Prior Aromatase Inhibitor Therapy Research Articles

Abstract PD2-07: Alpelisib + letrozole in patients with PIK3CA-mutated, hormone-receptor positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) previously treated with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + fulvestrant: BYLieve study results

Abstract Introduction: Mutations in PIK3CA, which encodes the α-isoform of phosphatidylinositol 3-kinase (PI3Kα), occur in ~40% of patients (pts) with HR+, HER2- ABC and can contribute to endocrine resistance. Alpelisib (ALP), a PI3Kα-selective inhibitor and degrader, plus fulvestrant (FUL) demonstrated efficacy in the phase 3 SOLAR-1 trial, which included 20 pts who had prior CDK4/6i in the PIK3CA-mutant cohort. Limited clinical data are available in the post-CDK4/6i setting for PIK3CA-mutated, HR+, HER2- ABC. BYLieve (NCT03056755), an ongoing phase 2, multicenter, open-label, 3-cohort noncomparative study, is the first trial evaluating ALP + endocrine therapy (FUL or letrozole [LET]) in pts with PIK3CA-mutated, HR+, HER2- ABC who progressed on/after prior therapy, including CDK4/6i. In the prior CDK4/6i + aromatase inhibitor (AI) cohort (Cohort A), pts received ALP + FUL. With median follow-up of 11.7 months (mo), the primary endpoint in Cohort A was met—50.4% of pts were alive and without disease progression (PD) at 6 mo per local investigator assessment (n=61; 95% CI, 41.2%-59.6%). Median progression-free survival (mPFS) was 7.3 mo (n=72; 95% CI, 5.6-8.3 mo); AEs were consistent with prior observations. Now, we report on the cohort of pts who received a CDK4/6i + FUL as immediate prior therapy before enrollment (Cohort B). Methods: Daily oral treatment in Cohort B consisted of ALP 300 mg + LET 2.5 mg. Each cohort planned to enroll at least 112 pts with centrally confirmed PIK3CA mutation, based on immediate prior treatment of either a CDK4/6i + AI (Cohort A), a CDK4/6i + FUL (Cohort B), or systemic chemotherapy or endocrine therapy (which may also include prior CDK4/6i + FUL; Cohort C, follow-up ongoing). The primary endpoint, the proportion of pts with centrally confirmed PIK3CA mutation alive without PD at 6 mo per local investigator using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, is assessed for each cohort separately and is met if the lower bound of the 95% CI is >30%. Men and premenopausal women were allowed goserelin 3.6 mg subcutaneously or leuprolide 7.5 mg intramuscularly every 28 days. Results: 126 pts whose immediate prior treatment was CDK4/6i + FUL were enrolled into Cohort B: 115 had centrally confirmed PIK3CA mutations. Median follow-up was 15.0 mo (range, 1-31 mo); 58 (46.0%) had ≥2 lines of prior therapy in the metastatic setting, and 103 (81.7%) pts progressed on prior AI therapy. The primary endpoint was met with 46.1% (95% CI, 36.8%-55.6%) of pts alive without PD at 6 mo. mPFS was 5.7 mo (95% CI, 4.5-7.2 mo). The most frequent all-grade AEs (≥25%) were diarrhea (67.5%), hyperglycemia (63.5%), nausea (54.8%), decreased appetite (44.4%), stomatitis (34.1%), fatigue (31.0%), rash (31.0%), and vomiting (24.6%). Most frequent grade ≥3 AEs included hyperglycemia (25.4%), rash (9.5%), and rash maculopapular (7.9%). Incidence of AEs leading to treatment discontinuation was 14.3% (n=18); most frequent AEs leading to discontinuation were rash (4 pts, 3.2%, including rash maculopapular), fatigue, and diarrhea (3 pts, 2.4% each). Conclusion: Alpelisib in combination with LET following progression on FUL + CDK4/6i and prior AIs was effective in this noncomparative trial. Consistent with the known safety profile of alpelisib, manageable toxicities were observed. These data suggest that alpelisib in combination with LET may be an effective treatment option for pts with PIK3CA-mutated, HR+, HER2- ABC in the post-CDK4/6i setting. Citation Format: Hope S. Rugo, Florence Lerebours, Dejan Juric, Nicholas Turner, Stephen Chia, Pamela Drullinsky, Aleix Prat, Rafael Villanueva Vázquez, Murat Akdere, Christina Arce, Yu-Ming Shen, Eva Ciruelos. Alpelisib + letrozole in patients with PIK3CA-mutated, hormone-receptor positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) previously treated with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + fulvestrant: BYLieve study results [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-07.

Abstract P1-19-04: Results from plasmaMATCH trial treatment cohort A: A phase II trial of extended-dose fulvestrant in patients with an ESR1 mutation identified via ctDNA screening (CRUK/15/010)

Abstract Background: Ligand binding domain ESR1 mutations are acquired in ER positive cancers during prior aromatase inhibitor therapy for advanced ER positive breast cancer (BC). ESR1 mutant cancer models are sensitive to fulvestrant at high concentrations, however standard dose fulvestrant may not achieve the concentration required to fully inhibit mutant ESR1 in the clinic. The plasmaMATCH trial Cohort A assessed the efficacy of extended-dose fulvestrant (double the current standard dose achieved by doubling the frequency of administration) in patients with an ESR1 mutation identified via ctDNA testing. Methods: The plasmaMATCH trial was an open-label, multi-centre, multi-cohort platform trial, consisting of ctDNA testing in ~1000 patients with advanced BC. Patients with an ESR1 mutation identified in ctDNA testing were potentially eligible to enter Cohort A. Patients were treated with fulvestrant 500mg intramuscularly on Cycle 1 Days 1, 8 and 15 of a 28 day cycle, and from Cycle 2 onwards every 15 days. Pharmacokinetics samples were collected pre-dose on Day 1 of Cycles 2, 3 and 4. The primary endpoint for Cohort A was confirmed objective response rate as defined by RECIST v1.1. The original planned sample size was 40 patients, to detect a 25% response rate, assuming predominantly clonally dominant mutations. As the trial progressed it became apparent that ctDNA screening may also detect sub clonal ESR1 mutations, which were expected to have a lower response rate. Using a single-stage A’Hern design with a target response rate of 20%, unacceptable response rate of 10%, alpha=5%, power=80, the sample size was increased to 78 evaluable patients with 13 or more responses required to infer efficacy. Results: Following ctDNA testing, 84 patients enrolled in Cohort A (38% of patients with ESR1 mutations identified in ctDNA testing). All were ER positive, seven were HER2 amplified, 78 (93%) had visceral metastases. The most common ESR1 mutations detected in baseline plasma were D538G (52.4%), Y537S (35.7%), E380Q (33.3%). In the 74 evaluable patients, confirmed response rate was 8.1% (95%CI 3.0-16.8%, 6/74). One additional patient had an unconfirmed partial response. Median progression free survival was 2.2 months (IQR 1.7-5.3 months) and median duration of response was 7.0 months (IQR 3.7-8.3 months) with 4 patients continuing on treatment. In exploratory analysis, 39 patients had clonally dominant ESR1 mutations in baseline ctDNA analysis whilst 25 patients had subclonal mutations and 10 had unknown clonality. The response rate in those with clonally dominant ESR1 mutations was 10% (95%CI: 2.9-24.2%, 4/39) with no confirmed responses in those with subclonal mutations. The most common clinically significant grade 3 or 4 adverse event was hypertension (13%). Pharmacokinetic analysis was consistent with elevated fulvestrant exposure compared to approved 500mg PopPk model (pre-dose Cycle 3, 71% increase, and pre-dose Cycle 4 66% increase). Conclusion: In the pre-treated population studied, the response rate of extended-dose fulvestrant did not meet pre-specified criteria for efficacy in patients with ESR1 mutations identified in ctDNA testing. Extended-dose fulvestrant was well tolerated and enhanced exposure was observed. Assessment of clonal dominance of ESR1 mutations in ctDNA may identify patients who are more likely to benefit from extended-dose fulvestrant therapy. Citation Format: Iain Macpherson, Lucy Kilburn, Sarah Kernaghan, Andrew M Wardley, Richard D Baird, Rebecca Roylance, Peter Stephens, Olga Oikonomidou, Jeremy P Braybrooke, Mark Tuthill, Jacinta Abraham, Matthew C Winter, Belinda Kingston, Katie Wilkinson, Alistair Ring, Judith M Bliss, Nicholas Turner, on behalf of the plasmaMATCH Trial Management Group. Results from plasmaMATCH trial treatment cohort A: A phase II trial of extended-dose fulvestrant in patients with an ESR1 mutation identified via ctDNA screening (CRUK/15/010) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-04.

Randomized trial of text messaging (TM) to reduce early discontinuation of aromatase inhibitor (AI) therapy in women with breast cancer: SWOG S1105.

6516 Background: Non-adherence to AI’s for breast cancer is common and increases risk of recurrence. Text messaging (TM) has been shown to increase adherence to medications for chronic conditions. We conducted a multicenter randomized trial to evaluate if TM reminders improve AI adherence. Methods: Patients taking an AI for ≥30 days and having ≥36 mos of planned therapy were eligible. Patients were randomly assigned 1:1 to receive either TM or NO-TM twice a week for 36 mos. Randomization was stratified by length of time on prior AI therapy ( < 12 (64%) vs. 12-24 mos (36%)) and AI class (anastrozole, letrozole, exemestane). Content themes of the 36 TMs focused on overcoming barriers to adherence. Patients were assessed for discontinuation of AIs every 3 mos for 36 mos. The primary outcome was time to non-adherence, where non-adherence was defined as urine AI metabolite assay results satisfying the following: < 10 [units], undetectable, or no submitted specimen. A stratified Log-rank test was conducted. Multiple sensitivity analyses were performed using Cox regression. Results: In total, 724 patients were registered between May, 2012 and September, 2013, among whom 696 (338/360 (93.9%) on TM and 338/364 (92.9%) on NO-TM) were eligible and adherent at baseline. Observed (time-independent) adherence at 36 mos was 55.4% for TM and 55.4% for NO-TM. The primary analysis showed no difference in time-to-adherence failure between patients on the TM and NO-TM arms (HR = 0.89, 95% CI:0.76,1.05 p = .18). An analysis of negative urine tests alone resulted in similar non-significant results. With missed appointments not counted as failures, time to self-reported discontinuation (89.6% vs. 89.7%; HR = 1.17, 95% CI:0.69-1.98, p = .57) and site reported discontinuation (78.1% vs. 81.1%; HR = 1.31, 95% CI:0.86-2.01, p = .21) were also similar between the 2 groups. Conclusions: As the first large long-term randomized trial of an intervention directed at improving AI adherence, we found high rates of AI discontinuation. Bi-weekly text reminders did not improve adherence to AIs compared to usual care. Improving long—term adherence will likely require sustained behavioral interventions and support. Clinical trial information: NCT01515800.

PCN27 - THE REAL-WORLD COST AND EFFECTIVENESS OF EVEROLIMUS IN METASTATIC BREAST CANCER IN THE CZECH REPUBLIC

Based on the results of the randomized phase III BOLERO-2 study, the everolimus plus exemestane combination was approved and is reimbursed in the Czech Republic in hormone-receptor (HR) positive, human epidermal growth factor receptor type 2 (HER-2) negative metastatic breast cancer after prior aromatase inhibitor therapy. However, the real-world outcomes are unknown. We retrospectively evaluated HR-positive, HER-2 negative mBC patients with discontinued everolimus treatment in comprehensive cancer centre in the Czech Republic. The cost of drug and outcomes in the real-life clinical practice were assessed and compared to registration study BOLERO-2 (phase III clinical trial results: median age 62 years; median duration of exposure to everolimus was 5.0 months with median PFS 10.6 months, dose interruptions or reductions were required in 66.8% of patients). A total of 73 patients with mBC (median age 64 years) were treated with everolimus plus exemestane in the Masaryk Memorial Cancer Institute between 2014 – 2017. The median duration of treatment was 5.98 months, median progression-free survival was 6.6 months, the mean everolimus cost according to individual drug consumption was EUR 22,190 (CZK 572,491; EUR 1 = CZK 25.8). Adverse events led to dose reductions and/or discontinuation of treatment in 27 (37%) patients. The real-world evidence confirms that everolimus and exemestane is an effective and safe treatment in HR-positive, HER-2 negative patients with mBC after previous therapy with non-steroidal aromatase inhibitor. Nevertheless, the real-world PFS, which is the key driver in all cost-effectiveness models based on BOLERO-2 results, was apparently lower than in the clinical trial settings.

Clinical value of circulating ESR1 mutations for patients with metastatic breast cancer: a meta-analysis.

BackgroundThe clinical implication of plasma ESR1 mutations in the estrogen receptor (ER)-positive metastatic breast cancer (MBC) patients who had progressed after prior aromatase inhibitor (AI)-based therapy remains controversial. We conducted the first meta-analysis to investigate the prognostic significance and predictive role of plasma ESR1 mutations in MBC patients with prior exposure to AI therapy.Materials and methodsWe searched PubMed, Embase, and Cochrane Library databases for eligible studies. Meta-analysis was conducted to calculate combined hazard ratios (HRs) with 95% CIs for progression-free survival (PFS) and overall survival (OS). Subgroup and sensitivity analyses were also performed.ResultsThis study enrolled a total of 1,530 patients with ER-positive MBC cases from six articles, including 429 ESR1 mutation carriers (28.04%). Meta-analysis demonstrated that plasma ESR1 mutation carriers had significantly worse PFS (HR: 1.40, 95% CI: 1.17–1.66; P<0.0001) and OS (HR: 1.65, 95% CI: 1.36–2.01; P<0.0001) compared to wild-type ESR1. Subgroup analysis showed that plasma ESR1 mutations were associated with shorter PFS after AI-based treatment, but were not significantly predictive of outcome on fulvestrant-containing therapy (HR: 1.26, 95% CI: 0.98–1.62; P=0.077). As for different ESR1 mutations, D538G mutation implied significantly worse PFS (HR: 1.50, 95% CI: 1.18–1.91; P=0.01), while Y537S mutation was not correlated with PFS (HR: 1.65, 95% CI: 0.87–1.73; P=0.134).ConclusionThe meta-analysis indicated that plasma ESR1 mutation assessment may have prognostic significance and clinical value in guiding further endocrine therapy choice in ER+ MBC patients who received prior AI therapy.

Genomic profiling of circulating tumor DNA (ctDNA) from patients (pts) with metastatic breast cancer (mBC).

1016 Background: Clonal evolution during progression to and treatment of mBC highlights the importance of genomic profiling of recent samples to guide clinical decision making. We undertook this study to characterize genomic alterations (GA) in ctDNA from pts with mBC during the course of clinical care. Methods: Hybrid-capture based genomic profiling of 62 genes (FoundationACT) was performed on ctDNA from 255 BC pts. The fraction of ctDNA in the blood was estimated using the maximum somatic allele frequency (MSAF) for each sample. Results: 168 pts were ER+ [16 HER2+, 134 HER2(-), 18 HER2 unknown (unk)]; 51 were ER(-) [7 HER2+, 38 triple negative (TNBC), 6 HER2 unk]; 36 were ER unk; 95% were stage 4. For pts with treatment information, 90% had prior chemotherapy and 90% ER+ pts had prior aromatase inhibitor therapy (AI). ≥1 GA was reported in 78% of all cases and in 88% of cases with evidence of ctDNA in the blood (MSAF &gt;0). For 226 cases with MSAF &gt;0, an average of 2.7 GA/case were reported. The most common GA for ER+ pts were in TP53 (44%), PIK3CA (39%), ESR1 (36%), CDH1 (11%), KRAS (10%) and ERBB2 ( HER2, 9%). 101 ESR1 GA were identified in 61 pts [54 ER+, 7 ER unk], including 4 HER2+ pts. For ER+ pts with treatment information: 37% (22/60) with prior AI had ESR1 GA; all pts with ESR1 GA had prior AI. 24 pts had &gt;1 ESR1 GA, with instances of GA in cis. Frequent ESR1 GA were Y537S/N (n=47), D538G (n=29) and E380Q (n=7); rearrangement (n=3) and amplification (n=1) were also detected. Concurrent GA with ESR1 were found in PIK3CA (41%), FGFR1 (13%), BRCA1/2 (5%), HER2 (5%) and AKT1 (3%). In ER(-) pts, the most common GA were in TP53 (74%), PIK3CA (17%), NF1 (11%), BRCA1 (9%) and EGFR (9%). HER2 activating mutation occurred in 3% of cases that were HER2(-) by prior testing. Kinase fusions in FGFR2/3 (3 ER+) and EGFR (1 TNBC) were observed. Conclusions: In this study, evidence of ctDNA in the blood was observed in 89% of cases. PIK3CA and ESR1 GA frequencies were similar to those reported in previous studies of ctDNA from ER+ pts after AI. Diverse ESR1 GA and co-occurring GA suggest therapeutic approaches for AI refractory ER+ mBC. Our results demonstrate that genomic profiling of ctDNA may be a complementary approach to tissue-based genomic testing for pts with mBC.

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

Abstract 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: &amp;gt;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&amp;lt;0.001). Median PFS (mPFS) in the BUP vs PBO arm was 3.9 vs 1.8 months. The 6-month PFS rate was 30.6% vs 20.1%. PFS per central assessment was consistent with these findings (HR 0.57; 95% CI: 0.44–0.74; p&amp;lt;0.001). PIK3CA status in ctDNA was available for 349 pts; 147 (42.1%) pts had PIK3CA-mutant (mut) status and 202 (57.9%) had PIK3CA-wildtype (wt) status. PFS improvement in the BUP vs PBO arm was greater in the PIK3CA-mut (mPFS 4.7 vs 1.6 months; HR 0.50; 95% CI: 0.33–0.76) than the PIK3CA-wt group (mPFS 3.7 vs 2.7 months; HR 0.73; 95% CI: 0.52–1.01). A similar treatment effect was seen in 321 pts with PIK3CA status based on PCR in tissue samples (PIK3CA-mut HR 0.39; 95% CI: 0.23–0.65. PIK3CA-wt HR 0.83; 95% CI: 0.60–1.14). ORR was 7.6% (95% CI: 4.8–11.3) vs 2.1% (95% CI: 0.4–6.0) in the BUP vs PBO arm, and CBR at 24 weeks was 24.6% (95% CI: 19.7–29.9) vs 15.4% (95% CI: 9.9–22.4). Most common (&amp;gt;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, Lønning P, Janni W, O'Regan 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.

Abstract LB-069: ESR1 mutations in circulating tumour DNA predict outcome to endocrine treatment in patients with estrogen receptor positive advanced breast cancer; analysis of 521 patients in the SoFEA and PALOMA3 trials

Abstract Background. ESR1 mutations are selected by prior aromatase inhibitor (AI) therapy for advanced breast cancer. We addressed the impact of ESR1 mutations on sensitivity to standard therapies in SoFEA and PALOMA3, two phase III randomised trials that represent the trends in the current therapy for estrogen receptor positive advanced breast cancer. Methods. We assessed plasma DNA ESR1 mutations in the SoFEA trial that compared exemestane with fulvestrant-containing regimens in patients with prior sensitivity to non-steroidal AI, and in the PALOMA3 trial that compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression on prior endocrine therapy. We developed and validated multiplex digital droplet PCR assays to detect ESR1 mutations in circulating free DNA. Plasma had been immediately processed in PALOMA3 but there was a delay of up to 9 days before processing of EDTA samples in the SoFEA trial. Results. In SoFEA we demonstrated that delayed processing of plasma samples had no effect on detection rate of ESR1 mutations (p = 0.71), which were found in 39.1%(63/161) patients. Patients with ESR1 mutations had improved progression free survival (PFS) on fulvestrant compared to exemestane (HR = 0.52, 95%CI 0.30 to 0.92, p = 0.02), while patients with wild type ESR1 had similar PFS on either treatment (HR = 1.07, 95%CI 0.68 to 1.67, p = 0.77). In PALOMA3, ESR1 mutations were found in the plasma of 25.3%(91/360) patients. ESR1 mutations were almost exclusively found in patients with prior AI exposure with or without tamoxifen, and were very rare with prior tamoxifen exposure only (28.9% (90/311) versus 2.0% (1/49) respectively, p&amp;lt;0.001). ESR1 mutations were strongly associated with sensitivity to prior endocrine therapy (sensitive to prior endocrine therapy, 29.8% (85/285) versus resistant 8.0% (6/75), p&amp;lt;0.001), bone metastases (p = 0.001), prior lines of therapy for metastatic disease (p = 0.01), and with a trend towards ER and PR positive disease as opposed to ER positive but PR negative disease. Fulvestrant plus palbociclib improved PFS compared to fulvestrant plus placebo in both ESR1 mutant (HR = 0.43, 95%CI 0.25 to 0.74, p = 0.002) and ESR1 wild type patients (HR = 0.49 95%CI 0.35 to 0.70, p&amp;lt;0.001). ESR1 mutations were polyclonal in up to 49% of patients, with outcome on fulvestrant similar for polyclonal and monoclonal mutations. In an exploratory analysis there was no association between specific mutations and outcome on fulvestrant. Conclusions. ESR1 mutation analysis in plasma after progression on prior AI therapy has clinical utility in directing choice of further endocrine therapy. Citation Format: Ben O’Leary, Charlotte Fribbens, Lucy Kilburn, Sarah Hrebein, Isaac Garcia-Murillas, Matthew Beaney, Massimo Cristofanilli, Fabrice Andre, Sherene Loi, Sibylle Loibl, John Jiang, Cynthia Huang Bartlett, Maria Koehler, Mitch Dowsett, Judith Bliss, Stephen Johnston, Nicholas Turner. ESR1 mutations in circulating tumour DNA predict outcome to endocrine treatment in patients with estrogen receptor positive advanced breast cancer; analysis of 521 patients in the SoFEA and PALOMA3 trials. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-069.

SOLAR-1: A phase III study of alpelisib + fulvestrant in men and postmenopausal women with HR+/HER2– advanced breast cancer (BC) progressing on or after prior aromatase inhibitor therapy.

TPS618Background: The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently activated in hormone receptor-positive (HR+) BC and is associated with resistance to endocrine therapy. The combination of the PI3Kα-specific inhibitor alpelisib (BYL719) and fulvestrant showed promising activity in a phase I study of HR+/human epidermal growth factor 2-negative (HER2–) BC, with the strongest treatment benefit in patients (pts) with PIK3CA-mutant tumors (Janku et al. SABCS 2014, Abstract PD5-5). Further data are required to confirm these observations. Methods: In the phase III, randomized, double-blind SOLAR-1 study (NCT02437318), men and postmenopausal women with HR+/HER2– advanced BC are randomized (1:1) to alpelisib or placebo (300 mg once daily) + fulvestrant (500 mg intramuscularly on Days 1 and 15 of Cycle 1 [28 days], and Day 1 of Cycles ≥ 2) until disease progression or discontinuation for other reason. Pts are assigned to 2 cohorts (PIK3CAmutant vs non-mutant ...

Abstract S6-03: Randomized phase II trial of fulvestrant alone or in combination with bortezomib in hormone receptor-positive metastatic breast cancer resistant to aromatase inhibitors: A New York cancer consortium trial

Abstract Purpose: Fulvestrant (F) is a selective estrogen receptor downregulator (SERD) with activity in aromatase-inhibitor (AI) resistant estrogen receptor (ER)-positive metastatic breast cancer (MBC). In preclinical studies, the proteasome inhibitor bortezomib (B) enhances the antineoplastic effects of F, in part by promoting accumulation of large ER-aggregates that lead to cell death (Ishii et al. Clin Cancer Res 2011 17:2292). The objective of this study was to determine if the combination of F+B was more efficacious than F alone in MBC after AI progression. Patients and Methods: Postmenopausal women with ER-positive MBC who had progressive disease after prior AI therapy were eligible. They were randomized to F alone (500 mg IM days -15, 1, 15 in cycle 1, and day 1 of each subsequent cycle) or in combination with B (1.6 mg/m2 IV on days 1, 8, 15). The primary endpoint was progression free survival (PFS), measured from cycle 1, day 1 of starting F. A sample size of 118 was pre-specified in order to provide sufficient power to detect an improvement in median PFS from 5.4 to 9.0 months, and compare PFS rates after 6 and 12 months (1-sided alpha=0.10, beta=0.10). Patients with progression on F could cross over to the F+B combination. Results: Of 118 patients enrolled, 59 received F alone (arm A), 57 received F+B (arm B), and 2 assigned to arm B never initiated protocol therapy. There were no significant differences in patient characteristics between arms with regard to median age (57 vs. 59 years), ECOG performance status (0 and 1, 64% and 36%, respectively), prior chemotherapy for metastasis (25%), or liver metastases (37%), although patients in arm A had longer median interval between diagnosis and metastasis (49 vs. 28 months) and were more likely to present with metastasis (32% vs. 26%). Patients in arm B had more adverse events (all grades), including nausea (63% vs. 29%), diarrhea (47% vs. 8%), sensory neuropathy (46% vs. 29%), and limb edema (37% vs. 19%), although grade 3-4 events were uncommon, and only 11% discontinued B due to toxicity. At 12 months, the PFS proportion in Arm A and Arm B was 13.6% vs. 28.1%, respectively (P=0.03, 1-sided chi-square test) (95% CI for difference [14.5%] = -0.06%, 29.1%). Although median PFS was similar in the two arms (2.69 vs. 2.73 months, respectively), the hazard ratio for Arm B vs. Arm A (referent) was 0.73 (95% CI = 0.49, 1.09, P=0.06, 1-sided log rank test). Both results were significant at the pre-specified 1-sided 0.10 alpha level. Of 27 patients on arm A who crossed over to F+B at progression, 4 (15%) were progression-free for at least 24 weeks and had periods of disease control that were longer than when treated with F alone. Conclusion: Adding bortezomib to fulvestrant in AI-resistant ER-positive MBC enhances its effectiveness by delaying acquired fulvestrant resistance. These results support additional evaluation of proteasome inhibitors in combination with SERDs. Acknowledgement: Supported by contract N01-CM-62204 to the New York Cancer Consortium (P.I. J. Sparano) and grant P30 CA013330 (P.I. D. Goldman) from the National Institutes of Health, and by a grant from Millennium, Inc. Citation Format: Kerin B Adelson, Bhuvaneswari Ramaswamy, Joseph A Sparano, Paul J Christos, John J Wright, George Raptis, Miguel C Villalona, Cynthia X Ma, Dawn Hershman, Joseph Baar, Paula Klein, Tessa Cigler, G Thomas Budd, Yelena Novik, Antoinette R Tan, Susan Tannenbaum, Anupama Goel, Ellis Levine, Charles L Shapiro, Eleni Andreopoulou, Michael Naughton, Kevin Kalinsky, Samuel Waxman, Doris Germain. Randomized phase II trial of fulvestrant alone or in combination with bortezomib in hormone receptor-positive metastatic breast cancer resistant to aromatase inhibitors: A New York cancer consortium trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S6-03.

Abstract S2-02: The FERGI phase II study of the PI3K inhibitor pictilisib (GDC-0941) plus fulvestrant vs fulvestrant plus placebo in patients with ER+, aromatase inhibitor (AI)-resistant advanced or metastatic breast cancer – Part I results

Abstract Background: Preclinical and clinical data indicate a key role for the PI3-kinase (PI3K) pathway in the pathogenesis of resistance to endocrine therapies in hormone receptor-positive (HR) breast cancer (BC) and suggest that combining PI3K inhibitors with endocrine therapy may partially overcome this resistance. FERGI is the first randomized Phase II study testing pictilisib (GDC-0941), a PI3K inhibitor, in combination with fulvestrant to evaluate this hypothesis in MBC patients with and without PIK3CA-mutant tumors. Methods: 168 post-menopausal pts with ER-positive, HER2-negative MBC were randomized (1:1) to receive fulvestrant with either pictilisib 340 mg QD (n=89, "combination" arm) or matching placebo (n=79, "control" arm). To be eligible, pts had to have relapsed during or within 6 mos of completing adjuvant AI treatment or have progressed on an AI for MBC. Pts were stratified based on tumor PIK3CA mutation status, resistance to prior AI therapy and presence of measurable disease. The primary endpoint was PFS by investigator assessment in the intent-to-treat (ITT) group and in pts with centrally confirmed PIK3CA-mutant tumors. The primary analysis was based on a 6 mo median duration follow up. Results: Baseline disease and prior treatment characteristics were similar between study arms. Observed treatment-emergent AEs were consistent with those previously described for single agent pictilisib and fulvestrant (primary toxicities were rash and GI disorders). In the ITT population (84 events) the median PFS (mPFS) was 6.2 mo in the combination arm vs 3.8 months for the control arm (HR, 0.77; 95% CI, 0.50-1.19). For pts with PIK3CA-mutant tumors (37 events), mPFS was 6.2 mo in the combination arm vs 5.1 mo in the control arm (HR, 0.92; 95% CI, 0.48-1.76). For pts without a detectable PIK3CA mutant tumor (43 events), mPFS was 5.8 months in the combination arm vs 3.6 months in the control arm (HR, 0.64; 95% CI, 0.35-1.17). Exploratory post-hoc subgroup analysis suggested improvement in PFS in pts with ER+ and PR+ tumors (centrally confirmed) treated with pictilisib plus fulvestrant. In the ER+/PR+ subgroup (57 events) mPFS was 7.2 mo in the combination arm vs 3.7 mo in the control arm (HR, 0.46; 95% CI, 0.27 to 0.78). This improvement was independent of tumor PIK3CA mutation status. Multivariate analysis suggests that this treatment effect in pts with ER+/PR+ tumors is maintained after adjusting for possible baseline imbalances. A similar analysis on pts with luminal A tumors (per PAM50 analysis) was also consistent with the findings in pts ER+/PR+ disease. Conclusions: This is the first report of a blinded, randomized clinical study evaluating a PI3K inhibitor in pts with MBC. In the ITT population, the addition of pictilisib to fulvestrant was associated with a mPFS improvement of 3.8 mo to 6.2 mo. Exploratory subgroup analyses suggested in pts with ER+/PR+ tumors are more likely to derive benefit from the addition of pictilisib to fulvestrant irrespective of PIK3CA mutation status, though the subgroup analyses are limited by the sample size. Additional biomarker analyses will be reported. Citation Format: Ian Krop, Stephen Johnston, Ingrid A Mayer, Maura Dickler, Vinod Ganju, Andres Forero-Torres, Bohuslav Melichar, Serafin Morales, Richard de Boer, Steven Gendreau, Mika Derynck, Mark Lackner, Jill Spoerke, Ru-Fang Yeh, Gallia Levy, Vivian Ng, Carol O'Brien, Heidi Savage, Yuanyuan Xiao, Timothy Wilson, Soo Chin Lee, Katarina Petrakova, Susanne Vallentin, Denise Yardley, Matthew Ellis, Martine Piccart, Edith A Perez, Eric Winer, Peter Schmid. The FERGI phase II study of the PI3K inhibitor pictilisib (GDC-0941) plus fulvestrant vs fulvestrant plus placebo in patients with ER+, aromatase inhibitor (AI)-resistant advanced or metastatic breast cancer – Part I results [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S2-02.

Abstract OT3-2-10: Phase 3, multicenter, randomized, double-blind, placebo-controlled trial of fulvestrant with or without PD-0332991 (palbociclib) ± goserelin in women with hormone receptor-positive, HER2-negative metastatic breast cancer (MBC) whose disease progressed after prior endocrine therapy

Abstract Background: Palbociclib (P) is a selective inhibitor of CDK 4/6 that prevents DNA synthesis by blocking G1-S phase cell cycle progression. Blockade of hormone signaling is synergistic with cell cycle arrest induction and results in significant clinical benefit. Combining P with anti-endocrine therapy is expected to have additive or synergistic effect on tumor growth and metastasis. In a randomized phase 2 study, postmenopausal women with hormone- sensitive ER+/HER2– advanced breast cancer had significantly longer progression-free survival (PFS) with P + letrozole (L) versus L. This study will assess efficacy of P + fulvestrant (F) in patients with endocrine-resistant MBC. Trial Design: In this double-blind phase 3 study, patients will receive F (500 mg given IM per standard of care) and be randomized 2:1 to receive P (125 mg/d orally for 3 wk followed by 1 wk off) + F (500 mg given per standard of care) or matched placebo + F. Pre- and perimenopausal women must also receive goserelin. Randomization will be stratified by documented sensitivity to prior endocrine therapy (yes vs no), menopausal status at study entry (pre-/peri- vs postmenopausal), and presence of visceral metastases (yes vs no). An external data monitoring committee will perform an early review of safety data from the first 40 randomized patients to confirm safety/tolerability, including pharmacokinetic data to explore potential drug-drug interactions. Eligibility Criteria: Eligible women are aged ≥18 y with ER+ and/or PR+, HER2– MBC, whose cancer has progressed during or within 12 mo of completing adjuvant therapy (with an aromatase inhibitor or tamoxifen if post-menopausal or pre-/perimenopausal, respectively) or while on or within 1 mo after the end of prior aromatase inhibitor therapy for their metastatic disease. One previous line of chemotherapy for metastatic disease is permitted. Patients must have measureable disease (per RECIST v1.1) or bone-only metastatic disease and be willing and able to provide tumor tissue for biomarker research. Aims: The primary endpoint will assess whether P + F vs placebo + F prolongs investigator-assessed PFS. Secondary endpoints include overall survival, objective response, duration of response, trough drug concentrations, patient-reported outcomes, biomarkers, and safety and tolerability. Statistical Methods: This study will have 90% power to detect an increase in PFS using 1-sided significance testing. One interim analysis is planned to re-estimate the sample size and assess patient safety as well as preliminary efficacy. Accrual: Target accrual is 417 patients (P + F, n = 278; placebo + F, n = 139). Contact Information: For further information, please contact the Director, Clinical Trials Disclosure Group, Pfizer Inc (marla.brickman@pfizer.com). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-10.

Comparative efficacy of everolimus plus exemestane versus fulvestrant for hormone-receptor-positive advanced breast cancer following progression/recurrence after endocrine therapy: a network meta-analysis

Postmenopausal women with advanced breast cancer recurring/progressing on or after initial (adjuvant or first-line) endocrine therapy may be treated multiple times with one of several endocrine or combinatorial targeted treatment options before initiating chemotherapy. In the absence of direct head-to-head comparisons of these treatment options, an indirect comparison can inform treatment choice. This network meta-analysis compared the efficacy of everolimus plus exemestane with that of fulvestrant 250 and 500 mg in the advanced breast cancer setting following adjuvant or first-line endocrine therapy. The reported hazard ratios (HRs) for progression-free survival (PFS) or time to progression from six studies that formed a network to compare everolimus plus exemestane (BOLERO-2 trial) with fulvestrant were analyzed by means of a Bayesian network meta-analysis. In the primary comparison (PFS analysis based on the local review of disease progression from BOLERO-2 with the data from the other studies), everolimus plus exemestane appeared to be more efficacious than both fulvestrant 250 mg (HR = 0.47; 95 % credible interval [CrI] 0.38–0.58) and 500 mg (HR = 0.59; 95 % CrI 0.45–0.77). Similar results were obtained in an alternate comparison based on central review of disease progression from BOLERO-2 with the data from the other studies (HR = 0.40; 95 % CrI 0.31–0.51 and HR = 0.50; 95 % CrI 0.37–0.67, respectively), and in a subgroup analysis of patients who had received prior aromatase inhibitor therapy (HR = 0.47; 95 % CrI 0.38–0.58 and HR = 0.55; 95 % CrI 0.40–0.76, respectively). These results suggest that everolimus plus exemestane may be more efficacious than fulvestrant in patients with advanced breast cancer who progress on or after adjuvant or first-line therapy with a nonsteroidal aromatase inhibitor.

Phase II trial of vorinostat, a histone deacetylase inhibitor to restore the hormone sensitivity to the anti-estrogen tamoxifen in patients with advanced breast cancer having failed prior aromatase inhibitor therapy

3501 Background: Modulation of estrogen receptor signaling is one of the most successful modalities in the treatment of estrogen receptor (ER) positive breast cancers. Many estrogen receptor-positive tumors show primary or acquired resistance to anti-estrogen therapy. Histone deacetylases (HDAC) play a central role in transcriptional regulation and HDAC inhibitors have been reported to restore sensitivity to anti-hormonal therapy by modulation of estrogen as well as progesterone receptors. Here, we report preliminary findings from a Phase II trial evaluating the HDAC inhibitor, vorinostat and the anti-estrogen, tamoxifen, placed in context with correlative studies. Methods: Patients with ER-positive metastatic breast cancer who failed prior therapy with aromatase inhibitors and up to three chemotherapy regimes were administered vorinostat (SAHA) 400 mg daily for three of four weeks and tamoxifen 20 mg daily, continuously. Histone acetylation was evaluated in peripheral blood mononuclear cells and baseline HDAC enzyme expression was evaluated in tumor blocks. Results: To date, 19 patients [median age 56 years (36–71)] have been enrolled and 17 patients were evaluated for response. Two patients (2/18, 11%) had a pulmonary embolus./DVT. Three patients (3/18, 17%) had Grade 3 fatigue, and one patient each (1/18, 6%) had diarrhea, nausea/vomiting, weight loss, AST/ALT elevations, neutropenia or thrombocytopenia. Predominant Grade 2 toxicities included fatigue, nausea/vomiting, anorexia, bleeding and myelosuppression. Four patients had an objective response (1 complete, 3 partial responses: 4/17, 24%), of those 50% had prior chemotherapy and 75% had failed two aromatase inhibitors for metastatic disease, 50% had failed prior tamoxifen. One additional patient had stable disease for 12 months. H3 and H4 histone acetylation was seen at day 8 suggesting adequate PK levels. Histone acetylation, baseline HDAC expression and PK data will be presented. Conclusions: These findings suggest that the addition of an HDAC inhibitor to tamoxifen in patients who have failed prior aromatase inhibitors or adjuvant tamoxifen may restore hormone sensitivity. No significant financial relationships to disclose.

Subgroup analysis of a randomized, phase III study of the effect of denosumab in women with nonmetastatic breast cancer receiving aromatase inhibitor (AI) therapy

546 Background: In postmenopausal women with breast cancer, adjuvant AI therapy contributes to accelerated bone loss and risk for fracture. Denosumab, a fully human monoclonal antibody to RANKL, inhibits osteoclast-mediated bone loss. Methods: In this 2-year, double-blind, placebo-controlled study, we evaluated factors that may influence BMD in patients (pts) ≥ 18 years old with hormone receptor-positive breast cancer who were receiving adjuvant AI therapy and had evidence of low bone mass. Pts were stratified by duration of prior AI therapy (≤ 6 vs >6 months) and randomized to receive, together with calcium and vitamin D, placebo (n = 125) or 60 mg denosumab (n = 127) subcutaneously every 6 months for 4 doses. A sample size of 104 pts/group was planned to provide 95% power to detect a 2% difference between groups (α = 0.05). An analysis of covariance model was used for subgroup analyses, adjusting for treatment, stratification factor, baseline BMD value, densitometer type, and baseline BMD value-by-densi...

Fulvestrant in Women With Advanced Breast Cancer After Progression on Prior Aromatase Inhibitor Therapy: North Central Cancer Treatment Group Trial N0032

Fulvestrant is an antiestrogen that leads to estrogen receptor degradation and has demonstrated efficacy in breast cancer patients who have had disease recurrence or progression after tamoxifen. This study was designed to examine the efficacy and toxicity of fulvestrant in patients with disease progression on a third-generation aromatase inhibitor (AI). A one-stage phase II trial was conducted in postmenopausal women with measurable disease by Response Evaluation Criteria in Solid Tumors criteria who experienced disease progression after treatment with a third-generation AI and, at most, one additional hormonal agent. Tumors must have been estrogen receptor and/or progesterone receptor positive. The primary end point was objective response rate, and secondary end points were time to disease progression, survival, duration of response, and toxicity. Eighty patients were enrolled, and three were ineligible. Characteristics of the 77 eligible patients included median age of 68 years, performance score of 0 or 1 in 91% of patients, visceral dominant disease in 88% of patients, two prior hormonal treatments in 73% of patients, and prior chemotherapy for metastatic disease in 32% of patients. Eleven patients (14.3%) achieved a partial response, and 16 patients (20.8%) had stable disease for at least 6 months, for a clinical benefit rate of 35%. Antitumor activity seemed to be higher in women with prior treatment with AI alone compared with women whose prior treatment also included tamoxifen. Median time to progression was 3 months, and median survival time was 20.2 months. Fulvestrant was well tolerated. Fulvestrant is a well-tolerated treatment and has efficacy against breast cancers that have progressed after therapy with a third-generation AI.

Exemestane in metastatic breast cancer: Effective therapy after third-generation non-steroidal aromatase inhibitor failure

Exemestane is a potent steroidal aromatase inhibitor (AI) with activity in post-menopausal women with metastatic breast cancer, with a reported clinical benefit (CB) rate of 24.3% after prior AI therapy. Data on 114 patients (112 female, 2 male) were obtained retrospectively at two cancer centres. Sixty-five percent of patients were confirmed as oestrogen receptor (ER) positive. All patients had received prior third-generation AI therapy. Responses were seen in 5% and the overall CB rate (CR+PR+SD24 weeks) was 46%. Median PFS and OS were 18 and 61 weeks, respectively. In patients with visceral disease, the CBR was 33%. Patients with known ER-positive disease had a CBR of 47%, and a median TTP of 19 weeks. No benefit was seen in patients with known ER-negative disease. Survival was better in those with CB (median survival not reached in those with CB, 28 weeks in those without CB P<0.0001). Efficacy persisted in those patients who had received 3 prior lines of hormonal therapy, including adjuvant treatment. These data confirm exemestane to be an effective therapy after third-generation non-steroidal AI in post-menopausal ER-positive metastatic breast cancer, including visceral disease.