Fulvestrant In Women Research Articles

Preclinical and clinical development of palbociclib and future perspectives.

Cyclin-dependent kinases (CDKs) play a key role in cell cycle regulation, which makes them a clear therapeutic target to interfere with cell division and proliferation in cancer patients. Palbociclib, a specific inhibitor of CDK4/6 with outstanding clinical efficacy data and limited toxicity, has been recently approved for the treatment of hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer, either in combination with an aromatase inhibitor or in combination with fulvestrant in women who have received prior endocrine therapy. This review describes the mechanism of action, preclinical experiences and clinical data of palbociclib, with a special focus on integrating this data with the positioning of palbociclib in the current clinical guidelines for advanced HR-positive/HER2-negative breast cancer. Aspects of the ongoing major studies are also presented, as well as future prospects in the development of palbociclib.

Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer

CDK4/6 inhibition substantially improves progression-free survival (PFS) for women with advanced estrogen receptor-positive breast cancer, although there are no predictive biomarkers. Early changes in circulating tumor DNA (ctDNA) level may provide early response prediction, but the impact of tumor heterogeneity is unknown. Here we use plasma samples from patients in the randomized phase III PALOMA-3 study of CDK4/6 inhibitor palbociclib and fulvestrant for women with advanced breast cancer and show that relative change in PIK3CA ctDNA level after 15 days treatment strongly predicts PFS on palbociclib and fulvestrant (hazard ratio 3.94, log-rank p = 0.0013). ESR1 mutations selected by prior hormone therapy are shown to be frequently sub clonal, with ESR1 ctDNA dynamics offering limited prediction of clinical outcome. These results suggest that early ctDNA dynamics may provide a robust biomarker for CDK4/6 inhibitors, with early ctDNA dynamics demonstrating divergent response of tumor sub clones to treatment.

Abstract OT2-07-06: Phase Ib study to assess the safety, tolerability, and clinical activity of gedatolisib in combination with palbociclib and either letrozole or fulvestrant in women with metastatic or locally advanced/recurrent breast cancer (B2151009)

Abstract Background:Hormone receptor positive (HR+) disease is the most common subset of advanced breast cancer (BC). The majority of women with HR+ metastatic BC (MBC) develop resistance to endocrine therapy (ET), with a median survival of 2-3 years. A new strategy to treat HR+ MBC involves the combination of ET and a cyclin-dependent kinase 4/6 inhibitor (CDKi 4/6), which has demonstrated improved progression-free survival (PFS) in both first-and later-line MBC. Preclinical evidence in PI3K-mutant cell-line xenografts demonstrated that combinations of PI3K and CDK4/6i reduced intrinsic and adaptive resistance to ET, leading to tumor regression (Vara, 2004; Pfizer data). Inhibition of the PI3K/mTOR pathway by gedatolisib (G) may provide a new therapy to overcome ET resistance. These findings support developing the triplet combination of G with the CDKi 4/6 palbociclib (P)+letrozole (L) or fulvestrant (F) for the treatment of patients (pts) with ER+/HER2- BC. Methods: This ongoing study in women with ER+/HER2- MBC, in first- and later-line settings, includes a dose-escalation (DE) to evaluate dose-limiting toxicities (DLTs, primary endpoint [pEP]) and determine the maximum tolerated dose and recommended phase 2 dose (RP2D) for a triplet regimen of G+P+L or G+P+F. The escalation rules follow the modified toxicity probability interval method (G doses: 180 and 215 mg IV weekly). Treatment assignment to the triplet is based on investigator decision and bone-only disease is permitted. After RP2D determination for each triplet, a 3-arm expansion for early signs of efficacy (ESOE) will investigate objective response rate (ORR) compared to historical controls [pEP] of Arm A) G+P+L in first-line, B) G+P+F in pts with no prior CDKi 4/6 in second-line and C) G+P+F in pts who have received prior CDKi 4/6. Pts receive G+P (125 mg oral daily for 21 days [D] on and 7 D off) + L (2.5 mg oral daily) or F (500 mg IM on D1, 15 of cycle [C] 1; D1 of C2 and then 500 mg IM on D1 of all 28-D cycles). Secondary endpoints include safety, tumor response (DE), PFS (ESOE), pharmacokinetics (PK), and biomarker correlations associated with the PI3K/mTOR pathway. Results: 27 pts received G (180 mg/week) in combination with P+L (L cohort, n=12) or P+F (F cohort, n=15). Median prior therapies were: L cohort: 1 (range: 0-4); F cohort: 2 (range 1-5). The 3 most common, drug-related adverse events (%) were in L cohort: nausea (75), neutropenia (67), and stomatitis (67); F cohort: stomatitis (67), nausea (60), and neutropenia (53). C1 DLTs were: L cohort: grade (gr) 3 neutropenia (n=1); F cohort: gr 3 stomatitis (n=1). Preliminary rates of stable disease/partial response were: L cohort: 33%/16%; F cohort: 40%/13%. PK parameters and next-generation sequencing of PI3K-related mutations are pending. Conclusions: G can be combined with P+L or P+F with manageable toxicity and promising preliminary antitumor activity, even in heavily pretreated pts. Dose escalation, followed by expansion for ESOE, is ongoing. This study is sponsored by Pfizer. Editorial support was provided by Engage Scientific Solutions and was funded by Pfizer. Citation Format: Forero A, Han HS, Dees EC, Wesolowski R, Bardia A, Kabos P, Kern KA, Perea R, Pierce KJ, Houk B, Rugo HS. Phase Ib study to assess the safety, tolerability, and clinical activity of gedatolisib in combination with palbociclib and either letrozole or fulvestrant in women with metastatic or locally advanced/recurrent breast cancer (B2151009) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-06.

Abstract P5-21-21: Palbociclib exposure-response analyses in the treatment of hormone-receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2–) advanced breast cancer (ABC)

Abstract Palbociclib (PAL) is approved for the treatment of HR+, HER2- ABC in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women or with fulvestrant in women with disease progression following endocrine therapy based on major progression-free survival (PFS) improvement in phase III studies. An exposure response analysis was conducted to evaluate how the changes in PAL exposure (PAL-E), e.g. due to the dose modifications, would affect the PFS. Data from PALOMA 2, a phase 3 study comparing the efficacy and safety of letrozole plus PAL (PAL+L) to letrozole plus placebo (L) in ABC patients (PTs), were used. The apparent PAL clearance (CL/F) for each PT was obtained from a population pharmacokinetic analysis. The individual PAL-E over the entire treatment (Cavg) was calculated using average daily dose intensity (ADI) and CL/F. PTs in the PAL+L group were divided into 4 quantiles (Q1, Q2, Q3, and Q4) based on their Cavg, and the median PFS in each quantile was compared to that of L using Kaplan-Meier plot. To account for the changes in PAL-E over time due to dose modifications during treatment, a time-varying PAL-E (Cavgt) was calculated using ADI and CL/F at each PFS time. The relationship between PFS and Cavgt was evaluated using Cox proportional hazard model. Univariate analyses were first conducted to identify any significant prognostic factors and the effect of Cavgt on PFS. Multivariate analysis was conducted to evaluate relationship between PFS and Cavgt when all significant prognostic factors identified from the univariate analysis were included in the model to account for their potential confounding effects. The median PFS were 14.5, 24.9, 27.7, 25.7, and 24.0 months for patients in the L, Q1, Q2, Q3, and Q4, respectively, indicating similar PFS across all exposure quartiles. The identified significant prognostic factors from univariate analysis were Ki67 score, age, baseline AST, baseline tumor size, baseline alkaline phosphatase, and baseline albumin levels. The estimated coefficients for Cavgt were -0.00377 and -0.00224 in univariate and multivariate analysis, respectively. The effect of PAL-E on PFS was not statistically significant (p <0.05). PFS was not found to be associated with Cavgt, suggesting that PTs with different PAL-E in P+L benefited similarly and the changes in PAL-E resulted from dose modifications in the trial would not significantly affect the efficacy. However, the impacts on efficacy are unknown for any other unstudied dose modifications algorithm. Citation Format: Zheng J, Yu Y, Durairaj C, Amantea M, Dieras V, Finn R, Wang D. Palbociclib exposure-response analyses in the treatment of hormone-receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2–) advanced breast cancer (ABC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-21.

Abemaciclib: First Global Approval.

Abemaciclib (Verzenio™) is an orally administered inhibitor of cyclin-dependent kinases 4 and 6 that is being developed by Eli Lilly and Company. Abemaciclib has been approved in the USA for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, in combination with fulvestrant in women with disease progression following endocrine therapy, and as monotherapy in adult patients with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. In addition, abemaciclib is in various stages of development internationally for a variety of cancers. This article summarizes the milestones in the development of abemaciclib leading to its first approval for the treatment of patients with HR-positive, HER2-negative advanced or metastatic breast cancer.

What are the effects of fulvestrant in women with hormone-sensitive locally advanced or metastatic breast cancer?

What are the effects of fulvestrant in women with hormone-sensitive locally advanced or metastatic breast cancer?

MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer

Purpose Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, demonstrated efficacy as monotherapy and in combination with fulvestrant in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer previously treated with endocrine therapy. Methods MONARCH 3 is a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Patients received abemaciclib or placebo (150 mg twice daily continuous schedule) plus either 1 mg anastrozole or 2.5 mg letrozole, daily. The primary objective was investigator-assessed progression-free survival. Secondary objectives included response evaluation and safety. A planned interim analysis occurred after 189 events. Results Median progression-free survival was significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; P = .000021; median: not reached in the abemaciclib arm, 14.7 months in the placebo arm). In patients with measurable disease, the objective response rate was 59% in the abemaciclib arm and 44% in the placebo arm ( P = .004). In the abemaciclib arm, diarrhea was the most frequent adverse effect (81.3%) but was mainly grade 1 (44.6%). Comparing abemaciclib and placebo, the most frequent grade 3 or 4 adverse events were neutropenia (21.1% v 1.2%), diarrhea (9.5% v 1.2%), and leukopenia (7.6% v 0.6%). Conclusion Abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR-positive, HER2-negative advanced breast cancer.

A phase 2 study of investigational TORC1/2 inhibitor TAK-228 with fulvestrant in women with ER+/HER2–advanced or metastatic breast cancer (mBC) that has progressed during or after aromatase inhibitor (AI) therapy.

TPS1118 Background: Antiestrogen therapy, including AI, is standard for ER+ tumors in the adjuvant and metastatic setting; however, resistance is common. These tumors may respond to alternative second-line anti-estrogen therapies such as fulvestrant but response durations are often short. Preclinical and clinical studies suggest that simultaneous inhibition of ER and PI3K/mTOR could prevent/delay the emergence of hormone-independent cancer cells, thereby improving patient (pt) outcomes. This study will test whether fulvestrant plus TAK-228, a dual TORC1/2 inhibitor, can overcome endocrine therapy resistance in ER+ mBC. This is an open-label, randomized, phase 2 study of continuous once-daily TAK-228 (4 mg) or once-weekly TAK-228 (30 mg) plus fulvestrant (per label), vs fulvestrant alone, in pts with ER+/HER2– advanced or mBC that has progressed during/after AI therapy (EudraCT 2015-003612-20). Methods: 153 pts will be randomized 1:1:1 and stratified (presence or absence of visceral metastasis, prior hormonal therapy sensitivity, and prior exposure to CDK 4/6 inhibitors). Pts will receive study drug(s) until progressive disease (PD), unacceptable toxicity, or consent withdrawal. Pts with histological confirmation of ER+/HER2– advanced or mBC with measureable disease, ECOG 0–1, PD during/after prior AI therapy (progression ≤12 mos after discontinuation of adjuvant therapy or ≤1 mo after discontinuation in the metastatic setting) and adequate organ function, but not prior therapy with mTOR, PI3K, dual PI3K-mTOR or AKT inhibitors, or fulvestrant, > 1 prior line of chemotherapy for mBC or recurrent or progressive disease on > 2 endocrine therapies for mBC are eligible. This study aims to determine the efficacy (primary endpoint: PFS; secondary endpoints: OS, TTP, ORR), safety and tolerability of TAK-228 plus fulvestrant vs fulvestrant alone. The primary hypothesis (TAK-228 plus fulvestrant can improve median PFS to 8 mos [hazard ratio, HR 0.5] vs fulvestrant-alone median PFS of 4 mos) is to be tested at the 0.10 significance level (2-sided; dropout rate 10%). To date, 24 pts have been enrolled. Clinical trial information: EudraCT 2015-003612-20.

Phase Ib study to assess the safety, tolerability, and clinical activity of gedatolisib in combination with palbociclib and either letrozole or fulvestrant in women with metastatic or locally advanced/recurrent breast cancer (B2151009; NCT02684032).

TPS1113 Background: Hormone receptor positive (HR+) disease is the most common subset of both early and late stage breast cancer (BC). The majority of women with HR+ metastatic BC (MBC) ultimately develop resistance to endocrine therapy, with a median survival of ~2-3 years. A new standard-of-care strategy to treat HR+ metastatic disease involves the combination of hormone therapy and cyclin-dependent kinase (CDK) 4/6 inhibition, which has demonstrated improved progression-free survival (PFS) in both the first- and later-line metastatic setting. More recently, preclinical data with the dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor gedatolisib (PF-05212384) suggest synergy with the combination of hormone therapy, CDK 4/6 inhibition, and inhibition of the PI3K/mTOR pathway. Methods: This phase Ib study includes a dose escalation portion to evaluate dose-limiting toxicities (primary endpoint) and determine the recommended phase II dose for triplet therapy with gedatolisib combined with palbociclib/letrozole or palbociclib/fulvestrant in women with HR+ HER2-negative MBC or locally advanced/recurrent BC, in the first- and later-line setting. Thereafter, a 3-arm expansion for early signals of efficacy will investigate objective response rates (primary endpoint) with gedatolisib combined with palbociclib/letrozole (n = 26), palbociclib/fulvestrant in patients without prior CDK 4/6 inhibition (n = 28), and palbociclib/fulvestrant in patients who have previously received palbociclib (n = 27). The rates of objective response will be compared to historical controls. Secondary endpoints include safety, tumor response, PFS (expansion portion only), pharmacokinetics, and biomarker correlations associated with the PI3K/mTOR pathway. This trial is now recruiting. Clinical trial information: NCT02684032.

Abstract OT3-02-08: Open label, phase 2 safety, efficacy, and pharmacokinetic study of pre-surgical intramuscular and intraductal fulvestrant in women with invasive breast cancer or DCIS undergoing mastectomy or lumpectomy

Abstract BACKGROUND: Breast cancer (BC) is the leading cause of cancer in women in the United States and the second leading cause of cancer-related death. Currently available options for prevention are oophorectomy, bilateral mastectomy, or medical therapy, such as tamoxifen, raloxifene or aromatase inhibitors. None of these options for prevention are without significant side effects with low patient uptake. This study proposes fulvestrant instilled directly into the breast via the nipple orifices as intraductal therapy. Providing a local therapy into the ducts could reduce the morbidity associated with prevention while potentially better targeting the carcinoma cell. Building on prior studies with cytotoxic agents, this study utilizes the pure anti-estrogen fulvestrant to be injected in up to 5 ducts to determine its effect on BC as well as the safety of this method of administration. TRIAL DESIGN: An open-label, non-randomized PK study of pre-surgical fulvestrant in women scheduled for mastectomy or lumpectomy. Eligible subjects will be undergoing mastectomy or lumpectomy. The first 6 subjects will be treated with the standard dose of 500 mg intramuscular fulvestrant to establish the reference PK curve. The subsequent 24 subjects will receive fulvestrant by intraductal instillation. Subjects where at least 1 suitable duct is identified will undergo nipple aspiration in order to facilitate duct identification and intraductal infusion of a fulvestrant. A maximum of 5 ducts will receive intraductal infusion of fulvestrant. Across all ducts, the total dose will not exceed 500 mg (10 mL). Subsequent to mastectomy or lumpectomy subjects will undergo serial blood draws to determine fulvestrant blood concentration levels and tissue drug levels. ELIGIBILITY: Female, age > 18, mastectomy/lumpectomy scheduled within 30 days, Stage 1/2, ER+ low grade invasive BC or DCIS, ECOG scale 0-1. Primary Objective: The safety and tolerability of intraductal administration of fulvestrant in women with Stage 1 or 2 invasive ductal carcinoma or DCIS, prior to mastectomy or lumpectomy. Secondary Objectives: The pathological effects, specifically changes in Ki67, ER/PgR expression between pre-fulvestrant biopsy and post-fulvestrant surgical specimen. STATISTICAL METHODS: Aim of this study is to assess safety and tolerability in subjects receiving intraductal fulvestrant. In addition this trial aims to characterize the PK of this alternative route of administration, and compare the intraductal PK profile to that of standard intramuscular administration. Finally, the 6 study subjects who receive intramuscular fulvestrant will be qualitatively compared with the main study cohort of 24 subjects who receive intraductal fulvestrant. Change in Ki67 labeling index will be compared between the two time points (baseline or time of diagnostic biopsy v. time of the surgically excised specimen collection). CONTACT INFO: Sheldon Marc Feldman MD Columbia University Medical Center sf2388@cumc.columbia.edu 212-305-9676. Citation Format: Feldman S, Gomberawalla A, Alonso A, Rea J, Quay S, Lawrence R. Open label, phase 2 safety, efficacy, and pharmacokinetic study of pre-surgical intramuscular and intraductal fulvestrant in women with invasive breast cancer or DCIS undergoing mastectomy or lumpectomy [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 OT3-02-08.

Abstract OT2-01-21: Phase 2 study of investigational TORC1/2 inhibitor TAK-228 with fulvestrant in women with ER-positive/HER2-negative advanced or metastatic breast cancer that has progressed during or after aromatase inhibitor therapy

Abstract Standard therapy for ER-positive tumors in the adjuvant and metastatic settings is antiestrogen therapy, including aromatase inhibitors (AI); however, resistance is common. These tumors may respond to alternative second-line anti-estrogen therapies such as fulvestrant but response durations are often short. Preclinical and clinical studies suggest that simultaneous inhibition of ER and PI3K/mTOR could prevent/delay the emergence of hormone-independent cancer cells thereby improving patient (pt) outcomes. This study will test whether fulvestrant plus TAK-228, a dual TORC1/2 inhibitor, can overcome endocrine therapy resistance in ER-positive breast cancer. This is an open-label, randomized, 3-arm, phase 2 study of continuous once-daily TAK-228 (oral, 4 mg) or once-weekly TAK-228 (oral, 30 mg) plus fulvestrant (500 mg intramuscularly on d1 and d15 of cycle 1 [loading regimen] then d1 of each subsequent 28-d cycle), compared with fulvestrant alone, in pts with advanced or metastatic ER-positive/HER2-negative breast cancer that has progressed during/after AI therapy. Pts will be randomized 1:1:1 to the 3 arms and stratified at randomization via presence or absence of visceral metastasis, prior hormonal therapy sensitivity, and prior exposure to CDK 4/6 inhibitors. Pts will receive study drug(s) until progressive disease (PD), unacceptable toxicity, or consent withdrawal. Postmenopausal women ≥18 yrs old with local histological confirmation of ER-positive/HER2-negative metastatic or advanced breast cancer; with measureable disease; ECOG status 0–1; PD during/after prior AI therapy (defined as progression ≤12 mos after discontinuing adjuvant therapy or ≤1 mo after discontinuation in the metastatic setting) and adequate organ function are eligible. Exclusion criteria include prior therapy with mTOR inhibitors, PI3K inhibitors, dual PI3K-mTOR inhibitors, AKT inhibitors, or fulvestrant; prior treatment with >1 line of chemotherapy for metastatic breast cancer; experienced recurrent or progressive disease on >2 endocrine therapies for metastatic breast cancer; or significant previous/existing cardiac conditions. This study aims to determine the efficacy (primary endpoint: PFS; secondary endpoints: OS, TTP, ORR), safety and tolerability of daily and weekly TAK-228 plus fulvestrant compared with fulvestrant alone. The distribution of PFS will be analyzed via the Kaplan-Meier method. The primary hypothesis (TAK-228 plus fulvestrant can improve median PFS to 8 mos [hazard ratio, HR 0.5] vs fulvestrant-alone median PFS of 4 mos) is to be tested at the 0.10 significance level (2-sided; dropout rate 10%). A total of 72 PFS events are needed for each pair-wise comparison; p-values from a stratified log-rank test and HRs will be presented. The safety profile and clinical laboratory parameters (and/or change from baseline) for all scheduled measurements over time will be summarized by descriptive statistics. Approximately 153 pts (51 pts per arm) will be enrolled from approximately 55 study centers in North America and Spain; to date, no pts have been enrolled. For more information, please contact Michelle Kneissl at michelle.kneissl@takeda.com. Citation Format: García-Sáenz JA, Carrasco E, Kneissl ML, Zohren F, Martin M. Phase 2 study of investigational TORC1/2 inhibitor TAK-228 with fulvestrant in women with ER-positive/HER2-negative advanced or metastatic breast cancer that has progressed during or after aromatase inhibitor therapy [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 OT2-01-21.

Abstract OT3-03-01: MADELINE: A prospective observational study of mobile app-based patient reported outcomes in advanced breast cancer

Abstract BACKGROUND: There have been few studies evaluating the day-to-day effects of advanced breast cancer (ABC) and its treatment on patients in a real-world setting.Palbociclib is a novel CDK4/6 inhibitor approved in the US for hormone-receptor positive, human epidermal growth factor receptor negative (HR+, HER2-) ABC/metastatic breast cancer (MBC) in combination with letrozole as initial endocrine based therapy in postmenopausal women or with fulvestrant in women with disease progression following endocrine therapy. With the introduction of this first-in-class drug it is important to understand the experiences of patients initiating ABC therapies including palbociclib in real-world settings and to document the management of these therapies. A smartphone-based mobile application has been developed to collect patient-reported outcome (PRO) data to assess the impact of ABC and associated treatment on symptoms, functioning and quality of life (QOL) as reported by patients. The application is further designed to provide patients initiating palbociclib with a virtual community to connect to others enrolled in the study for peer support. Additionally, clinical data on therapy management (e.g. dose modifications, interruptions, discontinuations, adverse event management and monitoring) will be obtained from patients' medical records to explore the association between patient reported functioning and neutropenia. Study Design: A prospective, observational, non-interventional study. PROs collected via a mobile application and clinical data via case report forms completed by investigator. Eligibility Criteria: Women with HR+/HER2– ABC receiving palbociclib in combination with letrozole or fulvestrant as per US label (Group 1) orapproved therapies for ABC other than palbociclib (Group 2). No comparison is intended between the 2 groups. Specific Aims: The primary goals are to describe changes in patients' general health status as measured by monthly administration of the 12-Item Short Form Health Survey, describe changes in patients' psychological distress as measured by monthly administration of the Center for Epidemiological Studies Depression Scale, and describe the extent to which ABC and its treatment are associated with changes in patients' lives in terms of symptoms, functioning and QOL as measured by daily and weekly administration of targeted patient-reported questions. Additionally, for patients who are employed at baseline, time lost from work in relation to breast cancer and its treatment will be quantified.Data from patients' medical records will be used to document changes in therapy as well as the incidence, severity, and duration of neutropenia. The association between patient reported functioning and neutropenia will also be assessed. Finally, real-world monitoring patterns will be assessed. Statistical Methods: Descriptive statistics will be used to summarize all endpoints. Meta-data regarding use of virtual community resources will be explored for relationships to PRO data. Present Accrual and Target Accrual: Approximately 450 patients from up to 30 US sites will be enrolled. Study duration will be approximately 12 months assuming 6 months of recruitment. It is expected the study will start enrollment Q3 2016. Sponsor: Pfizer. Citation Format: McRoy LL, Mitra D, Hollis K, Kaye JA, Zelnak A, Cheyl J. MADELINE: A prospective observational study of mobile app-based patient reported outcomes in advanced breast cancer [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 OT3-03-01.

Abstract P4-22-06: Treatment postprogression in women with endocrine-resistant HR+/HER2- advanced breast cancer who received palbociclib plus fulvestrant in PALOMA-3

Abstract Background: Palbociclib (PAL) plus fulvestrant (FUL) demonstrated significant improvement in progression-free survival (PFS) vs placebo (PBO) plus FUL in women with HR+/HER2- advanced breast cancer (ABC) whose disease had progressed on prior endocrine therapy (ET). Because the effectiveness of standard therapies after progression on PAL is unknown, it is important to understand whether the benefits of PAL with respect to PFS extend to subsequent treatments. Method: Pre-, peri-, and postmenopausal patients (pts) with HR+/HER2- ABC who had relapsed/progressed on prior ET were randomized 2:1 to PAL (125 mg/d oral [3 wk on drug, 1 wk off]) + FUL (500 mg/mo intramuscular, per standard of care) or PBO+FUL. One prior line of chemotherapy (CT) for ABC was allowed. For 9 mo immediately after participation in PALOMA-3, pts were assessed every 3 mo for information on poststudy progression and treatment; the type of treatment, its duration, and sites of progression were analyzed. Results: As of Oct 2015, with a median follow-up of 15.8 mo for PAL+FUL and 15.3 mo for PBO+FUL, 333 PFS events were observed (200 and 133, respectively). Median PFS was 11.2 vs 4.6 mo (hazard ratio [HR], 0.497 [95% CI, 0.398–0.620]; P<0.0001). In both treatment arms, the most common sites of disease progression were the liver (149 [43%] and 94 [54%]) and bone (55 [16%] and 43 [25%]). 1 pt in each treatment arm developed new brain metastasis. The most commonly used postprogression regimens were capecitabine (n=57 [28.8%]), paclitaxel (n=22 [11.1%]), and exemestane (n=34 [17.2%]). Median time to subsequent CT (from randomization to the start of the first CT treatment poststudy) was longer with PAL+FUL (252 d) than with PBO+FUL (132 d). This was also observed in pts with visceral disease who never received CT in the advanced setting at study entry (median 208 and 125 d, respectively). 252 pts had subsequent disease progression, treatment discontinuation on immediate subsequent therapy, or died. Proportionally fewer pts in the PAL+FUL vs PBO+FUL arm discontinued next-line treatment (33% vs 46%), indicating that PAL does not adversely affect the efficacy of subsequent treatments. Analysis of the time to end of next-line treatment showed that the HR between the 2 treatment arms was 0.623 ([95% CI, 0.482–0.805]; 1-sided P value=0.0001) in favor of PAL treatment (Table 1). Conclusion: The current analysis demonstrated that the treatment effect of PAL+FUL was retained in the most immediate line postprogression and that progression after PAL has no effect on the therapeutic benefit from subsequent treatments. Sponsor: Pfizer Table 1. PAL+FUL (n=347)PBO+FUL (n=174)Pts who progressed and were eligible for subsequent therapy, n (%)198 (57)130 (75)Pt with postprogression event, n (%)156 (45)96 (55)Objective progression on next-line therapy, n (%)15 (4)5 (3)Deaths, n (%)28 (8)11 (6)End of next-line therapy, n (%)113 (33)80 (46)Median (95% CI) probability of being event-free at 12 mo69.2 (64.0–73.8)54.4 (46.4–61.7)Median (95% CI) time to end of next-line therapy, mo17.9 (16.0–NR)12.8 (11.0–14.6)Hazard ratio (95% CI)0.623 (0.482–0.805)P value0.0001FUL=fulvestrant; NR=not reached; PAL=palbociclib; PBO=placebo. Citation Format: Turner NC, André F, Cristofanilli M, Verma S, Iwata H, Loi S, Harbeck N, Ro J, Colleoni M, Zhang K, Huang Bartlett C, Giorgetti C, Slamon D. Treatment postprogression in women with endocrine-resistant HR+/HER2- advanced breast cancer who received palbociclib plus fulvestrant in PALOMA-3 [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 P4-22-06.

Progress with palbociclib in breast cancer: latest evidence and clinical considerations.

Deregulation of the cell cycle is a hallmark of cancer, and research on cell cycle control has allowed identification of potential targets for anticancer treatment. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved, with their coregulatory partners cyclin D, in the G1-S transition. Inhibition of this step halts cell cycle progression in cells in which the involved pathway, including the retinoblastoma protein (Rb) and the E2F family of transcription factors, is functioning, although having been deregulated. Among breast cancers, those with functioning cyclin D-CDK4/6-Rb-E2F are mainly hormone-receptor (HR) positive, with some HER2-positive and rare triple-negative cases. Deregulation results from genetic or otherwise occurring hyperactivation of molecules subtending cell cycle progression, or inactivation of cell cycle inhibitors. Based on results of randomized clinical trials, palbociclib was granted accelerated approval by the US Food and Drug Administration (FDA) for use in combination with letrozole as initial endocrine-based therapy for metastatic disease in postmenopausal women with HR-positive, HER2-negative breast cancer, and was approved for use in combination with fulvestrant in women with HR-positive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. This review provides an update of the available knowledge on the cell cycle and its regulation, on the alterations in cyclin D-CDK4/6-Rb-E2F axis in breast cancer and their roles in endocrine resistance, on the preclinical activity of CDK4/6 inhibitors in breast cancer, both as monotherapy and as partners of combinatorial synergic treatments, and on the clinical development of palbociclib in breast cancer.

Abstract P1-16-05: MDV3100-08: A phase 1 study evaluating the safety and pharmacokinetics of enzalutamide plus fulvestrant in women with advanced hormone receptor-positive breast cancer

Abstract Background: Fulvestrant (FUL), an estrogen receptor (ER) antagonist, is an effective treatment for patients (pts) with hormone receptor-positive (HR+) breast cancer (BC) whose disease has progressed or recurred during previous anti-estrogen therapy. The androgen receptor (AR), expressed in the majority of HR+ BC, may contribute to resistance to hormonal therapy. Enzalutamide (ENZA) is a potent inhibitor of AR signaling. Preclinical models with ER+/AR+ BC cell lines showed synergistic inhibitory effects for ENZA combined with FUL on tumor cell growth. ENZA is a potent CYP3A4 inducer, and in vitro studies show that CYP3A4 is the only CYP enzyme involved in the oxidative metabolism of FUL. In this phase 1 trial (NCT01597193), we evaluated the potential for ENZA to affect FUL pharmacokinetics (PK), as well as the safety and tolerability of the combination of ENZA with FUL. Methods: Postmenopausal pts with HR+/AR+ advanced BC were enrolled; any number of prior therapies were permissible. Tumor tissue was analyzed centrally for AR expression; pts who had ?10% tumor cells with nuclear AR staining were eligible. All pts received at least 3 doses of FUL (500 mg intramuscularly on days 1, 15, and 29 and once monthly thereafter) to ensure steady-state concentrations prior to initiating ENZA 160 mg/day orally. The combination of ENZA with FUL was given until disease progression. PK and hormone sampling occurred on day 1 prior to ENZA initiation and on days 29 and 57. All pts were monitored for safety and response to treatment. Results: As of 01May2015, 11 pts were enrolled; PK data are available for 8 of 11 pts, and 6 pts remain on study. Median age was 59 years; median ECOG performance status was 1. Two pts previously received FUL as a prior therapy for advanced BC; 4 pts received no prior therapy for advanced BC. The median duration of exposure to the combination was 16.6 weeks (range 4.0-42.3); the median duration of exposure to FUL (including at least 3 preloading doses) was 24.4 weeks (range 11.7-67.3). Common (>2 pts) ENZA-related adverse events (AEs) included fatigue (n=6), nausea (n=5), cognitive disorder (n=4) and diarrhea (n=3). Cognitive changes Grade 1/2 were reported in 4 pts based on the cognitive function assessment questionnaire. Two pts reported unrelated serious AEs (erosive gastritis, urinary tract infection, iron deficiency anemia, and dehydration). Four pts had AEs ≥ Grade 3: hypertension, anemia, hyperglycemia, urinary tract infection, asthenia, erosive gastritis, dehydration, and iron deficiency anemia; only asthenia and hypertension were considered treatment-related. Circulating levels of estradiol and estrone were within the expected range. Trough plasma concentrations of FUL (Cmin) were similar for FUL alone and FUL combined with ENZA (Cmin=13.7 ± 2.8 and 12.5 ± 1.8 ng/mL, respectively). Conclusions: The safety profile for the combination of daily ENZA with FUL appears to be consistent with the published data for ENZA and FUL monotherapies. ENZA with FUL achieves similar plasma exposure to FUL alone, indicating no PK drug interaction. Citation Format: Elias AD, Burris HA, Patel MR, Schwartzberg LS, Richer JK, Kavalerchik E, Stopatschinskaja S, Gibbons J, Markova D, Steinberg JL, Traina TA. MDV3100-08: A phase 1 study evaluating the safety and pharmacokinetics of enzalutamide plus fulvestrant in women with advanced hormone receptor-positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-16-05.

Abstract OT1-1-07: A phase III study of abemaciclib (LY2835219) combined with fulvestrant in women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer (MONARCH 2)

Abstract Background: Abemaciclib (LY2835219), an oral drug administered twice daily on a continuous schedule, is a cell cycle inhibitor of both CDK4 and CDK6. In Study I3Y-MC-JPBA, abemaciclib demonstrated evidence of single agent activity in a tumor-specific cohort of patients with metastatic breast cancer (MBC) and a median of 7 prior therapies; all responses observed were in women with HR+ disease. Abemaciclib also demonstrated an acceptable safety profile both as a single agent and in combination with fulvestrant. Based on these results, abemaciclib has been entered into a Phase III study (MONARCH 2) in combination with fulvestrant for women with locally advanced or metastatic hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Trial design: MONARCH 2 (NCT02107703) is a randomized, double-blind, placebo-controlled Phase III study of fulvestrant with or without abemaciclib for women with HR+, HER2- locally advanced (not amenable to curative treatment by surgery) or metastatic breast cancer. Patients will be randomized 2:1 (Arm A [abemaciclib plus fulvestrant]: Arm B [placebo plus fulvestrant] with stratification based on the nature of disease (visceral metastases versus bone only metastases versus other) and sensitivity to endocrine therapy (no prior endocrine therapy versus primary resistance versus secondary resistance). Abemaciclib (200 mg every 12 hours [Q12H] on Days 1 to 28 of a 28-day cycle) or placebo will be given orally and fulvestrant 500 mg will be administered intramuscularly on Days 1 and 15 of Cycle 1, then on Day 1 of Cycle 2 and subsequent cycles. Eligibility criteria: Postmenopausal women with HR+, HER2- inoperable locally advanced or metastatic breast cancer who have either relapsed after prior endocrine therapy or have not received prior endocrine therapy are eligible. Patients are required to have either measurable disease or non-measurable bone only disease, adequate organ function and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤1. Specific aims: The primary objective of MONARCH 2 is to compare PFS between two treatment arms: abemaciclib plus fulvestrant versus placebo plus fulvestrant for women with HR+, HER2- locally advanced or metastatic breast cancer. Secondary objectives are to compare overall survival, objective response rate, clinical benefit rate, safety, pharmacokinetics and quality of life. Statistical methods: The study has 90% power to detect an increase in PFS of approximately 42% (hazard ratio = .703). Assuming a median PFS of 6.5 mos. in the control arm, this corresponds to a 2.75 month increase in the median PFS to 9.25 mos. PFS and OS will be hierarchically tested to maintain an overall type I error rate of 2.5%. Present accrual and target accrual: Target accrual is approximately 550 patients. Contact information: For further information please contact 1-877-CTLILLY (1-877-285-4559). Citation Format: Antonio Llombart, Masakazu Toi, Suzanne R Klise, Martin Frenzel, Edward M Chan, George W Sledge. A phase III study of abemaciclib (LY2835219) combined with fulvestrant in women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer (MONARCH 2) [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 OT1-1-07.

Combined Src and ER blockade impairs human breast cancer proliferation in vitro and in vivo

Antiestrogen therapies arrest susceptible estrogen receptor (ER)-positive breast cancers by increasing p27. Since Src phosphorylates p27 to promote p27 proteolysis, Src activation observed in up to 40% of ER-positive cancers may contribute to antiestrogen resistance. In this article, we show that treatment with the Src-inhibitor saracatinib (AZD0530) together with ER-blocking drugs increased breast cancer cell cycle arrest via p27. Saracatinib and fulvestrant together more effectively increased p27, reduced Ki67, and impaired MDA-MB-361 xenograft tumor growth in vivo than either of the drugs alone. In contrast, saracatinib monotherapy rapidly gave rise to drug resistance. Since combined ER and Src inhibition delays development of resistance in vivo, these data support further clinical investigation of saracatinib in combination with fulvestrant for women with ER-positive breast cancer. Proteomic analysis revealed striking bypass activation of the mTOR pathway in saracatinib-resistant tumors. mTORC1 activation also arose following long-term culture of ER-positive breast cancer lines in the presence of saracatinib. These data indicate the utility of proteomic analysis of drug-resistant tumors to identify potential means of drug resistance. The use of mTOR kinase inhibitors with saracatinib may subvert drug resistance and prove to be more effective than saracatinib alone.

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.