012). For pCR prediction SUVmax decrease cut-off of 40% provided optimal trade-off between sensitivity and specificity, with positive likelihood ratio 2.35, negative likelihood ratio 0.33, positive predictive value 80% and negative predictive value 64%. By ROC analysis, AUC for the prediction of pCR was 0.7604 (p=0.036). Conclusions. While high decrease of SUVmax relatively strongly indicates high pCR chance in TNBC neoadjuvant chemotherapy, lower decrease does not preclude pCR occurrence when intensive four-drug sequential regimen with carboplatin is used. Studies assessing response in reverse sequence chemotherapy with carboplatin are warranted. The study was supported by the Polish National Center of Research and Development MILESTONE project - Molecular diagnostics and imaging in individualized therapy for breast, thyroid and prostate cancer, grant no. STRATEGMED 2/267398/4/NCBR/2015. Citation Format: Marcin Kubeczko, Anna Michalik, Agnieszka Badora-Rybicka, Anna Polakiewicz-Gilowska, Andrea d'Amico, Michał Kalemba, Aleksandra Leśniak, Katarzyna Świderska, Marta Mianowska-Malec, Agnieszka Pasierbek, Barbara Łanoszka, Konstanty Chomik, Barbara Bobek-Billewicz, Michał Jarząb. Fdg PET/CT early response prediction for triple negative breast cancer neoadjuvant chemotherapy with addition of carboplatin [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 P2-12-07.

Abstract ES5-2: Optimizing the management of early stage TNBC

Abstract The recent approvals of the immunotherapeutic agent pembrolizumab, the antibody-drug conjugate sacituzumab govitecan and the PARP inhibitors olaparib and talazoparib for select patients with metastatic triple negative breast cancer (TNBC) have spurred interest in evaluating these and other novel agents in patients with earlier stage disease. For the last several decades, a standard approach to treating early stage TNBC was to administer neoadjuvant chemotherapy, most often an anthracycline/taxane-based regimen. Pathologic complete response (pCR) rates generally ranged 30-40%. Trials such as CALGB 40603, GeparSixto and BrighTNess demonstrated that the addition of carboplatin to an anthracycline and taxane based chemotherapy could increase the pCR rates (53-58%). At the most recent ESMO conference, the BrighTNess investigators reported that the addition of carboplatin improved event free survival (EFS) after a median follow-up of 4.5 years. For patients not experiencing a pCR, the Create-X trial showed benefit of capecitabine in the adjuvant setting.As of August 2021, there is a new standard for treating early stage TNBC. Specifically, based on the KEYNOTE-522 trial, pembrolizumab, in combination with chemotherapy, is FDA approved for this indication. KEYNOTE-522 enrolled over 1170 stage 2-3 TNBC patients and randomized them to chemotherapy +/- pembrolizumab. The most recent report showed the trial met it’s co-primary endpoints of improved pCR (63% vs 56%) and EFS (84.5% vs 76.8%) after a median follow-up of 39 months. Importantly, the benefit was regardless of the PD-L1 status of the patient’s tumor. With the approval of pembrolizumab comes a number of questions: 1) which patients should receive this regimen which is associated with immune-related toxicities, some of which are lifelong, 2) what is the optimal chemotherapy backbone, 3) is a full year of pembrolizumab required and 4) are there other biomarkers to be explored that may predict response to therapy or the development of toxicity? Other studies either have or are evaluating other targeted agents in the preoperative setting for early stage TNBC. In a small study of 20 BRCA mutation carriers treated preoperatively with single agent talazoparib, investigators reported a pCR rate of 53%. A study looking at sacituzumab monotherapy in the preoperative setting has completed accrual and the results are awaited. These two trials begin to address the question of whether we can identify an “achilles” heel in TNBC and if so, will targeting it improve patient outcomes. Good correlative studies that provide improved understanding of the impact of these therapies on the TNBC microenvironment will help inform the next generation of trials; likely combination therapies.There is also the question of adjuvant therapy, particularly for those that do not experience a pCR with preoperative therapy. As stated above, the CREATE-X trial supports the use of capecitabine in patients with residual disease, however EA1131 demonstrated that outcomes are still poor for this population. More recently, for patients with BRCA-mutated cancers, the OlympiA trial showed benefit to a year of adjuvant olaparib. There is also growing interest in whether patients with residual disease who are at highest risk for recurrence can be identified using technologies looking for cell-free DNA to find those with minimal residual disease. Historically we’ve thought about TNBC for what it’s not – it is not ER, PR or HER2 positive. With multiple studies now showing benefit of specific agents in TNBC, the next several years will provide an opportunity to more extensively dissect triple negative tumors and their. microenvironment. This will allow us to learn what TNBC “is”, and which of likely multiple different therapeutic strategies will be best applied to which patients. Citation Format: E Mittendorf. Optimizing the management of early stage TNBC [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 ES5-2.

Abstract ES6-4: Parp inhibitors for brca1/2mutation associated breast cancer

Abstract More than 15 years ago we and others showed the use of potent PARP1 inhibitors (PARPi), that both inhibit the catalytic activity of the PARP1 enzyme and trap PARP1 onto DNA, generate a “synthetic lethal” interaction with the malignant cell specific loss of function of genes crucial for homologous recombination (HR) gene function. This phenomenon has now been exploited with therapeutic intent in several contexts leading to approved single agent PARPi treatments for advanced forms of ovarian, prostate, pancreatic and breast cancers. These approvals have in large part been associated a biomarker requirement for evidence of loss of function of HR. Recently a number of trials have investigated PARPi in a (neo)adjuvant breast cancer treatment (NACT) setting in patients with (or enriched for) HR deficiency. These have included phase II neoadjuvant PARPi studies such as the NeoTALA study using single agent talazoparib in germline BRCA1 and BRCA2 mutation carriers and the combination chemotherapy and olaparib therapy studies GeparOLA and PARTNER, enriched for HR deficient breast cancer, that have reported important signals with regard efficacy and tolerability. Two recent phase III trials have influenced recent early breast cancer treatment guidelines. These are the BrighTNess trial in the neoadjuvant setting and OlympiA in the post-(neo)adjuvant setting. BrighTNess recruited patients with biologically heterogeneous triple negative breast cancer (TNBC) and used the weak PARP1 trapping PARPi veliparib and OlympiA restricted eligibility to patients with the germline “pathogenic” or “likely pathogenic” mutation in BRCA1 or BRCA2 but included patients with hormone receptor positive breast cancer. BrighTNess did not show convincing evidence of benefit to the addition of veliparib to standard of care in TNBC NACT but has shown the benefit to the addition of carboplatin to sequential paclitaxel-AC NACT with significant improvements in event free survival (HR 0.57 ) compared to sequential paclitaxel-AC alone. OlympiA has reported following an interim analysis showing 12 months of olaparib in the post-(neo)adjuvant chemotherapy setting improves both invasive disease free and distant disease free survival by approximately 40% with highly statistically significant hazard ratios of 0.58 and 0.57 respectively that met pre-specified early stopping boundaries. The publication of results for OlympiA has led to rapid updates of both genetic testing and treatment international guidelines for BRCA1 and BRCA2 mutation associated breast cancer to include use of olaparib in patients meeting the eligibility criteria for the trial. The lecture will both explore the data and the implications for practice of the adoption of these guidelines and some of the ongoing questions to be addressed by ongoing clinical trial and translational research initiatives. Citation Format: ANJ Tutt. Parp inhibitors for brca1/2mutation associated breast cancer [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 ES6-4.

Matched cohort study of germline BRCA mutation carriers with triple negative breast cancer in brightness

In the BrighTNess trial, carboplatin added to neoadjuvant chemotherapy (NAC) was associated with increased pathologic complete response (pCR) rates in patients with stage II/III triple-negative breast cancer (TNBC). In this matched cohort study, cases with a germline BRCA1/2 mutation (gBRCA; n = 75) were matched 1:2 with non-gBRCA controls (n = 150) by treatment arm, lymph node status, and age to evaluate pCR rates and association of benefit from platinum/PARP inhibitors with validated RNA expression-based immune, proliferation, and genomic instability scores among gBRCA with the addition of carboplatin ± veliparib to NAC. Among the well-matched cohorts, odds of pCR were not higher in gBRCA cancers who received standard NAC with carboplatin (OR 0.24, 95% CI [0.04-1.24], p = 0.09) or with carboplatin/veliparib (OR 0.44, 95% CI [0.10-1.84], p = 0.26) compared to non-gBRCA cancers. Higher PAM50 proliferation, GeparSixto immune, and CIN70 genomic instability scores were each associated with higher pCR rate in the overall cohort, but not specifically in gBRCA cases. In this study, gBRCA carriers did not have higher odds of pCR than non-gBRCA controls when carboplatin ± veliparib was added to NAC, and showed no significant differences in molecular, immune, chromosomal instability, or proliferation gene expression metrics.

Phase 1 multicenter study of the HSP90 inhibitor SNX-5422 plus carboplatin and paclitaxel in patients with lung cancers

ObjectivesSingle-agent heat shock protein 90 (HSP90) inhibition has demonstrated activity in oncogene-driven non-small cell and small cell lung cancers. SNX-5422 is an oral HSP90 inhibitor with increased activity in vitro with the addition of carboplatin and paclitaxel. Therefore, we conducted a phase 1, open-label, multicenter study to evaluate SNX-5422, carboplatin and paclitaxel followed by SNX-5422 maintenance in patients with advanced lung cancers. Materials and methodsIn part 1 (3 + 3 dose escalation), SNX-5422 (50/75/100-mg/m2) was dosed every other day (qod) for 21 days (28-day cycle) for ≤4 cycles; carboplatin (AUC 5)-paclitaxel (175 mg/m2) was administered once every 3 weeks for ≤6 courses. In part 2 (maintenance), subjects who achieved at least stable disease in part 1 received 100 mg/m2 SNX-5422 monotherapy qod for 21 days (28-day cycle). ResultsTwenty-three patients with advanced non-small cell lung cancer (NSCLC, n = 20) and small cell lung cancer (SCLC, n = 3) were enrolled. The median age was 60 years and 61% (n = 14/23) had ≥1 prior treatment regimens. The maximum tolerated dose of SNX-5422 was 100 mg/m2 qod in combination with carboplatin-paclitaxel. The most common treatment-related grade 3/4 adverse events (part 1/part 2) were diarrhea (26%/15%) and nausea (9%/0%). In response-evaluable patients with NSCLC, 33% (6/18) had a partial response, 56% (10/18) stable disease, and 11% (2/18) progressive disease. Patients who remained on single-agent SNX-5422 maintenance therapy ≥2 months (n = 9) had cancers enriched for oncogenic drivers (n = 3 KRAS mutation, n = 1 EGFR exon 20 mutation, n = 1 HER2 mutation, and n = 1 RET fusion). ConclusionsThe triplet combination of SNX-5422, carboplatin and paclitaxel followed by maintenance SNX-5422 therapy was well-tolerated and showed anti-tumor activity. Cancers for which disease control on single-agent SNX-5422 maintenance was observed were enriched for oncogene-driven NSCLCs.

Pathological complete response to neoadjuvant chemotherapy, but not the addition of carboplatin, is associated with improved survival in Chilean triple negative breast cancer patients: a report of real world data.

BackgroundBreast cancer (BC) is the leading cause of cancer death for Chilean women. About 11% of cases are triple-negative (TN) BC. These are characterised by poor prognosis, higher risk of early recurrence and visceral dissemination versus other BC subtypes. Current standard treatment for early-stage non-metastatic TNBC patients consists of neoadjuvant chemotherapy (NACT) followed by surgery and radiotherapy. Pathological complete response (pCR) to NACT is associated with an increase in survival rates. In general, NACT and adjuvant regimens involve similar cytotoxic drugs. Recent studies have postulated that the use of platinum compounds in TNBC would increase response rates. However, their effects on patient survival remain uncertain.Materials and methodsWe retrieved and analysed medical records from a total of 156 Chilean stage I–III TNBC female patients that received NACT and compared survival rates using carboplatin (Cb)-containing versus non-Cb-containing regimens at two health cancer centres.ResultsMedian age was 51 years (range: 24–81); 13.5% (n = 21) received Cb-containing regimens, 80.1% (n = 125) received sequential anthracyclines plus taxanes; 29.5% (n = 46) of the total group achieved pCR, 28% for the standard treatment and 35% (n = 8) for the Cb-containing group (p = 0.59). We confirmed pCR was associated with prolonged overall survival, invasive and distant disease-free survival (Log-rank p = 0.0236). But the addition of Cb was not associated with differences in survival measures (Log-rank p = 0.5216).ConclusionsTo the best of authors’ knowledge, this is the first report on real-world data in the Chilean population assessing the effect of Cb-containing NACT in TNBC. The authors’ results suggest no survival benefit by the addition of Cb to standard NACT. However, we confirm an increase in survival associated to pCR regardless of treatment.

Procoagulant activity in high grade serous ovarian cancer patients following neoadjuvant chemotherapy-The role of the activated protein C pathway

IntroductionOvarian cancer patients are at high risk of thrombosis particularly during chemotherapy treatment however the mechanism is not understood. The aim of this study is to investigate the role of the activated protein C (aPC) pathway in the procoagulant activity observed in ovarian cancer patients undergoing neoadjuvant chemotherapy. Patients and methodsThrombin generation was determined before and after addition of thrombomodulin (TM) in high grade serous ovarian cancer (HGSOC) patients treated with neoadjuvant chemotherapy (n = 29) compared with HGSOC patients who were chemo naïve (n = 23) and patients with benign tumours (n = 29). Plasma expression of proteins from the aPC pathway was analysed. mRNA expression was determined in endothelial (EA.hy926) and ovarian (OAW42) cell lines following addition of carboplatin and paclitaxel. ResultsLower levels of ETP (p < 0.007; p < 0.003) and peak thrombin (p < 0.0008; p < 0.0018) were found in the neoadjuvant group compared with both chemo naïve and benign groups. Following addition of TM, ETP (p < 0.0005) and peak thrombin (p < 0.0049) were higher in the neoadjuvant group compared with the benign controls indicating an increase in aPC resistance. Increased TM and lower levels of protein S were found in the neoadjuvant group compared with benign controls (p < 0.05; p < 0.003). Factor V levels were increased in the neoadjuvant group compared with the chemo naïve group (p < 0.05). Carboplatin and paclitaxel altered the expression of EPCR and thrombomodulin in OAW42 cells with a modest effect on EA.hy926 cells. ConclusionChemotherapy induced procoagulant activity in HGSOC is associated with an alteration in expression of key members of the aPC pathway. This acquired aPC resistance may explain the procoagulant phenotype associated with ovarian cancer patients undergoing chemotherapy.

Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer: A Pairwise and Network Meta-Analysis of Pathological Complete Response.

We performed a pairwise and network meta-analysis to compare pathological complete response (pCR) among neoadjuvant chemotherapy in patients with triple-negative breast cancer. We searched PubMed for randomized clinical trials between January 1, 2000 and December 1, 2020. s from meetings were also searched. A frequentist random-effect model was applied to compare pCR and toxicities. The P-score was used to rank treatment effects. Nineteen trials with 16 treatments and 7794 patients were included. On the basis of SoC, the addition of carboplatin (OR = 1.82, 95% CI, 1.24 to 2.68, P < .01) and the addition of checkpoint inhibitors (OR = 1.69, 95% CI, 1.23 to 2.32, P < .01) increased pCR in pairwise meta-analysis; compared with paclitaxel, nab-paclitaxel did not improve pCR rates (OR = 1.81, 95% CI, .80 to 4.12, P = .16). The anthracycline-sparing regimen led to similar pCR compared with the anthracycline-containing regimen (OR = 1.50, 95% CI, .82 to 2.76, P = .19). In network meta-analysis, the addition of carboplatin plus a PD-1 inhibitor (pembrolizumab), carboplatin plus bevacizumab, and carboplatin plus veliparib ranked as the top three treatments for achieving pCR, with corresponding P-scores of .91, .84, and .72, respectively. Among patients with homologous recombination deficiency, the addition of carboplatin (OR = 1.31, 95% CI, .69 to 2.50, P = .41) or carboplatin plus PARP inhibitors (OR = 1.19, 95% CI, .58 to 2.47, P = .63) did not increase pCR. For triple-negative breast cancer, combining carboplatin with taxane-anthracycline-containing neoadjuvant chemotherapy could be the standard of care, and the combination containing checkpoint inhibitor is promising. However, their role in long-term oncologic outcome remains to be determined.

Addition of carboplatin to chemotherapy regimens for metastatic castrate-resistant prostate cancer in post-second generation hormone therapy setting: Does it improve treatment response and survival outcomes?

e17540 Background: The clinical course in metastatic castrate-resistant prostate cancer (mCRPC) can be complicated when patients have disease progression after treatment with 2nd generation hormone therapy (2nd-HT), such as enzalutamide or abiraterone. Currently, limited data exist regarding the optimal choice of chemotherapy for mCRPC after failing 2nd-HT. We sought to evaluate three common chemotherapy regimens in this setting. Methods: We retrospectively identified 150 patients with mCRPC with disease progression on enzalutamide or abiraterone. 92 patients were chemo-naïve, while 58 patients had previously received docetaxel chemotherapy prior to 2nd-HT. After failing 2nd-HT, 90 patients received docetaxel-alone (group A), 33 patients received carboplatin plus docetaxel (group B), while 27 patients received cabazitaxel-alone (Group C). Favorable response was defined by ≥50% reduction in PSA level from baseline after a complete course of chemotherapy. Survival outcome was assessed for 30-month overall survival. Results: Mean (SD) age was 71.2 (8.28), 69.5(8.38) and 67.2 (8.36) for group (A), (B) and (C), respectively. Mean (SD) pre-chemotherapy PSA was 63.8 (138.18), 58.5 (118.15) and 53.7 (88.15) for group (A), (B) and (C), respectively. Mean (SD) Gleason score was 7.9 (1.1), 8.4 (0.88) and 8.1 (1.06) for group (A), (B) and (C), respectively. Patients in group (B) were 2.6 times more likely to have a favorable response compared to group (A) (OR = 2.625, 95%CI: 1.15 - 5.99) and almost 3 times compared to patients in group (C) (OR = 2.975, 95%CI: 1.04 – 8.54) (p-value = 0.0442). We report a Hazard Ratio (HR) of 3.1 (95% CI 1.31-7.35; p = 0.0037) between patients in group (A) versus group (B), and a HR of 4.18 (95% CI 1.58-11.06; p = 0.0037) between patients in group (C) versus group (B). Thirty-month overall survival was 70.7%, 38.9%, and 30.3% for group (B), (A), and (C) respectively (p-value = 0.008). Conclusions: Our data demonstrate improved response and cancer-specific survival in patients with treatment-refractory mCRPC on docetaxel plus carboplatin compared to docetaxel or cabazitaxel alone. Selection bias is inherent in any retrospective study; however, our finding suggests that clinicians may consider docetaxel plus carboplatin in mCRPC patients who fail 2nd-HT. Further prospective studies are warranted.

A pilot study of docetaxel and carboplatin for treatment of patients with mCRPC containing biallelic inactivation of genes in the BRCA1/2 pathway.

127 Background: Despite new treatments, metastatic castration resistant prostate cancer (mCRPC) remains ultimately lethal. Upwards of 25% of mCRPC tumors have alterations in homologous recombination DNA repair (HRD) genes, most frequently BRCA2. Retrospective data suggest addition of the DNA damaging agent carboplatin to standard docetaxel for patients with mCRPC whose tumors have biallelic inactivation of BRCA2 may be effective. Methods: In this prospective, pilot single-arm phase 2 study, we assess response to the combination of docetaxel 60mg/m2 and carboplatin AUC 5 IV q21 days in patients with mCRPC whose tumors have evidence of biallelic inactivation of BRCA1, BRCA2 or ATM and have progressed after any prior treatment, including prior docetaxel and/or PARP inhibitor (PARPi). The primary endpoint is rate of ≥50% PSA decline from baseline (PSA50). With H0 of PSA50 of 26%, 14 patients will provide 80% power to conclude H1 of PSA50 of 60% based on Simon's 2-stage design with 1-sided α = 5%. Secondary endpoints include PSA30, response duration, time to progression and correlative studies. Biallelic inactivation of other HRD-related genes were included at investigators’ discretion. Results: The study opened in Jan 2016 and has enrolled 8/14 (57%) of patients plus 5 patients with other HRD-related genes. 6/13 (46%) treated pts had grade 3 expected AEs, and no grade 4-5 AEs were observed. To date, 7/8 (88%) of pts with biallelic inactivation of BRCA1, BRCA2 and ATM (Table) and 10/13 (77%) of all pts achieved a PSA50 (other HRD-related genes include CDK12, CHD1, MRE11A and PALB2). Updated results will be reported at final presentation. Conclusions: Addition of carboplatin to docetaxel appears to be well-tolerated and effective for patients with mCRPC whose tumors have biallelic inactivation in selected HRD genes such as BRCA2, including those with prior treatment with PARP inhibitor. Clinical trial information: NCT02598895. [Table: see text]

Breast Conservation After Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer

Neoadjuvant systemic therapy (NST) is often administered to enable breast-conserving therapy (BCT) in stages II to III breast cancer. To prospectively evaluate the role of NST in conversion from BCT ineligibility to BCT eligibility and to assess the association of response to NST, germline BRCA (gBRCA) status, and region of treatment with surgical choice in women with triple-negative breast cancer (TNBC). This prespecified secondary analysis of a multicentered, phase 3, double-blind, randomized clinical trial (BrighTNess) enrolled 634 eligible women across 145 centers in 15 countries in North America, Europe, and Asia. Women with operable, clinical stages II to III TNBC who underwent gBRCA mutation testing before initiating NST were eligible to participate. Data were collected from April 1, 2014, to December 8, 2016. This preplanned analysis was performed from January 5, 2018, to October 28, 2019. Study participants were randomized to receive 12 weeks of weekly paclitaxel alone or with the addition of carboplatin and/or veliparib, followed by 4 cycles of doxorubicin hydrochloride and cyclophosphamide. Surgeons assessed BCT candidacy by clinical and radiographic criteria before and after NST. Surgical choices and whether BCT eligibility was associated with the likelihood of pathologic complete response were then analyzed. Among the 634 randomized patients (median age, 51 [range, 22-78] years), pre- and post-NST assessments were available for 604 patients. Of 141 patients deemed BCT ineligible at baseline, 75 (53.2%) converted to BCT eligible. Overall, 342 (68.1%) of 502 patients deemed BCT eligible after NST underwent BCT, including 42 (56.0%) of the 75 who converted to BCT eligible. Patients treated in Europe and Asia were more likely to undergo BCT (odds ratio, 2.66; 95% CI, 1.84-3.84) compared with those treated in North America. Among patients without gBRCA mutation undergoing mastectomy, those treated in North America were more likely to undergo contralateral prophylactic mastectomy (57 of 81 [70.4%] vs 6 of 30 [20.0%]; P < .001). Rates of pathologic complete response were similar between patients deemed BCT eligible at baseline and those who were BCT ineligible but converted to BCT eligibility after NST (55.3 [235 of 425] vs 49.3% [37 of 75]; P = .38). This prospective analysis of NST and BCT eligibility in TNBC demonstrates a conversion from BCT ineligibility to BCT eligibility of 53.2%. Lower BCT rates among eligible patients and higher bilateral mastectomy rates among patients without gBRCA mutation in North America merit investigation. ClinicalTrials.gov identifier: NCT02032277.

Abstract P1-13-08: A prospective non-randomized clinical trial of adjuvant carboplatin chemotherapy in triple negative breast cancer

Abstract Background: The addition of carboplatin in the neoadjuvant setting has demonstrated improved outcomes in patients with triple negative breast cancer (TNBC). Carboplatin in the adjuvant setting has not been demonstrated to be an accepted regimen to date. This trial addresses this issue. Methods: The primary objectives of this study were to assess the toxicity of an adjuvant carboplatin-containing regimen for early stage TNBC patients, and to correlate outcomes with molecular markers including Spy-1. Secondary objectives included determination of progression free (PFS) and overall survival (OS), and comparing these to our institutional historical controls. Patients received the backbone of a dose dense anthracycline, taxane, cyclophosphamide (DD ACT), with the addition of carboplatin. Results: Ninety patients with stage I to III patients with triple negative breast cancer were accrued to this trial between Jan 2011 and June 2017. We discovered that DD ACT with carboplatin with an AUC of 5 given on the second and last paclitaxel was well tolerated. Chemotherapy delays were minimized when the parameters for administration of the carboplatin was to allow chemotherapy to proceed if the platelet count was &amp;gt;/= 70,000 x10^9/L and dose adjustment of paclitaxel was allowed based on neuropathy. There were no grade 4 adverse events. 4% of patients had grade 3 peripheral neuropathy (PN), 28% had grade 2 PN and 45% had grade 1 PN. Results of molecular profiles will be reported. Univariate analysis are reported, and were found to be very promising. Using log-rank statistic, a trend to improvement in overall survival was found when compared to historical controls (p=0.089). Median follow-up is 24 months. Longer follow-up is necessary to determine PFS and overall survival benefit. Conclusion: If considering an adjuvant regimen for triple negative breast cancer patients DDAC/TC with the carboplatin administered with an AUC of 5 on the second and fourth taxol of DDACT is a well-tolerated regimen. Univariate Analysis Comparing Carboplatin vs Historical Controls that did not receive CarboplatinVariableHistorical (no carbo)Carbo containing chemop overall n = 179n = 82 Age56.3 (13.1)49.8 (11.0)&amp;lt; 0.001Stage0.188Stage I47 (26.3%)15 (18.3%) Stage II88 (49.2%)50 (61.0%) Stage III44 (24.6%)17 (20.7%) Grade0.011Grade 18 (4.5%)0 (0.0%) Grade 233 (18.4%)7 (8.8%) Grade 3138 (77.1%)73 (91.2%) Remission Status0.009In Remission126 (70.4%)70 (86.4%) Relapsed53 (29.6%)11 (13.6%) Survival&amp;lt; 0.001Alive121 (67.6%)73 (90.1%) Deceased58 (32.4%)8 (9.9%) Citation Format: Hamm C, Kulkarni S, Gupta R, Mathews J, Amin K, Hussein A, Porter L. A prospective non-randomized clinical trial of adjuvant carboplatin chemotherapy in triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-13-08.

Abstract P1-15-19: Carboplatin-addition in neoadjuvant treatment of women with triple negative breast cancer (TNBC): Prognostic value in real-world patients

Abstract Background The addition of carboplatin to an anthracycline/taxane-based chemotherapy(CT) in neoadjuvant setting has been suggested to improve pathological complete response(pCR) in TNBC. However, the impact of pCR in prognosis is unknown. We aim to study the value and feasibility of the addition of carboplatin in neoadjuvant setting. Methods Demographic and clinical data of TNBC patients treated with neoadjuvant CT in a comprehensive cancer center between 2010-2018 were retrospectively collected. Two cohorts were defined: one treated with Carboplatin/Paclitaxel followed by dose-dense Doxorrubicin/Cyclophosphamide(CP-AC) and other with AC followed by Docetaxel(AC-D). Median follow-up time was 3.1 and 6.9 years, respectively. pCR was defined as absence of residual invasive tumor in breast/axilla. Survival analysis using Kaplan-Meier method and Cox proportional-hazards model were applied. Statistical significance was set at p&amp;lt;0.05. Results One-hundred and sixty patients were enrolled: 78 CP-AC and 38 AC-D. Groups were balanced regarding patients and tumor characteristics with exception of pre-menopausal status, more frequent in CP-AC(68% vs 47%;p=.04). Age at diagnosis was 47(28-76)years, the majority had ECOG 0(92%) ductal carcinomas(82%), clinicalT2/3 stages(76%), grade 3(81%) with lymph node involvement(N+)(57%). 14% had Inflammatory breast cancer(IBC)(CP-AC 14%;AC-D 13%; p=.9). Neutropenia was the most prevalent adverse event(G3/4: CP-AC 61%;AC-D 16%;p=.02), 12% and 16% of febrile neutropenia(p=.8). G3/4 thrombocytopenia occurred only in CP-AC(6%). Hypersensitivity reactions were more prevalent in CP-AC(19% vs 2.7%;p=.02), majority to paclitaxel, all G1/2. Hospital admission occurred in 12%(CP-AC 13%;AC-D 9%; p=.8). There were no treatment-related deaths. Treatment schedule was complete in 89%(CP-AC 87%;AC-D 92%;p=.5), with 20% dose reductions(CP-AC 25%;AC-D 11%;p=0.9). pCR was achieved in 42%(CP-AC 50%;AC-D 28%;p=.03). 1- and 3-year disease-free survival(DFS) was 94%/85% for CP-AC and 72%/58% for AC-D(p=.3). Risk of recurrence was higher in IBC(HR 25.1;CI95% 7.7-81.3;p&amp;lt;.0001), N+ disease(HR 3.6;CI95% 1.2-10.5;p=.02) and non-pCR(HR 10.9;CI95% 2.3-52.3,p=.003). N+ disease was associated with higher recurrence only in AC-D(HR 11.7;CI95% 1.3-104;p=.03). Cancer-related deaths were 20%(CP-AC 10%;AC-D 40%;p=.001). 1- and 2-year overall survival (OS) was 99%/95% for CP-AC and 70%/61% for AC-D(p=.06). N+ disease was associated with higher risk of death in AC-D(HR 6.3;CI95% 1.1-24.6;p=.04). Risk of death was independently associated with IBC(HR 4.1;CI95% 2.1-18.7; p=.001) but not with N+ disease(HR 2.7;CI95% 0.8-9.5;p=.13) or pCR(HR 4.1;CI95% 0.9-19.7;p=.08) although pCR was statistically significant in univariate analysis (1- and 2-year OS 97% vs 92% and 94% vs 86% for pCR and non-PCR;p=.003). Conclusions Carboplatin addition clearly increased pCR with a trend to DFS and OS benefit. This regimen was associated with more, nevertheless manageable, adverse events with most of the patients able to tolerate and complete the full-dose regimen. Though we did not find a subgroup of patients that benefit with carboplatin regimen, we should consider avoiding AC-D at least in N+ disease. Citation Format: Coelho S, Abreu MH, Sales C, Lopes AR, Sousa MF, Couto R, Pousa I, Ferreira A, Ferreira M, Vieira C, Leal C, Castro F, Sousa S, Pereira D. Carboplatin-addition in neoadjuvant treatment of women with triple negative breast cancer (TNBC): Prognostic value in real-world patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-19.

Abstract P1-15-16: Pathological complete response rates with the addition of carboplatin to standard neoadjuvant chemotherapy in a cohort of real–world patients with triple negative breast cancer

Abstract Objectives: Addition of carboplatin to standard neoadjuvant chemotherapy (NACT) for triple negative breast cancer (TNBC) remains controversial. There are several randomized trials showing that carboplatin increases the likelihood of achieving pathological complete response (pCR) in TNBC. Patients with TNBC who achieve pCR has been shown to have better disease-free and overall survival. The aim of this study was to asses the impact of adding carboplatin to standard NACT in TNBC in terms of pCR rates and toxicity. Methods:In this cross-sectional study, 252 consecutive patients with primary TNBC who were submitted to neoadjuvant chemotherapy between 2013 and 2018, in a single center, were selected. Patients with biopsy-confirmed TNBC, previously untreated, with clinical stages I-III were included (n=179). Clinical pathological features, pathological response, treatment protocol, and toxicities were analyzed and considered for statistical analysis. Eighty patients treated from 2013 to 2015 received doxorubicin plus cyclophosphamide once every 3 weeks (AC) for four cycles, followed by 12 weeks (wP) or every 3 weeks (P) paclitaxel(AC-T group). Ninety-nine patients, treated from 2015 to 2018 had four cycles of AC followed by wP plus weekly carboplatin (Cb) area under curve (AUC) 1.5-2.0 (AC-TCb group). Pathologic response was determined locally, and pCR was defined as the absence of residual invasive disease with or without ductal carcinoma in situ in the breast and axilla. Results: Data from 179 patients were included in the analysis (AC-T: n=80; AC-TCb: n=99). Patients in AC-TCb group had a median age of 51.7 years vs. 47.4 years in AC-T group, p=0.01. In AC-TCb group 61.6% of patients were postmenopausal vs 43.7% in AC-T group, p=0.03. The distribution of clinical stage in groups AC-TCb and AC-T were as follows: stage I 6.0% vs 0%; stage II 42.4% vs 43.7%; stage III 51.6% vs 56.3%, respectively (p=0.02). In AC-TCbgroup, 34 patients (35.0%) had pCR in comparison to 20 patients (25.0%) on AC-T group (p=0.22). Pathological stage distribution in groups AC-TCb and AC-T were: stage I 24.7% vs 33.7%; stage II 23.7% vs 26.3%; stage III 16.4% vs 15%, respectively (p=0.42). More than 85.0% of patients in AC-TCb group received at least 9 weeks of carboplatin and less than 20.0% required dose reduction due to toxicity.Conclusions: An improved pathological complete response for TNBC patients submitted to standard NACT plus carboplatin was observed. The results are in accordance with previous studies demonstrating that the addition of carboplatin to NACT improves pCR rate in TNBC with a favorable risk to benefit profile. Therefore carboplatin might be a potential component of NACT and should be considered in this context. Distribution of patients with TNBC submitted to NACT with AC-T and AC-TCb according clinical–pathological characteristicsClinical pathological characteristicsAC-T n= 80AC-TCb n=99pMenopausal 0.03yes3561 no4538 Clinical stage 0.02I06 II3542 III4551 Histologic type 0.25IDC8096 others03 Histologic grade 0.86101 22932 35164 Pathological stage 0.42O2034 I2724 II2123 III1216 pCR 0.22yes2034 no6063 Citation Format: Ramalho S, Natal RdA, Cardoso Filho C, Xavier MB, da Silva AER, Silva LR, Vasconcelos V, Reinert T, Coelho GP, Silva GRdP, dos Santos CC. Pathological complete response rates with the addition of carboplatin to standard neoadjuvant chemotherapy in a cohort of real–world patients with triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-16.

Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial

Although several randomised trials in patients with triple-negative breast cancer have shown that the addition of carboplatin, with or without poly(ADP-ribose) polymerase (PARP) inhibitors, to neoadjuvant chemotherapy increases the likelihood of achieving a pathological complete response, the use of these therapies in this setting has remained controversial. The BrighTNess trial was designed to assess the addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer. We did a phase 3, randomised, double-blind, placebo-controlled trial (BrighTNess) across 145 sites in 15 countries. Patients aged 18 years and older with previously untreated histologically or cytologically confirmed clinical stage II-III triple-negative breast cancer, who were candidates for potentially curative surgery and had an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly assigned (2:1:1) by an interactive response technology system via permuted blocks (block size of four) within strata to receive one of three segment 1 regimens: paclitaxel (80 mg/m2 intravenously weekly for 12 doses) plus carboplatin (area under the curve 6 mg/mL per min, intravenously every 3 weeks, for four cycles) plus veliparib (50 mg orally, twice a day); paclitaxel plus carboplatin plus veliparib placebo (twice a day); or paclitaxel plus carboplatin placebo (every 3 weeks for four cycles) plus veliparib placebo. Following segment 1, all patients were assigned to segment 2 in which they received doxorubicin and cyclophosphamide every 2-3 weeks for four cycles. Randomisation for segment 1 was stratified by germline BRCA mutation status, nodal stage, and planned schedule of doxorubicin and cyclophosphamide administration. The primary endpoint was pathological complete response in breast and lymph nodes as determined by site pathologists following completion of neoadjuvant therapy. Efficacy analyses were done by intention to treat and safety analyses included all patients who received at least one dose of study treatment. These are the first results of an ongoing clinical trial; the data cutoff for the analyses presented was Dec 8, 2016. This study is registered with ClinicalTrials.gov, number NCT02032277. Between April 4, 2014, and March 18, 2016, 634 patients were randomly assigned: 316 to paclitaxel plus carboplatin plus veliparib, 160 to paclitaxel plus carboplatin, and 158 to paclitaxel alone. The proportion of patients who achieved a pathological complete response was higher in the paclitaxel, carboplatin, and veliparib group than in patients receiving paclitaxel alone (168 [53%] of 316 patients vs 49 [31%] of 158, p<0·0001), but not compared with patients receiving paclitaxel plus carboplatin (92 [58%] of 160 patients, p=0·36). Grade 3 or 4 toxicities, and serious adverse events were more common in patients receiving carboplatin, whereas veliparib did not substantially increase toxicity. The most common grade 3 or 4 events overall were neutropenia (352 [56%] of 628 patients), anaemia (180 [29%]), and thrombocytopenia (75 [12%]) through complete treatment, and febrile neutropenia (88 [15%] of 601 patients) during segment 2. The most common serious adverse events were febrile neutropenia (80 [13%] of 628 patients) and anaemia (20 [3%]). Although the addition of veliparib and carboplatin to paclitaxel followed by doxorubicin and cyclophosphamide improved the proportion of patients with triple-negative breast cancer who achieved a pathological complete response, the addition of veliparib to carboplatin and paclitaxel did not. Increased toxicities with the addition of carboplatin (with or without veliparib) to paclitaxel were manageable and did not substantially affect treatment delivery of paclitaxel followed by doxorubicin and cyclophosphamide. Given the consistent results with previous studies, the addition of carboplatin appears to have a favourable risk to benefit profile and might be considered as a potential component of neoadjuvant chemotherapy for patients with high-risk, triple-negative breast cancer. AbbVie.