Mona El-Hashimy

Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2

BACKGROUND In the BOLERO-2 trial, everolimus (EVE), an inhibitor of mammalian target of rapamycin, demonstrated significant clinical benefit with an acceptable safety profile when administered with exemestane (EXE) in postmenopausal women with hormone receptor-positive (HR+) advanced breast cancer. We report on the incidence, time course, severity, and resolution of treatment-emergent adverse events (AEs) as well as incidence of dose modifications during the extended follow-up of this study. PATIENTS AND METHODS Patients were randomized (2:1) to receive EVE 10 mg/day or placebo (PBO), with open-label EXE 25 mg/day (n = 724). The primary end point was progression-free survival. Secondary end points included overall survival, objective response rate, and safety. Safety evaluations included recording of AEs, laboratory values, dose interruptions/adjustments, and study drug discontinuations. RESULTS The safety population comprised 720 patients (EVE + EXE, 482; PBO + EXE, 238). The median follow-up was 18 months. Class-effect toxicities, including stomatitis, pneumonitis, and hyperglycemia, were generally of mild or moderate severity and occurred relatively early after treatment initiation (except pneumonitis); incidence tapered off thereafter. EVE dose reduction and interruption (360 and 705 events, respectively) required for AE management were independent of patient age. The median duration of dose interruption was 7 days. Discontinuation of both study drugs because of AEs was higher with EVE + EXE (9%) versus PBO + EXE (3%). CONCLUSIONS Most EVE-associated AEs occur soon after initiation of therapy, are typically of mild or moderate severity, and are generally manageable with dose reduction and interruption. Discontinuation due to toxicity was uncommon. Understanding the time course of class-effect AEs will help inform preventive and monitoring strategies as well as patient education. TRIAL REGISTRATION NUMBER NCT00863655.The BOLERO-2 trial demonstrated that adding everolimus to exemestane substantially improved clinical benefit with acceptable safety in postmenopausal women with HR+ breast cancer relapsing/progressing on a nonsteroidal aromatase inhibitor. Incidences and severities of everolimus-related toxicity were consistent with other oncology settings, and were manageable using established strategies.

Randomized, open-label, phase III study comparing patupilone (EPO906) with pegylated liposomal doxorubicin in platinum-refractory or -resistant patients with recurrent epithelial ovarian, primary fallopian tube, or primary peritoneal cancer.

PURPOSE This study compared the efficacy and safety of patupilone with those of pegylated liposomal doxorubicin (PLD) in patients with platinum-refractory or -resistant epithelial ovarian, primary fallopian tube, or primary peritoneal cancer. PATIENTS AND METHODS Patients with three or fewer prior regimens were eligible if they had received first-line taxane/platinum-based combination chemotherapy and were platinum refractory or resistant. Patients were randomly assigned to receive patupilone (10 mg/m(2) intravenously every 3 weeks) or PLD (50 mg/m(2) intravenously every 4 weeks). RESULTS A total of 829 patients were randomly assigned (patupilone, n = 412; PLD, n = 417). There was no statistically significant difference in overall survival (OS), the primary end point, between the patupilone and PLD arms (P = .195; hazard ratio, 0.93; 95% CI, 0.79 to 1.09), with median OS rates of 13.2 and 12.7 months, respectively. Median progression-free survival was 3.7 months for both arms. The overall response rate (all partial responses) was higher in the patupilone arm than in the PLD arm (15.5% v 7.9%; odds ratio, 2.11; 95% CI, 1.36 to 3.29), although disease control rates were similar (59.5% v 56.3%, respectively). Frequently observed adverse events (AEs) of any grade included diarrhea (85.3%) and peripheral neuropathy (39.3%) in the patupilone arm and mucositis/stomatitis (43%) and hand-foot syndrome (41.8%) in the PLD arm. CONCLUSION Patupilone did not demonstrate significant improvement in OS compared with the active control, PLD. No new or unexpected serious AEs were identified.

Effect of Everolimus on Bone Marker Levels and Progressive Disease in Bone in BOLERO-2

BACKGROUND Breast Cancer Trials of Oral Everolimus 2 (BOLERO-2), a phase III study in postmenopausal women with estrogen receptor-positive breast cancer progressing despite nonsteroidal aromatase inhibitor therapy, showed statistically significant benefits with adding everolimus to exemestane. Moreover, in preclinical studies, mammalian target of rapamycin inhibition was associated with decreased osteoclast survival and activity. Exploratory analyses in BOLERO-2 evaluated the effect of everolimus on bone marker levels and progressive disease in bone. METHODS Patients were treated with exemestane (25mg/day) and randomized (2:1) to everolimus (10mg/day; combination) or placebo (exemestane only). Exploratory endpoints included changes in bone turnover marker levels vs baseline and progressive disease in bone, defined as unequivocal progression of a preexisting bone lesion or the appearance of a new bone lesion. RESULTS Baseline disease characteristics were well balanced between arms (N = 724); baseline bisphosphonate use was not (43.9% combination vs 54.0% exemestane only). At a median of 18 months of follow-up, median progression-free survival (primary endpoint) was statistically significantly longer with the combination vs exemestane only (Cox proportional hazard ratio = 0.45, 95% confidence interval = 0.38 to 0.54; log-rank, 1-sided P < .0001). Bone marker levels at 6 and 12 weeks increased with exemestane only, as expected, but decreased with the combination. The cumulative incidence rate of progressive disease in bone was lower in the combination arm. Bone-related adverse events occurred with similar frequency in both arms (3.3% combination vs 4.2% exemestane only). CONCLUSION These exploratory analyses suggest that everolimus has beneficial effects on bone turnover and progressive disease in bone in patients receiving exemestane for hormone receptor-positive breast cancer progressing during/after nonsteroidal aromatase inhibitor therapy.

Abstract S4-07: BELLE-3: A phase III study of buparlisib + fulvestrant in postmenopausal women with HR+, HER2–, aromatase inhibitor-treated, locally advanced or metastatic breast cancer, who progressed on or after mTOR inhibitor-based treatment

Background: Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway activation is a hallmark of hormone receptor-positive (HR+) breast cancer (BC) resistant to endocrine therapy (ET). Preclinical and clinical data suggest that adding a PI3K inhibitor (PI3Ki) to ET may overcome resistance. In BELLE-2, a Phase III randomized study, buparlisib (BUP; BKM120; pan-PI3Ki) + fulvestrant (FULV) demonstrated clinical activity and manageable safety in patients (pts) with HR+, human epidermal growth factor receptor 2-negative advanced BC, with the greatest treatment effect in pts with PIK3CA mutation in circulating tumor DNA (ctDNA). Here, we report results from the final progression-free survival (PFS) analysis of the BELLE-3 study. Methods: Pts (N=432) were randomized 2:1 to BUP (100mg/day) or placebo (PBO) + FULV (500mg per standard of care) and stratified by visceral disease status. Key inclusion criteria: prior aromatase inhibitor therapy; disease progression ≤30 days from combination therapy of ET + mTOR inhibitor as last regimen. Key exclusion criteria: >1 chemotherapy regimen for advanced BC; prior PI3Ki, AKT inhibitor, or FULV; history of/active mood disorders. Primary and key secondary endpoints were PFS (local assessment; Response Evaluation Criteria In Solid Tumors v1.1) and overall survival (OS), respectively. Other secondary endpoints included: overall response rate (ORR); clinical benefit rate (CBR); efficacy by PIK3CA status in ctDNA (BEAMing technology); safety. Results: BELLE-3 met its primary endpoint with a statistically significant improvement in PFS per investigator assessment in favor of BUP + FULV (BUP arm) vs PBO + FULV (PBO arm; hazard ratio [HR] 0.67; 95% confidence interval [CI]: 0.53–0.84; p 10%; BUP vs PBO arm) Grade 3/4 AEs were increased alanine aminotransferase (21.9% vs 2.9%), increased aspartate aminotransferase (17.7% vs 2.9%), and hyperglycemia (12.2% vs 0). Conclusions: BELLE-3 met its primary endpoint in the full population. PFS improvement in the BUP vs PBO arm was greater in pts with PIK3CA-mut than PIK3CA-wt tumors, based on ctDNA and PCR. Secondary endpoints showed improved clinical benefit with BUP + FULV vs PBO + FULV. Safety was in line with that previously seen with the combination. Keywords: Breast cancer; PI3K inhibitor; Fulvestrant; Buparlisib. Citation Format: Di Leo A, Seok Lee K, Ciruelos E, Lonning P, Janni W, O9Regan R, Mouret Reynier M-A, Kalev D, Egle D, Csoszi T, Bordonaro R, Decker T, Tjan-Heijnen VC, Blau S, Schirone A, Weber D, El-Hashimy M, Dharan B, Sellami D, Bachelot T. BELLE-3: A phase III study of buparlisib + fulvestrant in postmenopausal women with HR+, HER2–, aromatase inhibitor-treated, locally advanced or metastatic breast cancer, who progressed on or after mTOR inhibitor-based treatment [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S4-07.

Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND Activation of the PI3K/AKT/mTOR pathway occurs frequently in breast cancer that is resistant to endocrine therapy. Approved mTOR inhibitors effectively inhibit cell growth and proliferation but elicit AKT phosphorylation via a feedback activation pathway, potentially leading to resistance to mTOR inhibitors. We evaluated the efficacy and safety of buparlisib plus fulvestrant in patients with advanced breast cancer who were pretreated with endocrine therapy and mTOR inhibitors. METHODS BELLE-3 was a randomised, double-blind, placebo-controlled, multicentre, phase 3 study. Postmenopausal women aged 18 years or older with histologically or cytologically confirmed hormone-receptor-positive, HER2-negative, locally advanced or metastatic breast cancer, who had relapsed on or after endocrine therapy and mTOR inhibitors, were recruited from 200 trial centres in 22 countries. Eligible patients were randomly assigned (2:1) via interactive response technology (block size of six) to receive oral buparlisib (100 mg per day) or matching placebo starting on day 1 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles. Randomisation was stratified by visceral disease status. The primary endpoint was progression-free survival by local investigator assessment as per the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 in the full analysis population (all randomised patients, by intention-to-treat). Safety was analysed in all patients who received at least one dose of treatment and at least one post-baseline safety assessment. This study is registered with ClinicalTrials.gov, number NCT01633060, and is ongoing but no longer enrolling patients. FINDINGS Between Jan 15, 2013, and March 31, 2016, 432 patients were randomly assigned to the buparlisib (n=289) or placebo (n=143) groups. Median progression-free survival was significantly longer in the buparlisib versus placebo group (3·9 months [95% CI 2·8-4·2] vs 1·8 months [1·5-2·8]; hazard ratio [HR] 0·67, 95% CI 0·53-0·84, one-sided p=0·00030). The most frequent grade 3-4 adverse events in the buparlisib versus placebo group were elevated alanine aminotransferase (63 [22%] of 288 patients vs four [3%] of 140), elevated aspartate aminotransferase (51 [18%] vs four [3%]), hyperglycaemia (35 [12%] vs none), hypertension (16 [6%] vs six [4%]), and fatigue (ten [3%] vs two [1%]). Serious adverse events were reported in 64 (22%) of 288 patients in the buparlisib group versus 23 (16%) of 140 in the placebo group; the most frequent serious adverse events (affecting ≥2% of patients) were elevated aspartate aminotransferase (six [2%] vs none), dyspnoea (six [2%] vs one [1%]), and pleural effusion (six [2%] vs none). On-treatment deaths occurred in ten (3%) of 288 patients in the buparlisib group and in six (4%) of 140 in the placebo group; most deaths were due to metastatic breast cancer, and two were considered treatment-related (cardiac failure [n=1] in the buparlisib group and unknown reason [n=1] in the placebo group). INTERPRETATION The safety profile of buparlisib plus fulvestrant does not support its further development in this setting. Nonetheless, the efficacy of buparlisib supports the rationale for the use of PI3K inhibitors plus endocrine therapy in patients with PIK3CA mutations. FUNDING Novartis Pharmaceuticals Corporation.

Effects of everolimus (EVE) on disease progression in bone and bone markers (BMs) in patients (pts) with bone metastases (mets).

102 Background: BOLERO-2, a multinational, double-blind, placebo-controlled, phase III study in postmenopausal women with estrogen-receptor-positive breast cancer (BC) refractory to nonsteroidal aromatase inhibitors (NSAIs), showed significant clinical benefits with the addition of EVE to exemestane (EXE) (Baselga J et al. NEJM2011 Epub). As bone resorption is an important factor in BC mets, it is interesting to study bone-related effects of EVE. In preclinical studies, mTOR inhibition was associated with decreased osteoclast survival and activity. Exploratory analyses in BOLERO-2 evaluated the effects of EVE vs placebo (PBO) on BM levels and BC progression in bone in pts with bone mets at baseline. METHODS Eligible pts were treated with EXE (25 mg once daily) and randomized (2:1) to EVE (10 mg once daily) or PBO. Bone turnover markers (BMs) were exploratory endpoints analyzed at 6 and 12 wks after treatment initiation and included bone-specific alkaline phosphatase, amino-terminal propeptide of type I collagen, and C-terminal cross-linking telopeptide of type I collagen. Progressive disease in bone (PDB) was defined as worsening of a preexisting bone lesion or a new bone lesion. RESULTS Baseline disease characteristics, including bone mets at baseline (n = 370, 76% EVE vs n = 184, 77% PBO), were well balanced between arms (N = 724), and baseline bisphosphonate use was not (44% EVE vs 55% PBO). At 12.5 mo median follow-up, progression-free survival (primary endpoint), overall response rate, and clinical benefit rate (p < 0.0001, all) were significantly higher with EVE (n = 485) vs PBO (n = 239). BM levels at 6 and 12 wks increased vs baseline with PBO but decreased with EVE. The cumulative incidence rate of BC PBD was lower for EVE vs PBO at day 60 (3.03% vs 6.16%, respectively), and this trend was sustained beyond 6 months. Updated results will be presented. All bone-related adverse events reported were grade 1-2 and occurred with similar frequency in EVE (2.9%)- and PBO (3.8%)-treated patients. CONCLUSIONS Exploratory analyses from BOLERO-2 suggest that adding EVE has beneficial effects on bone turnover and BC progression in bone in pts receiving EXE therapy for NSAI-refractory BC.

Abstract A050:PIK3CAmutation status in tumor tissue and ctDNA as a biomarker for PFS in patients with HR+, HER2- ABC treated with buparlisib or placebo plus fulvestrant: results from the BELLE-2 and BELLE-3 randomized studies

Background: PIK3CA mutation status is a potential biomarker for treatment response to buparlisib (BUP; pan-phosphatidylinositol 3-kinase [PI3K] inhibitor) plus fulvestrant (FUL) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Here, we report progression-free survival (PFS) per PIK3CA mutation status (by polymerase chain reaction [PCR] in tumor tissue or BEAMing in circulating tumor [ct]DNA) in two distinct studies: BELLE-2 (NCT01610284) and BELLE-3 (NCT01633060). Methods: The double-blind Phase III BELLE-2 study randomized (1:1) postmenopausal pts with HR+, HER2- ABC who progressed on/after aromatase inhibitor therapy to receive oral (PO) BUP or placebo (PBO) plus intramuscular (IM) FUL. PIK3CA mutation status was determined by PCR in tumor tissue or BEAMing in ctDNA at baseline in a subset of pts with available samples. The double-blind phase III BELLE-3 study randomized (2:1) postmenopausal pts with HR+, HER2- ABC who relapsed on/after endocrine therapy and a mammalian target of rapamycin inhibitor to receive PO BUP or PBO plus IM FUL. PIK3CA mutation status was determined by PCR in tumor tissue or BEAMing in ctDNA at baseline in a subset of pts with available samples. Results: BELLE-2 randomized 1147 pts, including 587 with PIK3CA status per BEAMing and 1002 per PCR. A clinically meaningful improvement in PFS was seen in 200 pts with PIK3CA-mutant status per BEAMing treated with BUP+FUL vs PBO+FUL (median=7.0 vs 3.2 months; hazard ratio [HR] 0.56 [95% confidence interval {CI} 0.39-0.80]; 1-sided nominal P=0.0005), but not in 387 with wild-type status (median=6.8 vs 6.8 months; HR 1.05 [95% CI 0.82-1.34]; 1-sided nominal P=0.642), suggesting a predictive utility of PIK3CA status per BEAMing in ctDNA at baseline. Analysis based on PIK3CA status per PCR showed that PFS was prolonged with BUP+FUL vs PBO+FUL in both 412 pts with PIK3CA-mutant status (median=7.1 vs 5.1 months; HR 0.73 [95% CI 0.57-0.92]; 1-sided nominal P=0.004) and 590 with wild-type status (median=6.8 vs 4.6 months; HR 0.84 [95% CI 0.70-1.02]; 1-sided nominal P=0.042). BELLE-3 randomized 432 pts, including 348 with PIK3CA status per BEAMing and 313 per PCR. PFS benefit was more pronounced in 135 pts with PIK3CA-mutant status per BEAMing treated with BUP+FUL vs PBO+FUL (4.2 vs 1.6 months; HR 0.46 [95% CI 0.29-0.73]; 1-sided nominal P Citation Format: Jose Baselga, Dalila Sellami, Mona El-Hashimy, Bharani Dharan, Amanda Wang, Nicolas Scheuer, Banu Sankaran, Angelo Di Leo. PIK3CA mutation status in tumor tissue and ctDNA as a biomarker for PFS in patients with HR+, HER2- ABC treated with buparlisib or placebo plus fulvestrant: results from the BELLE-2 and BELLE-3 randomized studies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A050.

Abstract A029: Biomarker analysis in HR+, HER2-, locally advanced, or metastatic breast cancer patients treated with buparlisib: results from BELLE-3

Background: Endocrine therapy resistance in hormone receptor-positive breast cancer often leads to activation of phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin pathway. In the BELLE-3 study the progression-free survival (PFS) improvement in buparlisib (BUP) vs placebo (PBO) arm was greater in patients (pts) with PIK3CA-mutant than PIK3CA-wildtype (Wt) tumors, based on circulating tumor DNA. In the current study we report the additional exploratory biomarker results from BELLE-3. Methods: The relationship between PFS and frequently mutated genes (PIK3CA, CCND1, ESR1 and 8q11.23 region) and pathways (PI3K and CDK pathways) was explored using NGS in tumor and pts were classified as altered (Alt) vs Wt. Genes and pathways with at least 10% frequency in both arms were carried forward to correlative analyses with PFS. In addition, ESR1 mutations were detected by BEAMing technology in baseline cell free DNA (cfDNA) for 167 pts. Results: NGS data were available for 185 pts and the NGS panel covered 500+ gene mutations, short insertions/deletion, copy number alterations, and translocations. PIK3CA was altered in 41% of pts and PI3K pathway was altered in 64% of pts. Benefit of BUP treatment was observed in PIK3CA altered pts, but did not extend to other alterations in the PI3K pathway. CCND1 was altered in 19% of pts and the CDK pathway was altered in 34% of pts and improved benefit of BUP was observed in altered pts in both the groups (HR = 0.31 and 0.38 respectively). Alterations in the 8q11.23 region (ZNF703, WHSC1L1 and FGFR1) were observed in 21% of pts with the benefit of BUP observed only among wildtype. In cfDNA, a higher treatment effect was observed in the ESR1 mutant subgroup (HR = 0.76 [Wt] and 0.27 [Alt]). Subgroup analyses of ESR1 mutations revealed a greater improvement in median PFS among pts with D538G mutation (BKM vs PBO = 8.25 vs 1.51; HR = 0.18) than among pts with Y537N/S/C mutation (BKM vs PBO = 4.17 vs 2.76; HR = 0.45). The PFS of different groups analyzed by NGS is mentioned in the table. Conclusions: A trend for stronger treatment effect was observed among pts with alterations in PIK3CA, CDK pathway, CCND1 (tumor), and ESR1 (ctDNA). The possibility of correlation among identified biomarkers is currently being explored. * To assess the impact of genes in the PI3K pathway other than PIK3CA, the altered group includes patients who are PIK3CA wildtype but have an alteration in a different gene in the PI3K pathway. Citation Format: Nadia Solovieff, Ying A. Wang, Banu Sankaran, Nicolas Scheuer, Mona El-Hashimy, Denis Weber, Dalila Sellami, Angelo Di Leo. Biomarker analysis in HR+, HER2-, locally advanced, or metastatic breast cancer patients treated with buparlisib: results from BELLE-3 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A029.

PO59 EFFICACY AND SAFETY OF EVEROLIMUS PLUS EXEMESTANE COMBINATION THERAPY VERSUS MONOTHERAPY WITH EVEROLIMUS OR CAPECITABINE IN HR+, HER2− BREAST CANCER: A MULTI-CENTER, OPEN-LABEL, PHASE 2 TRIAL BOLERO-6

benefit in patients who received EVE plus EXE as first-line therapy in the advanced setting. The ongoing BOLERO-4 trial is investigating the efficacy and safety of EVE plus letrozole (LET) in the first-line ER+ advanced BC setting, as well as the potential benefits of continuing EVE plus endocrine therapy beyond initial disease progression. Methods: BOLERO-4 (NCT01698918) is a multicenter, open-label, single-arm, phase 2 trial that is enrolling postmenopausal women with ER+ metastatic or locally advanced unresectable BC who have received no prior therapy for advanced disease. Patients will receive EVE (10 mg/ day) plus LET (2.5 mg/day) until first disease progression. Thereafter, patients will have the option to receive EVE plus EXE (25 mg/day) until further disease progression, or unacceptable toxicity; EVE plus EXE will not be offered to patients who discontinue therapy because of unacceptable toxicity in the first-line metastatic BC setting. The primary endpoint is PFS in the first-line setting. Secondary endpoints include PFS in the second-line setting, response rate, overall survival, and safety. The effectiveness of a dexamethasone oral rinse to reduce the severity and/ or duration of stomatitis will also be evaluated. Exploratory endpoints include biomarker analysis of bone resorption and formation and evaluation of additional biomarkers for further elucidation of disease characteristics. Results: The trial opened for enrollment in Europe, Asia, and the Americas in the first quarter of 2013. The trial plans to enroll a total of 200 patients during the 18-month enrollment period and is estimated to be completed in the fourth quarter of 2015. Conclusions: BOLERO-4 will provide insight regarding the efficacy and safety of first-line EVE plus LET in the metastatic BC setting as well as the efficacy of continuing EVE-based therapy following initial disease progression.

Characterization of patients who received prior chemotherapy for advanced breast cancer (ABC) in BOLERO-2.

151 Background: In patients with hormone receptor-positive (HR+) breast cancer, endocrine therapy is the standard of care both in the adjuvant setting and as front-line therapy for ABC. Chemotherapy (CT) is commonly used for HR+ ABC patients if disease burden is high and rapid symptom control is required (Barrios CH. GAMO. 2010). In the phase III BOLERO-2 study (NCT00863655), first-line of prior CT in the ABC setting was allowed. This subset analysis examined disease characteristics and the efficacy of everolimus (EVE) + exemestane (EXE) in patients who received CT for ABC prior to BOLERO-2 study entry. METHODS In BOLERO-2, 724 patients with HR+, human epidermal growth factor receptor 2-negative (HER2-) ABC whose disease recurred or progressed during/after a nonsteroidal aromatase inhibitor were randomized 2:1 to EVE (10 mg/d) + EXE (25 mg/d) or placebo (PBO) + EXE. The primary endpoint was progression-free survival (PFS) by local investigator review (confirmed by blinded independent central review). RESULTS A total of 186 patients (26%) received prior CT for ABC (125 in the EVE + EXE group and 61 in PBO + EXE). In this subset, 54% (67 of 125) of EVE+ EXE patients received prior CT in the advanced setting only while 46% (58 of 125) of EVE + EXE patients received prior CT in both the neoadjuvant/adjuvant and advanced settings. Visceral metastases (67% vs. 56%), multiple metastases (79% vs. 66%), and ≥ 4 metastatic sites (18% vs. 15%) were more frequent in ABC patients with prior CT for ABC at study entry compared with those with no prior CT for ABC. History of disease recurrence <6 months from initial diagnosis was recorded in 32% (n = 60) of prior CT patients versus 17% (n = 93) of patients with no prior CT. Median PFS (by local assessment) in patients who received prior CT for ABC was substantially longer with EVE + EXE versus PBO + EXE (6.1 vs. 2.7 mo; hazard ratio = 0.38; 95% CI, 0.27-0.53). PFS by central review showed similar results (7.1 vs. 2.8 mo, respectively; hazard ratio = 0.42; 95% CI, 0.27-0.65). CONCLUSIONS These results demonstrate that patients with HR+, HER2 ABC who received previous CT in the advanced setting had a higher tumor burden but derived significant and clinically meaningful benefit from combination therapy with EVE + EXE. CLINICAL TRIAL INFORMATION NCT00863655.