Adjuvant Epirubicin Plus Cyclophosphamide Followed by Taxanes With or Without Carboplatin in Early-Stage Triple-Negative Breast Cancer (RJBC 1501): A Randomized Phase III Trial.

INTRODUCTION
Approximately 15%-20% of the breast cancer are triple-negative breast cancer (TNBC).1 TNBC is associated with aggressive biologic behavior, featured with higher histologic grade, highly proliferative behavior with frequently elevated Ki67 expression, and a greater rate of distant metastasis2,3 and are predominantly treated with chemotherapy before the introduction of immune checkpoint inhibitor (ICI).3,4 Although anthracycline and taxane agents have significantly improved disease outcome for early-stage TNBC, and are routinely recommended in the adjuvant setting, these patients still suffer from high risk of recurrence.5 Thus, novel adjuvant regimens are needed to improve prognosis.

CONTEXT

Key Objective

To evaluate the efficacy and safety of adding carboplatin to epirubicin plus cyclophosphamide followed by taxanes (EC-T) in the adjuvant treatment of patients with early-stage triple-negative breast cancer (TNBC).

Knowledge Generated

In this phase III study, the addition of adjuvant carboplatin to the standard EC-T regimen significantly improved disease-free survival, distant disease-free survival, and overall survival in patients with TNBC, with no new safety profiles.

Relevance (K.D. Miller)

This trial adds to the growing body of data supporting the inclusion of platinum in the treatment of patients with early-stage TNBC.*

*Relevance section written by JCO Senior Deputy Editor Kathy D. Miller, MD.

Preclinical data suggested that TNBC may be more sensitive to DNA-damaging agents because of the deficiencies in BRCA-associated DNA repair mechanism. Several trials and meta-analysis,6 including CALGB 406037 and GeparSixto,8 found that the addition of carboplatin to standard anthracycline and taxane agents could improve pathologic complete response (pCR) rate. On the basis of these results, carboplatin has been considered for high-risk early-stage TNBC in the neoadjuvant setting. Nevertheless, the evidence of carboplatin in adjuvant setting for patients with TNBC was limited.
Here, RJBC 1501 (ClinicalTrials.gov Identifier: NCT02455141) is a randomized, controlled, open-label, phase III trial evaluating the efficacy and safety of adding carboplatin to epirubicin plus cyclophosphamide followed by taxanes (EC-T) in the adjuvant setting for patients with early-stage TNBC.

PATIENTS AND METHODS
The RJBC1501 trial is a randomized, open-label, multicenter, phase III clinical trial. This study was approved by the ethics committees or institutional review boards at each participating institution. All participants provided written informed consent. The study was conducted in accordance with the Declaration of Helsinki.

Study Design and Participants
Eligible patients were women age 18-69 years with invasive TNBC who had undergone complete tumor resection and were suitable for adjuvant chemotherapy. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) statuses were determined locally at each participating center on the basis of immunohistochemistry (IHC) of primary tumor sections according to ASCO/College of American Pathologists test guidelines. ER and PR negativity was initially defined as <1% of tumor cells with positive nuclear staining; in June 2018, the protocol was amended to allow patients with ER <10% and PR <10% positivity to be included in this study (version 3.0).9 HER2-negative status was defined as a score of 0 or 1 by IHC or the absence of HER2 amplification by fluorescence in situ hybridization with an IHC score of 2. Patients with pathologically confirmed node-positive disease or node-negative disease with a primary tumor diameter of 10 mm or greater were included. The detailed inclusion and exclusion criteria are shown in the Protocol (online only).

Random Assignment and Masking
Patients were centrally allocated 1:1 to receive either EC-T or EC-T plus carboplatin (EC-TCb) regimen using a computer-generated random numbers table with permuted blocks, stratified by pathologic lymph node status (N0 v N1 v N2-3) according to the American Joint Committee on Cancer guideline (version 7). Random assignment was implemented through a telephone system managed by a research nurse at the central center who was independent of patient enrollment, treatment, or data analysis. Considering the unique adverse event profile of carboplatin, an open-label design was adopted, where investigators, patients, and the study team were not masked to the treatment.

Procedures
Patients' demographic and clinicopathologic characteristics were collected at random assignment. Then, patients were randomly assigned to receive EC-T or EC-TCb. In the control group, patients received EC with epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 on day 1 once every 3 weeks for four cycles, followed by paclitaxel 80 mg/m2 on days 1, 8, and 15 once every 3 weeks for four cycles. In the carboplatin group, patients received same EC regimen for four cycles, followed by paclitaxel 80 mg/m2 and carboplatin at a dose of AUC = 2.0 on days 1, 8, and 15 once every 4 weeks for four cycles. In November 2016, our study protocol was modified where either paclitaxel or docetaxel was applicable as the taxane agents, determined by the local investigator. The dosage of docetaxel was 80-100 mg/m2 on day 1 once every 3 weeks for four cycles in the EC-T group. In the carboplatin combination groups, patients would receive docetaxel 75 mg/m2 and carboplatin at an AUC dose of 5.0-6.0 AUC on day 1 once every 3 weeks for four cycles. Other concurrent adjuvant treatment (ie, capecitabine, Olaparib, ICI, and other chemotherapeutic regimens) were not allowed, while adjuvant endocrine therapy for patients with ER/PR expression (between 1% and 9%) was permitted per local physician's decision. Adjuvant radiotherapy was recommended by local treating physicians as indicated after the completion of adjuvant chemotherapy, as per guideline and consensus recommendations.10

Outcomes
The study's primary end point was disease-free survival (DFS), which was defined as the time from random assignment to local or regional recurrence, distant metastases, other non-breast secondary primary malignancies, contralateral breast carcinoma, or death due to any cause, whichever comes first. Secondary end points included distant DFS (DDFS), overall survival (OS), and toxicity (recorded according to National Cancer Institute Common Toxicity Criteria, version 4.0), as detailed in the Protocol. DDFS was defined as the time from random assignment to distant metastases, other non-breast second primary invasive cancers, or death due to any cause, whichever occurs first. Patients who experienced locoregional recurrence or contralateral breast carcinoma were not considered as DDFS events nor censored and continued to be followed until a DDFS event occurred or data cutoff date, whichever came first.

Statistical Analysis
The original design of this study was powered to detect a 3-year DFS rate difference of 7.3% (from 78.0% to 85.3%, corresponding to a hazard ratio [HR] of 0.64), considering 10% dropout, using z-test for two proportions with 485 patients in each arm (version 1.0). On March 1, 2023, after finding that approximately 70% of the enrolled patients were lymph node negative, whereas the original control arm's DFS assumption was based on predominantly node-positive populations,11 the investigators identified that the assumed DFS rate for the control arm was no longer appropriate. Therefore, the sample size re-estimation was performed using a statistically more efficient and clinically relevant method (ie, log-rank test) to compare the entire survival curve instead of a single point. An estimated 3-year DFS rate of approximately 84% was employed, assuming an exponential distribution based on previous reports including similar percentage of lymph node-negative disease.12-14 The recalculation was performed without any comparative analyses or access to any efficacy data, relied solely on the overall recruitment characteristics and updated external evidence, and did not result in changes in patient inclusion or exclusion criteria, stratification factors, or outcome definitions.
Specifically, a total of 706 patients and 160 events will be required to detect a HR of 0.64 in terms of DFS between the two arms (an improvement of 3-year DFS rate from 84% to 89.4%),12-14 with 80% power and two-sided type I error of 0.05. The follow-up period will last for 2 years after the accrual period of 7 years. The analysis for the primary end point would be triggered when 160 events were observed or 2 years after last patient enrolled, whichever comes first. After accounting for a 10% loss to follow-up rate, 776 patients are required. On March 1, 2023, 786 patients had been randomly assigned, and the investigators stopped the study enrollment since then. The study protocol was amended to reflect these updates (version 3.1). The detailed amendment is summarized in the Protocol.
Efficacy analyses were performed according to the intention-to-treat (ITT) principle, including all randomly assigned patients. The median follow-up time was calculated as the median of the individual follow-up durations for all patients. DFS, DDFS, and OS were compared between the EC-T and EC-TCb group using stratified log-rank test, while the corresponding stratified HRs and 95% CIs were estimated with stratified Cox proportional hazard models. A prespecified hierarchical test procedure was employed, where if significance was found for DFS, DDFS will be tested for the ITT population, and if significance was demonstrated for DDFS, OS will be tested for the ITT population.
Subgroup analysis for DFS and DDFS were performed. Participants who received allocated intervention and without major protocol violation were included in the per-protocol set (PPS). The primary and secondary efficacy end points were compared between arms with the same method above in the PPS. Safety profiles were assessed among patients who received at least one dose of taxane agent, and those patients who received only EC regimen were excluded (n = 12). The study database was locked on March 1, 2025, and data analyses were performed from March 1, 2025, to May 1, 2025. All analyses were performed using the R statistic software (version 4.3.1).

RESULTS

Patents and Treatment
Between March 2016 and March 2023, a total of 786 patients were recruited and randomly assigned across 19 centers in China (391 in the EC-T group and 395 in the EC-TCb group; Fig 1 and Appendix Table A1, online only). The demographic and clinicopathologic characteristics were well-balanced between treatment groups (Table 1), where 191 (48.8%) and 199 (50.4%) with the age at study entry younger than 50 years; 181 (46.3%) and 185 (46.8%) with T1 stage; and 282 (72.1%) versus 286 (72.4%) with node-negative disease, in the EC-T and the EC-TCb groups, respectively. There were 300 (76.7%) and 292 (73.9%) patients received docetaxel as taxane regimen in the EC-T and EC-TCb arms, respectively. Dose reductions were observed in 15 (3.8%) and 36 (9.1%) patients among EC-T and EC-TCb arms, respectively. Study treatment discontinuations because of intolerable treatment-related toxicities occurred for one (0.3%) and nine (2.3%) patients in EC-T and EC-TCb groups, respectively.

Efficacy
At data cutoff date (March 1, 2025), with a median follow-up of 4.52 years (IQR, 2.83-6.06), a total of 103 DFS events occurred, of which 62 and 41 events recorded in EC-T group and EC-TCb group, respectively (Table 2). The addition carboplatin treatment significantly improved DFS (HR, 0.66 [95% CI, 0.44 to 0.97], two-sided stratified log-rank P = .034, Fig 2A). The cumulative incidence curves for each DFS events are demonstrated in Appendix Figure A1. Distant metastasis was observed as the first DFS event among 30 patients (7.7%) in the EC-T group and 13 patients (3.3%) in the EC-TCb group. One patient in each treatment arm encountered AML/myelodysplastic syndrome. The 3-year DFS rate was 89.8% (95% CI, 86.8 to 92.9) and 93.1% (95% CI, 90.5 to 95.7) in the EC-T and EC-TCb groups, respectively; where the DFS benefit was further separated at the 5-year time point (82.6% [95% CI, 78.5 to 87.0] among EC-T group and 89.5% [95% CI, 86.1 to 92.9] among EC-TCb group). Regarding DDFS, 44 (11.3%) and 28 (7.1%) events occurred among EC-T and EC-TCb group, respectively. EC-TCb regimen was also associated with superior DDFS (HR, 0.61 [95% CI, 0.38 to 0.98]; two-sided stratified log-rank P = .040, Fig 2B). At the data cutoff date, 25 patients had died (18 in the EC-T group and seven in the EC-TCb group). Prolonged OS was observed for EC-TCb arm (HR, 0.39 [95% CI, 0.16 to 0.94], two-sided stratified log-rank P = .029, Fig 2C). Similar trends were observed in PPS analyses (Appendix Fig A2). Exploratory subgroup analyses demonstrated that the DFS benefit of carboplatin was comparable across most subgroups, with the exception of age (≤50 years v >50 years, HR, 1.22 [95% CI, 0.72 to 2.06] v 0.27 [95% CI, 0.13 to 0.54], interaction P = .001), and HER2 1+ to 2+ status (HER2-0 v 1+ to 2+, HR, 0.93 [95% CI, 0.58 to 1.49] v 0.29 [95% CI, 0.13 to 0.64], interaction P = .01; Fig 3). The participants' characteristics stratified by age and HER2 status were shown in the Appendix Tables A2 and A3. Remarkable 3-year DFS rate difference were observed for patients age >50 year (EC-T v EC-TCb, 87.1% [95% CI, 82.5 to 91.9] v 95.7% [95% CI, 92.8 to 98.7], Appendix Fig A3A) and HER2-low disease (EC-T v EC-TCb, 88.7% [95% CI, 83.5 to 94.3] v 95.5% [95% CI, 92.0 to 99.1], Appendix Fig A3B) between two treatment arms, compared with their counterparts, respectively. This pattern was similarly observed in the subgroup analysis of DDFS (Appendix Fig A4). However, age and HER2 status were not independently associated with DFS or DDFS, respectively (Appendix Table A4). A total of 138 patients (17.6%) underwent homologous recombination repair (HRR, including gBRCA and gPALB mutation) gene testing (Appendix Table A5). DFS stratified by HRR gene status (mutated: 21 patients v wild type: 117 patients) and BRCA status (mutated: 17 patients v wild type: 121 patients) was presented in Appendix Figure A5.

Safety
Overall, 774 patients were included in the safety analysis set. Treatment-related adverse events (AEs) are summarized in Table 3. Both the EC-T regimen and the EC-TCb regimen were generally well-tolerated. AEs were reported in 282 patients (67.0%) and 258 (73.1%) patients in the EC-T and EC-TCb groups, respectively. Treatment-related death or fatal AEs were not observed for either arm. Grade 3 to 4 AEs were more frequent among EC-TCb arm (176 patients [49.9%]) than the EC-T arm (163 patients [38.7%]), which was primarily driven by higher incidence rates of neutropenia (166 patients [47.0%] v 159 patients [37.8%]) and thrombocytopenia (16 patients [4.5%] v none). Febrile neutropenia was comparable between two arms (11 patients [2.6%] v eight patients [2.8%] for EC-T and EC-TCb regimens, respectively). The median durations of any grade 3 to 4 and hematologic grade 3 to 4 toxicity onset are shown in Appendix Table A6. Nonhematologic AEs were also more common in the EC-TCb group. The most frequent ones were alopecia (201 [56.9%] v 188 [44.7%] in the EC-TCb and EC-T groups, respectively), fatigue (201 [56.9%] v 185 [43.9%]), nausea (190 [53.8%] v 186 [44.2%]), and vomiting (172 [48.7%] v 171 [40.6%]), mostly grade 1 to 2 in severity (all post hoc P values for Chi-square test <.05). Notably, adding carboplatin did not significantly increase the incidence of grade 3 to 4 nonhematologic AEs.

DISCUSSION
Adjuvant carboplatin significantly reduced the recurrence risk of early-stage TNBC, when added to standard anthracycline and taxane-based treatment. Toxicity was manageable with no new safety signals identified, although increased hematologic AEs were observed for the EC-TCb regimen. Together, these findings highlight that carboplatin in combination with standard EC-T regimen, can be considered in the adjuvant setting for patients with early-stage TNBC who were treated first with primary surgery.
In the neoadjuvant setting, several clinical trials have shown that carboplatin showed antitumor effect in TNBC. Our previous study demonstrated that neoadjuvant nonanthracycline containing weekly paclitaxel combined with carboplatin has significant efficacy, especially for TNBC.15 Furthermore, the BrighTNess study showed that neoadjuvant carboplatin was associated with a superior pCR and EFS for high-risk TNBC.16 However, there were few studies evaluating carboplatin in the adjuvant setting. The PATTERN study demonstrated that six cycles of PCb regimen outperformed the CEF-T regimen.13 Meanwhile, the NRG-BR003 trial demonstrated a 5-year invasive DFS (iDFS) improvement of 4.9% when the dose-dense doxorubicin and cyclophosphamide regimen followed by paclitaxel with carboplatin was compared with paclitaxel. Although this difference did not reach statistical significance for iDFS (HR, 0.78 [95% CI, 0.58 to 1.06]; P = .12), the improvement magnitude would be considered as clinically meaningful, which was comparable with ours.17 Different ethnic background, back bone regimen, or patient selection may have influenced the results.
Interestingly, we found that the benefit of carboplatin among those with HER2-low tumor tended to be more pronounced. Activated metabolic pathway and BRCA2 mutations were more frequently observed in HER2-low disease.18-20 These biological characteristics may increase oxidative stress and exacerbate DNA damage, thereby enhancing sensitivity to platinum-based chemotherapy. Nevertheless, the mechanisms remain to be elucidated and require further investigation. We also found that adjuvant carboplatin conferred greater benefit among patients with TNBC age >50 years. This finding may be supported by the secondary analysis of the GeparSixto trial, which reported that the survival benefit of neoadjuvant carboplatin was mainly observed in gBRCA wild-type patients, a subgroup more prevalent among older patients with TNBC.21 By contrast, Gupta et al22 reported that the benefit of neoadjuvant carboplatin was only observed among premenopausal patients, which may be related with the treatment modality with neoadjuvant therapy. Younger TNBCs are often characterized by immune-modulatory subtype, and in the neoadjuvant setting, the presence of primary tumor allows chemotherapy to induce more antigen release,23 possibly to stimulate more antitumor immune responses. Moreover, estrogen signaling may promote tumor cell survival through nongenomic pathways, potentially counteracting the benefit of carboplatin in younger patients.24,25 Collectively, these findings highlight the biologic complexity underlying age-dependent carboplatin responsiveness in the adjuvant setting. Further biomarker studies are warranted to explore predictive markers, including genomic profiles, tumor-infiltrating lymphocytes (TILs),26 and radiomic features.27
Neoadjuvant pembrolizumab in combination with chemotherapy, followed by adjuvant pembrolizumab monotherapy significantly improved pCR rate, EFS, and OS for high-risk TNBC, which has been recognized as a preferred regimen in selected patients with TNBC.28,29 Although ICI has reshaped the treatment landscape of early-stage TNBC, particularly through neoadjuvant chemoimmunotherapy for patients with high-risk TNBC, the findings of our study remain clinically relevant. In real-world practice, a substantial proportion of patients with clinically low-risk TNBC (eg, cT1N0 who did not meet Keynote-522 eligibility) undergo primary surgery without neoadjuvant therapy. Some of these patients are found to have node-positive or high-risk disease after surgery and require effective adjuvant chemotherapy. As ICI has not shown benefit in adjuvant setting,30 an unmet clinical need remains for optimizing adjuvant therapy. Moreover, ICI access is still uneven worldwide, and EC-TCb regimens could be considered as an option in many low- and middle-income regions.31 Since our study population well represented those patients received primary surgery without neoadjuvant treatment, the findings of this study might fulfill this gap in the era of neoadjuvant chemoimmunotherapy.
The combination of carboplatin and taxane in our study exhibited favorable tolerability, with only nine patients (2.3%, of whom six experienced intolerable toxicity in TCb phase) in the EC-TCb arm discontinuing treatment because of AEs (one [0.3%] patient in the control arm). The incidence of grade 3 to 4 thrombocytopenia was similar with the PATTERN study (4.5% v 5.0%), whereas grade 3 to 4 anemia was lower (0.6% v 9.9%),16 possibly because of the shorter cumulative carboplatin exposure (12 v 18 weeks) in our regimen. However, the overall rate of grade 3 to 4 toxicity was higher than that reported by Gupta et al,22 which may relate to differences in treatment modality or duration. In the EC-TCb arm, approximately 50% of the patients experienced grade 1 to 2 GI AEs, fatigue, or alopecia, which was significantly elevated. The incidence of grade 3 to 4 GI AEs was relatively low in both arms, which was consist with other studies evaluating carboplatin with or without taxane regimen.13,22,32 Of note, prophylactic antiemetic agents (including palonosetron, aprepitant, and dexamethasone) were recommended for patients undergoing the EC regimen, which would mitigate the higher-grade GI toxicities. However, it remains plausible that incidence was underreported in some centers—because of either patients' reporting behaviors or inadequate physician-patient communication. Last but not least, although no new safety signals emerged, adding carboplatin still could rise grade 3 to 4 hematologic toxicity and grade 1 to 2 GI toxicity. Cancer survivorship should be emphasized as an integral component of decision making, with greater attention to balancing therapeutic efficacy against toxicity.
This study has several limitations. First, the benefit of carboplatin in adjuvant setting should be interpreted in the context of the evolving treatment paradigm with neoadjuvant chemoimmunotherapy. Second, the findings were based on a Chinese population, which limited the generalizability because of different genetic backgrounds. Third, only a limited number of patients (17.6%) in our study underwent testing for HRR genes mutations, which hindered further investigation of the potential mechanisms underlying carboplatin sensitivity. Fourth, as this was an open-label trial, some patients randomly assigned to the experimental arm declined carboplatin, leading to protocol violations. However, PPS analyses confirmed the robustness of our findings. Further translational study (eg, TILs and genomic profile) is warranted to guide tailored adjuvant treatment with carboplatin.
In conclusion, our study demonstrated that adding adjuvant carboplatin to taxanes, following anthracycline plus cyclophosphamide regimens would improve DFS, DDFS, and OS for early-stage TNBC with manageable toxicity, supporting adjuvant chemotherapy integrating carboplatin is an effective regimen for TNBC treatment for patients not receiving neoadjuvant treatment.

Supplementary Material

SUPPLEMENTARY MATERIAL