Fulvestrant In Postmenopausal Women Research Articles

Abstract PO2-18-09: A phase 3 randomized open-label study of extended adjuvant therapy with camizestrant vs standard endocrine therapy in patients with ER+/HER2– early breast cancer and an intermediate or high risk of recurrence (CAMBRIA 1)

Abstract Background: Definitive locoregional (surgery ± radiotherapy) and standard adjuvant endocrine therapy (ET) (± chemotherapy or cyclin-dependent kinase 4/6 inhibitor [CDK4/6i]) can achieve cure in many patients (pts) with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2–) early breast cancer (BC). Nevertheless, a significant proportion of pts with stage I–III disease will experience recurrence to metastatic, incurable disease (5- and 10-year cumulative incidences of recurrence of 8.3% and 14.0%, respectively). There is evidence that incorporating a more effective endocrine therapy after 2 years of standard adjuvant ET can result in clinical benefit for high-risk individuals. Camizestrant is a next-generation oral selective ER degrader and pure ER antagonist. In SERENA-2, camizestrant 75 mg and 150 mg significantly prolonged progression-free survival vs fulvestrant in postmenopausal women with ER+/HER2– advanced BC with disease recurrence or progression after ET. The CAMBRIA-1 study (NCT05774951) is evaluating the potential of extended adjuvant therapy with camizestrant to improve outcomes in pts with ER+/HER2– early BC with an intermediate or high risk of recurrence after definitive locoregional therapy and standard adjuvant ET. Trial design: This phase 3 randomized, open-label study is enrolling women (pre- or postmenopausal) and men with ER+/HER2– (immunohistochemistry 0/1+/2+/in situ hybridization-negative) early BC who have completed definitive locoregional therapy and standard adjuvant ET (± CDK4/6i) for ≥2 and ≤5 years (+ 3 months) without disease recurrence. Pts must be considered at intermediate or high risk of recurrence based on clinical, biological, and genomic factors. Pts are randomized (1:1) to continue standard ET of the investigator’s choice (tamoxifen or aromatase inhibitor ± luteinizing hormone-releasing hormone [LHRH] agonist) or camizestrant ± LHRH agonist for up to 60 months. The primary endpoint is invasive BC-free survival (STEEP 2.0 criteria). Secondary endpoints include invasive disease-free survival and distant relapse-free survival (STEEP 2.0 criteria), overall survival, safety, and health-related quality of life. Primary endpoint analysis will use a stratified log-rank test adjusting for stratification factors, assuming a two-sided significance level of 5%. Approximately 4300 pts will be randomized; enrollment is ongoing. Clinical trial identification: NCT05774951 Editorial acknowledgment: Writing assistance was provided by Alison Lovibond, PhD, of BOLDSCIENCE Inc., funded by AstraZeneca. Legal entity responsible for the study: AstraZeneca Funding: This study was supported by AstraZeneca. Citation Format: Erika Hamilton, Sibylle Loibl, Naoki Niikura, Priya Rastogi, Kamal S. Saini, Ioanna Gioni, Teresa Klinowska, Ingrid A. Mayer, Mary Stuart, Emilia Syta, Andrew Walding, Thomas Bachelot. A phase 3 randomized open-label study of extended adjuvant therapy with camizestrant vs standard endocrine therapy in patients with ER+/HER2– early breast cancer and an intermediate or high risk of recurrence (CAMBRIA 1) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-18-09.

EE166 Cost-Effectiveness of Alpelisib Plus Fulvestrant in Postmenopausal Women with Hr+/HER2- Advanced Breast Cancer (ABC) in Qatar

The aim of this current study is to estimate the cost-effectiveness of Alpelisib plus Fulvestrant in HR+/HER2- advanced Breast Cancer patients with a PIK3CA mutation.

EE46 Cost-Effectiveness of Alpelisib Plus Fulvestrant in Postmenopausal Women with Hr+/HER2- Advanced Breast Cancer (ABC) in Oman

The aim of this current study is to estimate the cost-effectiveness of Alpelisib plus Fulvestrant in HR+/HER2- advanced Breast Cancer patients with a PIK3CA mutation.

Abstract GS3-02: GS3-02 Camizestrant, a next generation oral SERD vs fulvestrant in post-menopausal women with advanced ER-positive HER2-negative breast cancer: Results of the randomized, multi-dose Phase 2 SERENA-2 trial

Abstract Background Camizestrant (C), a next-generation oral selective estrogen receptor (ER) antagonist and degrader (ngSERD) has shown promising clinical activity in ER+ breast cancer (BC) in the Phase 1 SERENA-1 study1,2 with a dose-dependent safety profile. The Phase 2 randomized SERENA-2 study (NCT04214288) initially assessed three doses of C vs fulvestrant (F) in post-menopausal women with ER+ HER2˗ BC with disease recurrence or progression after ≤1 endocrine therapy (ET) in the advanced setting. Methods SERENA-2 evaluated efficacy and safety of C 75, 150 or 300 mg monotherapy QD vs F (per label). Eligible patients were randomized 1:1:1:1. The Primary objective was to determine clinical efficacy of C vs F by investigator-assessed progression-free survival (PFS). Secondary endpoints included objective response rate, response duration, clinical benefit rate at 24 weeks, overall survival and safety. Patients had no prior F or oral SERD and ≤1 ET and ≤1 chemotherapy (CTX) in the advanced setting. To assess the impact of prior CDK4/6 inhibitor (CDK4/6i) treatment, randomization was stratified so that 50% of patients had prior CDK4/6i. Planned enrolment of 288 patients began in April 2020. The C 300 arm was closed after 20 patients were enrolled, changing target enrolment to 236. By August 2021, 240 patients had been randomized. Primary analysis was triggered when 108 progression events (75% maturity) had occurred in the best performing pair (C vs F) in August 2022. Efficacy analyses compared C 75 and 150 mg doses with F, with no formal analyses of C 300 vs F. 108 events for pairwise comparison vs F gave 86% power at the 2-sided 10% significance level. Primary analyses used a Cox proportional hazards model to compare PFS, adjusting for prior CDK4/6i and lung/liver metastases. ESR1 mutations (ESR1m) were detected in plasma samples using next-generation sequencing. Results 119/240 (49.6%) patients had had prior CDK4/6i therapy. At baseline, 88 (36.7%) patients had detectable ESR1m and 140 (58.3%) had lung/liver metastases. Prior CTX or ET rates in the advanced setting were 19.2 and 65.4%. Treatment-emergent adverse events (AEs) (grade ≥3) occurred in 77.0 (12.2), 90.4 (21.9) and 68.5 (13.7) % of patients in the C 75, C 150 and F arms. AEs leading to treatment discontinuation occurred in 2.7, 0 and 0% of patients in the C 75, C 150 and F arms. The most common AEs considered by the investigator to be causally related to study drug were photopsia (18.4%) and (sinus) bradycardia (13.6%) – all were grade 1 or 2. Hot flush (2.7%) and myalgia (2.7%) were the most common AEs related to F. Conclusions SERENA-2 is the first Phase 2 trial investigating multiple dose levels of an ngSERD vs F in post-menopausal women with advanced ER+ HER2˗ BC with disease recurrence or progression after ≤1 ET in the advanced setting. C at both 75 and 150 mg dose levels showed a statistically significant and clinically meaningful benefit in PFS vs F in the overall study population, and was well tolerated. The results of SERENA-2 support the further development of C in ER+ HER2- BC. Acknowledgements AstraZeneca sponsored this trial and funded medical writing support from Helen Heffron (InterComm International).

Quality of life with palbociclib plus fulvestrant versus placebo plus fulvestrant in postmenopausal women with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer: patient-reported outcomes from the FLIPPER trial.

In the FLIPPER trial, palbociclib/fulvestrant significantly improved progression-free survival (PFS) compared with placebo/fulvestrant in postmenopausal women with HR+/HER2- advanced breast cancer (ABC). We assessed health-related quality of life (QoL) using patient-reported outcomes (PROs). In this phase II double-blinded study, PROs were assessed at baseline after every three cycles and at the end of the treatment using the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23. Time to deterioration (TTD) in global health status (GHS)/QoL was defined as a decrease of ⩾10 points. Changes from baseline (CFB) and TTD were analysed using linear mixed-effect and Cox regression models, respectively. Of the 189 randomised (1:1) patients, 178 (94%) completed ⩾1 post-baseline assessment; 50% received ⩾22 cycles of study treatment, with a questionnaire compliance >90%. Mean baseline scores were comparable between arms. GHS/QoL scores were maintained throughout the palbociclib/fulvestrant treatment. CFB showed significant differences for GHS/QoL, appetite loss, constipation and systemic therapy side effect scores favouring placebo/fulvestrant. TTD in GHS/QoL was delayed in placebo/fulvestrant versus palbociclib/fulvestrant [30.3 versus 11.1 months; adjusted hazard ratio (aHR): 1.57, 95% CI: 1.03-2.39, p = 0.036]; this difference was not significant in patients with progressive disease (aHR: 1.2, 95% CI: 0.6-2.2, p = 0.658). No statistically significant differences in TTD were found for the other QLQ-C30 and QLQ-BR23 scales. Although TTD in GHS/QoL was prolonged with placebo/fulvestrant, no differences were observed on other functional or symptom scales. This finding and the improvement in PFS support the combination of palbociclib/fulvestrant as a beneficial therapeutic option for HR+/HER2- ABC. Sponsor Study Code: GEICAM/2014-12EudraCT Number: 2015-002437-21ClinTrials.gov reference: NCT02690480.

Real-world Treatment Patterns and Clinical Outcomes Associated With Palbociclib Combination Therapy: A Multinational, Pooled Analysis From the Ibrance Real World Insights Study

PurposePalbociclib was the first cyclin-dependent kinase 4/6 inhibitor approved by the US Food and Drug Administration for use in combination with aromatase inhibitors (AIs) as initial endocrine-based therapy or with fulvestrant in postmenopausal women who previously received endocrine therapy based on data from randomized clinical trials. Real-world studies examining the effectiveness of palbociclib in large, diverse patient populations in routine clinical practice were needed. Patients and MethodsIbrance Real World Insights (IRIS) was a retrospective medical record review study of women with confirmed hormone receptor–positive, HER2-negative advanced/metastatic breast cancer treated with palbociclib plus an AI or with palbociclib plus fulvestrant according to approved indications. Participating physicians reviewed medical records of up to 16 sequentially presenting patients, collecting demographic and clinical data. Outcomes included objective response rates, progression-free rates, and survival rates overall and in patients stratified according to age, race and ethnicity, Eastern Cooperative Oncology Group (ECOG) performance status (PS), disease-free interval, visceral disease, liver metastases, bone-only metastases, and previous lines of therapy. FindingsData were abstracted by 417 physicians for 2954 patients in 13 countries; 1415 patients (47.9%) were ≥65 years of age, 369 patients (12.5%) had an ECOG PS ≥2 at initiation, and 835 patients (28.3%) were races other than White. The 12-month progression-free rate was 88% for palbociclib plus an AI and 79% for palbociclib plus fulvestrant; the 12-month survival rate was 96% in both groups. The objective response rates were 80% for palbociclib plus an AI and 75% for palbociclib plus fulvestrant. Palbociclib was similarly effective in most subgroups examined. ImplicationsData from IRIS provide in-depth, real-world evidence for the use of palbociclib in a range of breast cancer populations in multiple countries. These data support the findings of the randomized PALOMA-2 and PALOMA-3 studies.

Quality-Adjusted Survival with Ribociclib Plus Fulvestrant Versus Placebo Plus Fulvestrant in Postmenopausal Women with HR±HER2− Advanced Breast Cancer in the MONALEESA-3 Trial

BackgroundMONALEESA-3 demonstrated an overall survival (OS) benefit for ribociclib plus fulvestrant (R+F) in postmenopausal women with hormone receptor (HR) positive, HER2 negative advanced breast cancer (ABC). This study estimated quality-adjusted (QA) survival outcomes for patients receiving R+F vs. placebo (P)+F in MONALEESA-3. MethodsKaplan-Meier OS was partitioned into health states: (1) toxicity (TOX)=time spent with grade 3 –4 adverse events before progression (DP); (2) progression (PROG)=time between DP and death; and (3) time without symptoms or toxicity (TWiST)=time not in TOX or PROG. QA time was calculated by combining estimated mean time in each health state with treatment-group specific health-state utility values estimated using EQ-5D-5L questionnaire. Outcomes included QA progression-free survival (QAPFS), QAOS, and QA TWiST (Q-TWiST). Q-TWiST was calculated with health-state utility values for TOX and PROG defined relative to TWiST. ResultsMean PFS and OS were significantly greater with R+F vs. P+F (difference 0.56 and 0.19 years). Mean time in TOX and TWiST were greater with R+F; mean time in PROG was greater with P+F. QAPFS was 0.45 years (95% CI 0.27 –0.63) greater with R+F than P+F (P <.001). QAOS was numerically greater with R+F vs. P+F (0.16 years, 95% CI 0.07 –0.45, P = .0569). Q-TWiST was 0.23 years greater with R+F (95% CI 0.07 –0.45, P = .0069). In a sensitivity analysis using an estimate of disutility for PROG, the difference in QAOS was 0.23 years (95% CI 0.08 –0.41, P = .0022). ConclusionR+F in postmenopausal women with HR+/HER2- ABC improves QAPFS, resulting in clinically important improvements in Q-TWiST and may improve QAOS.

Sapanisertib Plus Exemestane or Fulvestrant in Women with Hormone Receptor-Positive/HER2-Negative Advanced or Metastatic Breast Cancer.

This open-label, multicenter, phase IB/II study evaluated sapanisertib, a dual inhibitor of mTOR kinase complexes 1/2, plus exemestane or fulvestrant in postmenopausal women with hormone receptor-positive (HR+)/HER2-negative (HER2-) advanced/metastatic breast cancer. Eligible patients had previously progressed on everolimus with exemestane/fulvestrant and received ≤3 (phase IB) or ≤1 (phase II) prior chemotherapy regimens. Patients received sapanisertib 3 to 5 mg every day (phase IB), or 4 mg every day (phase II) with exemestane 25 mg every day or fulvestrant 500 mg monthly in 28-day cycles. Phase II enrolled parallel cohorts based on prior response to everolimus. The primary objective of phase II was to evaluate antitumor activity by clinical benefit rate at 16 weeks (CBR-16). Overall, 118 patients enrolled in phase IB (n = 24) and II (n = 94). Five patients in phase IB experienced dose-limiting toxicities, at sapanisertib doses of 5 mg every day (n = 4) and 4 mg every day (n = 1); sapanisertib 4 mg every day was the MTD in combination with exemestane or fulvestrant. In phase II, in everolimus-sensitive versus everolimus-resistant cohorts, CBR-16 was 45% versus 23%, and overall response rate was 8% versus 2%, respectively. The most common adverse events were nausea (52%), fatigue (47%), diarrhea (37%), and hyperglycemia (33%); rash occurred in 17% of patients. Molecular analysis suggested positive association between AKT1 mutation status and best treatment response (complete + partial response; P = 0.0262). Sapanisertib plus exemestane or fulvestrant was well tolerated and exhibited clinical benefit in postmenopausal women with pretreated everolimus-sensitive or everolimus-resistant breast cancer.

Abstract PD1-01: Open-label, randomized, phase 2 study of sapanisertib (TAK-228/MLN0128) in combination with fulvestrant in postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor-2-negative (HER2-) advanced or metastatic breast cancer (MBC) that previously progressed during or after aromatase inhibitor therapy (NCT02756364)

Abstract Background: Sapanisertib (S) is an investigational, oral, and highly selective adenosine triphosphate (ATP)-competitive inhibitor of target of rapamycin complex 1/2 (TORC1/2). Simultaneous inhibition of ER and phosphoinositide 3kinase (PI3K)/serine/threonine-specific protein kinase (AKT)/mammalian target of rapamycin (mTOR) pathway with S may restore sensitivity to endocrine therapies in patients (pts) with breast cancer, who have progressed during or after aromatase inhibitor (AI) therapy. Here we report data from a phase 2 study of continuous once-daily or once-weekly S + fulvestrant (F) compared with single-agent F in pts with breast cancer. Methods: Postmenopausal women with ER+ and HER2- advanced or metastatic breast cancer following progression during/after AI therapy were randomized 1:1:1 to receive F (500 mg intramuscularly on day 1 of a 28-day cycle) alone (Arm A) or in combination with oral S either daily (4 mg; Arm B) or weekly (30 mg; Arm C) until progressive disease (PD), unacceptable toxicity, or consent withdrawal. Pts were stratified according to presence/absence of visceral metastases, previous sensitivity to hormonal therapy, and previous exposure to cyclin-dependent kinase (CDK) 4/6 inhibitors. Pts on Arm A could receive S at PD. Key exclusion criteria were: prior therapy with mTOR inhibitors, PI3K inhibitors, or F; &amp;gt;1 prior line of chemotherapy for MBC; recurrent disease or PD on &amp;gt;2 endocrine therapies for MBC. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR; any duration and at 24 weeks), overall survival (OS), and safety. Results: Between Aug 2016 and May 2018, 141 pts were randomized (Arm A: 46; Arm B: 47; Arm C: 48). One patient in Arm C was not treated. Median age was 58 years (range 33-84). Stratification was well balanced across arms; overall, 65% had visceral metastases, 84% had prior sensitivity to hormonal therapy, and 34% had received prior CDK 4/6 inhibitors. Pts received a median of 4 cycles (range 1-40) of F on Arm A, 5 cycles (range 1-33) of daily S + F on Arm B, and 4 cycles (range 1-39) of weekly S + F on Arm C. The last follow-up visit was in Nov 2019. The main reasons for treatment discontinuation included PD (76%, 60%, 53%; Arm A, B, and C, respectively) and adverse events (AEs; 4%, 32%, 36%; Arm A, B, and C, respectively). Of the pts in Arm A with confirmed PD, 18 crossed over to Arm B and C (9 each); crossover was analyzed separately. Efficacy data are shown in the table; median PFS was 3.5, 7.2, and 5.6 months in Arm A, B, and C, respectively. OS data were immature at the primary data cut-off. Three pts died during the study (2 and 1 in Arm A and B, respectively); all deaths were attributed to underlying disease. Most common any-grade AEs were: asthenia (24%), hyperglycemia, fatigue, and headache (22% each) in Arm A; hyperglycemia (57%) and nausea (49%) in Arm B; nausea (87%) and vomiting (70%) in Arm C. Conclusion: Daily or weekly treatment with S + F demonstrated modest clinical benefit in ER+/HER2- advanced or MBC pts who progressed during/after AI compared with single-agent F. The S + F combinations had increased toxicity leading to more treatment discontinuations compared with single-agent F. Table: PFS and response dataArm A Single-agent F (n = 46)Arm B S (QD) + F (n = 47)Arm C S (QW) + F (n = 48)Median PFS (95% CI), months3.5 (1.9-5.6)7.2 (3.9-10.6)5.6 (4.1-9.0)HR (95% CI)0.77 (0.47-1.26)0.88 (0.53-1.45)ORR*, n/N (%)5/46 (10.9)10/47 (21.3)†6/47 (12.8)CBR*, n/N (%)28/46 (60.9)35/47 (74.5)31/47 (66.0)CBR≥6 months*, n/N (%)15/46 (32.6)23/47 (48.9)12/47 (25.5)*Safety population †Including 2 complete responses Citation Format: José Á García-Saenz, Noelia Martínez Jáñez, Miguel Martin, Ainhara Lahuerta Martínez, Santiago González-Santiago, Nieves Ferrer, Manuel Ramos Vázquez, José Luis Alonso Romero, Antonio Antón, Eva Carrasco, Jingjing Chen, Rachel Neuwirth, E Jane Leonard, Dennis Slamon. Open-label, randomized, phase 2 study of sapanisertib (TAK-228/MLN0128) in combination with fulvestrant in postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor-2-negative (HER2-) advanced or metastatic breast cancer (MBC) that previously progressed during or after aromatase inhibitor therapy (NCT02756364) [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 PD1-01.

Abstract OT-09-05: A randomized, pre-surgical study to investigate the biological effects of AZD9833 doses in women with ER-positive HER2-negative primary breast cancer (SERENA-3)

Abstract Background AZD9833 is an orally bioavailable selective estrogen receptor (ER) antagonist and degrader (SERD) that has shown anti-tumor efficacy in a range of preclinical breast cancer models. SERENA-1, an ongoing first-in-human study assessing AZD9833 as a monotherapy and in combination with palbociclib, established dose-dependent tolerability in pre- and post-menopausal women at doses of 25-450 mg once daily (QD), with clinical benefit and target engagement at all dose levels. Two randomized, open-label Phase 2 trials are also ongoing in women with ER+ HER2- breast cancer. SERENA-2 compares the efficacy of AZD9833 with fulvestrant in post-menopausal women with advanced breast cancer following treatment with ≤1 endocrine therapy. SERENA-3 will examine the biological effects of different doses of AZD9833 in treatment-naïve women with primary breast cancer. Methods SERENA-3 is a randomized, open-label, parallel-group, pre-surgical study to investigate the biological effects of different doses of AZD9833 in ER+, HER2- primary breast cancer. Eligible patients will be post-menopausal (and potentially pre-menopausal) women awaiting curative-intent surgery for newly diagnosed, ER+ HER2- primary breast cancer. The study is designed in two stages. In Stage 1, 24 post-menopausal women will be randomized 1:1 to receive either 75 mg or 150 mg oral AZD9833 QD for 5-7 days, followed by a minimum 5-day pre-surgery washout period; Stage 2 gives provision for additional groups depending on emerging data from Stage 1. The primary objective of this study is to explore the effect of AZD9833 on ER expression in pre- and on-treatment tumor samples from women with primary breast cancer, as assessed by immunohistochemistry and H-score. Safety and tolerability will be assessed as secondary endpoints, along with the pharmacokinetic and pharmacodynamic effects of AZD9833 on other biomarkers. Blood will be collected at screening, on the day of biopsy and the day of surgery to assess circulating tumor DNA and exploratory biomarkers. Primary endpoint analysis will be performed on the pharmacodynamic analysis set. The study will be conducted in 20 centers across 3 countries. For more information please contact Professor John Robertson at: john.robertson@nottingham.ac.uk. Citation Format: John FR Robertson, Iain Moppett, Juan Enrique Bargalló Rocha, Giorgi Dzagnidze, Joanna Harding, Teresa Klinowska, Richard Mather, Alastair Mathewson, Rhiannon Maudsley, Christopher J Morrow, Andrew Saunders, Andy Sykes, Li Zhang, Justin PO Lindemann. A randomized, pre-surgical study to investigate the biological effects of AZD9833 doses in women with ER-positive HER2-negative primary breast cancer (SERENA-3) [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 OT-09-05.

Abstract OT-09-02: A randomized, open-label, parallel-group, multicenter phase 2 study comparing the efficacy and safety of oral AZD9833 versus fulvestrant in women with advanced ER-positive HER2-negative breast cancer (SERENA-2)

Abstract Background AZD9833 is a next-generation oral selective estrogen receptor (ER) antagonist and degrader (SERD) that has shown anti-tumor efficacy in a range of pre-clinical xenograft models of breast cancer. The first-in-human study, assessing AZD9833 as a monotherapy and in combination with palbociclib (SERENA-1; NCT03616587), established a dose-dependent safety profile with clinical benefit and target engagement in pre- and post-menopausal women at all dose levels. Here, we describe the design of SERENA-2, a Phase 2 randomized, open-label trial of three different doses of AZD9833 versus fulvestrant. Methods SERENA-2 is a global comparative study of three different doses of AZD9833 versus fulvestrant in post-menopausal women with advanced ER+, HER2− breast cancer with disease recurrence or progression after ≥1 endocrine therapy. The study will evaluate the efficacy and safety of AZD9833 monotherapy once daily at three dose levels, versus fulvestrant monotherapy administered according to its label. Eligible patients will have received no prior fulvestrant or other oral SERD, and no more than one endocrine therapy and one chemotherapy in the advanced setting. Prior treatment with CDK4/6 inhibitors is permitted. Patients will be randomized 1:1:1:1 to one of four treatment groups: AZD9833 75 mg, 150 mg, 300 mg, or fulvestrant. The primary objective of the study is to determine the clinical efficacy of AZD9833 as assessed by progression-free survival, compared with fulvestrant. Secondary objectives include objective response rate, duration of response, percentage change in tumor size at 16 weeks, clinical benefit rate at 24 weeks, and overall survival. Pharmacokinetics, pharmacodynamic biomarker changes from baseline, and effects of AZD9833 and fulvestrant on patients’ health-related quality of life will also be assessed. Exploratory endpoints include predictive markers of response and/or acquired resistance to AZD9833 and fulvestrant, including circulating tumor DNA mutation profiling and dynamics, circulating tumor cell enumeration, and analysis of tumor samples. Patient enrollment commenced in Q2 2020, with a target enrollment of 288 patients across approximately 100 sites in up to 17 countries. Efficacy analyses will compare each dose of AZD9833 with fulvestrant. Sample size was calculated to provide 80% power for the primary endpoint. The primary analysis will use a Cox proportional hazards model stratified by prior use of CDK4/6 inhibitors and presence of lung and/or liver metastases to compare progression-free survival in each dose of AZD9833 versus fulvestrant. Another randomized, open-label, parallel-group, pre-surgical study investigating the biological effects of AZD9833 in ER+, HER2− primary breast cancer (SERENA-3) is also ongoing. For more information please contact Dr Mafalda Oliveira at: moliveira@vhio.net. Citation Format: Mafalda Oliveira, Maxine Bennett, Ali Khalil, Richard Mather, Rhiannon Maudsley, Sam McGuinness, Christopher J Morrow, Andy Sykes, Li Zhang, Teresa Klinowska, Justin PO Lindemann, Danielle Carroll. A randomized, open-label, parallel-group, multicenter phase 2 study comparing the efficacy and safety of oral AZD9833 versus fulvestrant in women with advanced ER-positive HER2-negative breast cancer (SERENA-2) [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 OT-09-02.

Abstract PS10-49: Phase 3b CompLEEment-1 study of ribociclib plus letrozole in the treatment of HR+/HER2- advanced breast cancer: Final results from the UK cohort

Abstract Background: Ribociclib is an oral selective CDK4/6 inhibitor approved for use in combination with an aromatase inhibitor (AI) or fulvestrant, in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) in several countries, including the UK. Ribociclib plus endocrine therapy (ET) significantly improved PFS outcomes in phase III registration studies (MONALEESA-2, -3, and-7) compared with placebo plus ET; and significantly increased OS in combination with AI in premenopausal women (MONALEESA-7), and in combination with fulvestrant in postmenopausal women (MONALEESA-3). This analysis aims to report the final efficacy and safety results for the UK cohort of CompLEEment-1, a phase 3b trial evaluating ribociclib plus letrozole in an expanded patient population.Methods: Patients with HR+, HER2- ABC, ≤1 line of prior chemotherapy (CT), and no prior ET in the advanced setting, received ribociclib + letrozole. Baseline characteristics and interim results of the UK cohort have been reported previously (Ring et al. SABCS 2019. Poster 443).Results: A total of 139 UK patients received ≥1 dose of study treatment at UK sites. At the cut-off date, November 8th 2019, 53 patients (38.1%) had completed treatment and 86 discontinued due to disease progression (30.9%), adverse events (24.5%), physician or subject/guardian decision (2.9% each), and protocol deviation (0.7%). The mean age of patients was 61.3 (SD10.67). 138 (99.3%) patients were female, 125 (89.9%) were post-menopausal and 50 (35.9%) had an ECOG status of ≥1. 85 (61.1%) patients had received prior chemotherapy in any setting.89 (64.0%) patients had measurable disease at baseline. 80 (60.4%) patients presented with visceral disease, 35 (25.2%) with bone-only metastases and 4 (2.9%) had CNS metastases. 59 (42.5%) of patients had ≥3 metastatic sites. The median duration of exposure to study treatment was 18.4 months with a median time to progression of 27.6 months. The overall response rate was 25.9% (95% CI: 18.8, 34.0) and clinical benefit rate was 74.1% (95% CI: 66.0, 81.2). Overall, the adverse event (AE) profile was consistent with previous phase III trials. Neutropenia (68.3%), nausea (59.7%), and fatigue (54%) and neutropenia (48.9%) were the most common adverse events (all grades). Neutropenia was the most common AE leading to dose reduction (12.2%) or interruption (33.8%), with ALT increase the most common cause for treatment discontinuation (10.1%). QT prolongation (all grades) led to 3 (2.2%) dose interruptions and 2 (1.4%) dose reductions, but no treatment discontinuations. Conclusions: This subgroup analysis of the COMPLEEMENT-1 study provides further clinically meaningful outcomes on first-line ribociclib and letrozole treatment in a UK cohort. This treatment combination showed consistent efficacy and side effect profile in UK HR+, HER2- ABC patients, consistent with the overall ITT population as well as results observed in the other pivotal ribociclib registration studies. NCT02941926. Citation Format: Mark Tuthill, Hardeep Marwaha, Christoph EA Hartmann. Phase 3b CompLEEment-1 study of ribociclib plus letrozole in the treatment of HR+/HER2- advanced breast cancer: Final results from the UK cohort [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 PS10-49.

Abstract P1-19-37: Pharmacokinetic assessment of ribociclib, an oral CDK4/6 inhibitor, and the interaction with endocrine therapy partners in patients with advanced breast cancer

Background: Ribociclib (RIB) is an oral CDK4/6 inhibitor used in combination with endocrine therapy (ET) to treat women with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative locally advanced breast cancer (ABC). ET partners are aromatase inhibitors (AI), eg letrozole or anastrozole, in pre-/perimenopausal women, and AI or fulvestrant in postmenopausal women. Here we characterize the pharmacokinetics (PK) of RIB as a single agent in patients with advanced cancer, assess the potential for drug-drug interactions (DDIs) between RIB and these ET partners in patients with HR+ ABC, and estimate the in vivo potency of RIB on CDK4. Methods: The PK of RIB as a single agent was characterized in patients with advanced cancer in study CLEE011X2101 (X2101; NCT01237236). The potential for DDIs was assessed by comparing the steady-state exposures (AUC, Cmax and Ctrough) of RIB when used alone in study X2101 with those of RIB when used in combination with ET in patients with HR+ ABC (studies CLEE011X2107 [X2107; NCT01872260], MONALEESA-2 [ML-2; NCT01958021], MONALEESA-7 [ML-7; NCT02278120], and MONALEESA-3 [ML-3; NCT02422615]). The effect of RIB on the PK of ET was also assessed in these studies. The CDK4 inhibition of RIB in patients was estimated based on its steady-state exposure and in vitro potency. Results: In study X2101, RIB showed rapid absorption (median Tmax 1-4 h), mean effective half-life (t1/2,acc) of 12.0-33.1 h, and slightly over-proportional increases in exposure (Cmax and AUC) over the dose range of 50-1200 mg QD. Steady state was generally achieved by Day 8, with a geo-mean accumulation ratio of 2.51 at the dose of 600 mg. The PK of RIB in combination with letrozole in studies X2107, ML-2 and ML-7 was consistent with that of RIB in study X2101 (Table 1). Additionally, in study ML-7, exposure parameters for letrozole were similar between the letrozole + RIB 600 mg and letrozole alone arms: Ctrough geo-mean (geo-CV%) 92.7 ng/mL (50.2%) vs 96.8 ng/mL (55.9%). In study ML-7, the steady-state exposure (Ctrough) of RIB in combination with anastrozole was consistent with that in study X2101 (Table 1). Furthermore, in the same study, anastrozole Ctrough geo-mean (geo-CV%) values were broadly similar in the anastrozole + RIB 600 mg and anastrozole alone arms considering variability: 38.5 ng/mL (59.5%) and 28.4 ng/mL (70.4%). Mean plasma Ctrough of RIB in combination with fulvestrant observed in study ML-3 was consistent with the results in study X2101 (Table 1). Although PK of fulvestrant was not evaluated, it is unlikely to have a DDI with RIB because induction or inhibition of CYP3A4 have been shown to have no impact on the PK of fulvestrant. Population PK analysis suggests that concomitant use of letrozole, anastrozole, or fulvestrant has no statistically significant or clinically relevant impact on RIB exposure. Based on steady-state RIB exposure in patients, and its in vitro potency measured by inhibition of Rb phosphorylation in CDK4-dependent breast cancer cell lines, RIB is predicted to attain approximately 90% inhibition of CDK4 inhibition at steady state. Conclusion: RIB demonstrated rapid absorption and a mean t1/2,acc of 32.0 h after oral administration of 600 mg QD in patients with cancer. Concomitant use of ET partners letrozole, anastrozole, and fulvestrant appears to have no clinically relevant PK interaction with RIB in patients with ABC. Citation Format: Yan Ji, Tanay Samant, Michelle Quinlan, Abhijit Chakraborty. Pharmacokinetic assessment of ribociclib, an oral CDK4/6 inhibitor, and the interaction with endocrine therapy partners in patients with advanced breast cancer [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 P1-19-37.

Cyclin-dependent kinase 4/6 inhibitors for the management of advanced or metastatic breast cancer in women.

The pharmacology, clinical activity, safety, and place in therapy of the cyclin-dependent kinase (CDK) inhibitors palbociclib, ribociclib, and abemaciclib are reviewed. CDK 4 and CDK 6 are downstream agents in the estrogen signaling pathway that control entry into the cell cycle. CDK4/6 inhibition may prevent tumor cell progression in the cell cycle. Three CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) are available for women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer. These medications' indications in the treatment of HR+/HER2- advanced breast cancer include use with an aromatase inhibitor (AI) as initial therapy in postmenopausal women and with fulvestrant in women whose disease progressed during endocrine therapy. Ribociclib is also indicated as initial therapy with an AI in premenopausal or perimenopausal women and as initial therapy with fulvestrant in postmenopausal women. Abemaciclib is also indicated as monotherapy in women with disease progression after endocrine therapy and prior chemotherapy. A significant increase in progression-free survival (PFS) was seen with use of all 3 agents as initial therapy with an AI in controlled trials. Each agent also was demonstrated to produce a significant increase in PFS when used with fulvestrant in women whose disease progressed with prior endocrine therapy. Neutropenia is a dose-limiting adverse effect of palbociclib and ribociclib. Fatigue is more common with use of palbociclib and abemaciclib, and gastrointestinal effects are more common with abemaciclib use. CDK4/6 inhibitors have significant demonstrated clinical activity in combination with AIs or fulvestrant in women with HR+/HER2- advanced or metastatic breast cancer and are becoming a standard of care in these patients.

Abstract PD2-05: Biomarker analysis by baseline circulating tumor DNA alterations in the MONALEESA-3 study

Abstract Background: In the Phase III MONALEESA-3 (NCT02422615) study, ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor) + fulvestrant (FUL) significantly prolonged progression-free survival (PFS) vs placebo (PBO) + FUL in postmenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC). Here we present MONALEESA-3 efficacy data by molecular alterations detected in circulating tumor DNA (ctDNA) at baseline. Methods: Postmenopausal women (N=726) with HR+, HER2– ABC (treatment naïve or received ≤1 line of prior endocrine therapy for ABC) were randomized 2:1 to RIB or PBO (600 mg/day; 3-weeks-on/1-week-off) + FUL (500 mg per label). Biomarker analysis of baseline ctDNA was an exploratory endpoint. Baseline plasma samples were collected from 692 patients (pts), and plasma ctDNA was analyzed using next-generation sequencing with a targeted panel of ˜550 genes. The subgroup analysis was performed in 600 pts (RIB + FUL n=400; PBO + FUL n=200) with evaluable ctDNA data. Results were not adjusted for multiple testing. Results: Alterations (frequency) were observed in the following genes: PIK3CA (35%), ESR1 (14%), TP53 (18%), CDH1 (12%), FGFR1 (5%), FGFR1/ZNF703/WHSC1L1 (11%), cell cycle-related (CCC) genes (16%), and genes involved in receptor tyrosine kinase (RTK) signaling (20%), and the mitogen-activated protein kinase (MAPK) pathway (10%). PFS hazard ratios favored RIB vs PBO regardless of baseline ctDNA gene alteration status (Table). Events, n/NMedian PFS, months Gene(s)RIB + FULPBO + FULRIB + FULPBO + FULHazard ratio; 95% confidence intervalPIK3CAWT108/26570/12422.3416.490.67; 0.49–0.91Altered75/13549/7616.3611.100.75; 0.52–1.08ESR1WT141/33899/17622.3414.880.66; 0.51–0.85Altered42/6220/249.236.110.71; 0.41–1.23TP53WT132/32598/17022.3414.880.62; 0.47–0.80Altered51/7521/309.177.390.75; 0.44–1.27CDH1WT156/35697/17320.6316.490.70; 0.54–0.90Altered27/4422/2712.095.130.46; 0.24–0.86FGFR1WT165/378113/19221.3214.550.65; 0.51–0.83Altered18/226/88.346.110.64; 0.23–1.75FGFR1/ZNF703/WHSC1L1WT155/356105/18121.3214.650.67; 0.52–0.85Altered28/4414/1910.976.670.73; 0.37–1.43CCCWT138/331103/17422.0814.650.61; 0.47–0.79Altered45/6916/2612.659.130.92; 0.51–1.65RTKWT126/31595/16622.3414.820.61; 0.47–0.80Altered57/8524/349.175.780.82; 0.50–1.35MAPKWT158/357105/18320.0414.820.69; 0.54–0.89Altered25/4314/1714.723.610.47; 0.22–1.00 Numerically shorter PFS was observed in pts with altered vs wildtype (WT) genes, irrespective of treatment. A slight trend towards limited RIB benefit vs PBO was observed in pts with altered CCC and RTK genes. RIB benefit was more pronounced vs PBO in pts with altered CDH1 and MAPK genes. PIK3CA and ESR1 analyses for pts receiving treatment in the first- or second-line setting will be presented at the meeting. Conclusions: Generally consistent PFS benefit for RIB + FUL vs PBO + FUL was observed irrespective of baseline ctDNA alterations; altered status trended to correlate with a shorter PFS. Results are hypothesis generating and should be interpreted with caution for some subgroups due to small sample sizes. Citation Format: Neven P, Petrakova K, Val Bianchi G, De la Cruz-Merino L, Jerusalem G, Sonke GS, Nusch A, Beck JT, Chia S, Solovieff N, Rodriguez Lorenc K, Miller M, Su F, Lm S-A. Biomarker analysis by baseline circulating tumor DNA alterations in the MONALEESA-3 study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD2-05.

Abstract PD1-09: Phase 2 safety and efficacy results of TAK-228 in combination with exemestane or fulvestrant in postmenopausal women with ER-positive/HER2-negative metastatic breast cancer previously treated with everolimus

Abstract Background: TAK-228 is an investigational, oral and highly selective ATP-competitive inhibitor of TORC1/2. Targeting the PI3K/AKT/mTOR pathway with the dual TORC1/2 inhibitor TAK-228 may restore sensitivity to endocrine therapies in patients (pts) with breast cancer who have progressed on the combination of an endocrine agent plus a TORC1 inhibitor. Here we report data from the phase 2 portion of a phase 1b/2 study of TAK-228 plus exemestane (E) or fulvestrant (F). Methods: Postmenopausal women with ER+ and HER2-, inoperable or metastatic breast cancer (MBC) following everolimus (EVE) plus E or F after progression, received oral TAK-228 (4 mg QD) plus E (25 mg QD) or F (500 mg monthly) for 28-day cycles until progressive disease (PD) or unacceptable toxicity (NCT02049957). Pts were enrolled into parallel cohorts based on prior response to EVE plus E or F and were given the same prior therapy (E or F) at their established dose: EVE-sensitive, defined as disease progression after complete response (CR), partial response (PR), or ≥6 mos stable disease (SD); or EVE-resistant, defined as disease progression without a CR or PR, or after &amp;lt;6 mos SD. Primary endpoint was clinical benefit rate at 16 wks (CR, PR, or SD at 16 wks; CBR-16). Secondary endpoints included CBR at 24 wks (CBR-24), overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety. Results: From Oct 2015 to Dec 2017, 94 pts were enrolled. Median age was 58 y (range 32–83). At baseline, most pts (67%) had stage IV disease and others were stage IA–IIIC (24%), other (3%) or unknown (5%); 94% of EVE-sensitive (93% E vs 100% F) and 88% of EVE-resistant pts (91% E vs 75% F) had received ≥4 prior lines of therapy. Pts received a median of 3 cycles (1–15) of TAK-228. At data cutoff (24 Apr 2018), 98% of pts had discontinued treatment, mainly due to PD (76%) or adverse events (AEs; 14%). CBR-16 was 41% (n=21) in EVE-sensitive and 26% (n=11) in EVE-resistant pts (table). CBR-24 was 24% in EVE-sensitive (19% E vs 50% F) and 23% in EVE-resistant (23% E vs 25% F) pts. Eleven of 21 pts who achieved CBR-16 also achieved CBR-24 (6 SD, 5 PR) in the EVE-sensitive cohort and 8 of 11 pts in the EVE-resistant cohort (6 SD, 2 PR). The ORR was 12% in EVE-sensitive pts and 9% in EVE-resistant pts (table). Median PFS (95% CI) was 4.1 mos (2.2–5.5) and 3.4 mos (1.9–5.4), and median OS (95% CI) was 15.9 mos (14.1–19.5) and 14.0 mos (13.0–16.0) in the EVE-sensitive and -resistant cohorts, respectively. Drug-related any grade and grade ≥3 AEs were seen in 90% and 29% of pts, respectively. Most common drug-related any grade AEs were nausea (50%), fatigue (38%), hyperglycemia and diarrhea (each 29%); 22% of pts reported a serious AE. No deaths were reported. Treatment is ongoing in two pts. Conclusion: TAK-228 plus E or F showed modest clinical benefit in pts with previously treated, EVE-sensitive or -resistant MBC, with an acceptable safety profile. EVE-sensitive (N=51)EVE-resistant (N=43) TAK-228+TAK-228+Best response, n (%)E (n=43)F (n=8)E (n=35)F (n=8)ORR=CR+PR4 (9)2 (25)3 (9)1 (13)CR001 (3)0PR4 (9)2 (25)2 (6)1 (13)CBR-1617 (40)4 (50)9 (26)2 (25) Citation Format: Diamond JR, Potter D, Salkeni M, Silverman P, Haddad T, Forget F, Awada A, Canon J-L, Danso M, Lortholary A, Bourgeois H, Tan-Chiu E, Patel C, Neuwirth R, Leonard EJ, Lim B. Phase 2 safety and efficacy results of TAK-228 in combination with exemestane or fulvestrant in postmenopausal women with ER-positive/HER2-negative metastatic breast cancer previously treated with everolimus [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-09.

Patterns of treatment and outcome with 500-mg fulvestrant in postmenopausal women with hormone receptor-positive/HER2-negative metastatic breast cancer: a real-life multicenter Italian experience

Background:Fulvestrant 500 mg (F500) is the most active endocrine single agent in hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC). Few data are available regarding the effectiveness of the drug in a real-world setting.Patients and methods:This prospective, multicenter cohort study aimed to describe the patterns of treatment and performance of F500 in a large population of unselected women with MBC, focusing on potential prognostic or predictive factors for disease outcome and response. The primary endpoints were progression-free survival (PFS) and clinical benefit rate.Results:From January 2011 to December 2015, 490 consecutive patients treated with F500 were enrolled. Overall, three different cohorts were identified and analyzed: the first received F500 after progression from previous chemotherapy (CT) or endocrine therapy; the second received the drug for de novo metastatic disease; and the third was treated as maintenance following disease stabilization or a response from a previous CT line. Median overall survival (OS) in the whole population was 26.8 months, ranging from 32.4 in first line to 22.0 and 13.7 months in second line and subsequent lines, respectively. Both the presence of liver metastasis and the treatment line were significantly associated with a worse PFS, while only the presence of liver metastasis maintained its predictive role for OS in multivariate analysis.Conclusions:The effectiveness of F500 was detected in patients treated both upon disease progression and as maintenance. The relevant endocrine sensitivity of 80% of patients included in the study could probably explain the good results observed in terms of outcome.

ASCO 2018 highlights: metastatic breast cancer.

SummaryThis article reviews the clinically most relevant presentations at the American Society of Clinical Oncology (ASCO) annual meeting 2018 on the topic of metastatic breast cancer. In the randomized placebo-controlled phase 3 trial MONALEESA-3, testing ribociclib vs. placebo in combination with fulvestrant in postmenopausal women or men with hormone receptor-positive (HR+) and HER2-negative (HER2−) advanced breast cancer (ABC), an increase of median progression-free survival (PFS) from 12.8 months to 20.5 months by the addition of the CDK4/6 inhibitor was reported (HR 0.59; P > 0.01). Taselisib, an alpha specific PI3K inhibitor, was tested in combination with fulvestrant in pretreated HR+/HER2− ABC patients with PIK3CA mutations in the placebo-controlled phase 3 trial SANDPIPER. PFS was significantly longer (7.4 months vs 5.4 months; HR 0.70, P < 0.01) but severe adverse events were more frequent (32% and 9%) in the taselisib group. In triple-negative breast cancer, the AKT inhibitor capivasertib (AZD5363) was combined with paclitaxel as first-line treatment in the placebo-controlled phase 2 trial PAKT. In patients with altered PIK3CA, AKT1 or PTEN, median PFS increased from 3.7 months to 9.3 months (HR 0.30; two-sided P = 0.01). No treatment effect was shown in the non-altered group. The most common adverse events attributed to capivasertib were diarrhea, fatigue and stomatitis. Results of two phase I trials of trastuzumab antibody-drug conjugates (ADCs) indicated HER2 as a non-oncogenic surface target in breast cancer patients expressing HER2.

The efficacy and safety of targeted therapy plus fulvestrant in postmenopausal women with hormone-receptor positive advanced breast cancer: A meta-analysis of randomized-control trials.

ObjectiveTo evaluate the efficacy and safety of targeted therapy plus fulvestrant for postmenopausal patients with hormone receptor-positive advanced breast cancer.MethodsPubmed, Embase and Web of Science databases were systematically searched on February 26, 2018. Eligible studies were screened according to selection criteria, and two reviewers independently extracted outcome data which included progression-free survival, overall survival, objective response rate, clinical benefit rate and toxicities. RevMan 5.3 and STATA 11.0 software were used to conduct meta-analysis.ResultsThirteen articles including twelve randomized-control trials fulfilled selection criteria. There was no evidence regarding the existence of publication bias and high-risk bias of quality in the selected studies. In previously endocrine therapy-treated postmenopausal patients with hormone-receptor positive advanced breast cancer, the PFS (HR = 0.77, 95%CI: 0.66–0.91) and ORR (RR = 1.78, 95%CI: 1.35–2.34) of combination therapy group were significantly higher than that from fulvestrant monotherapy group. Besides, a statistically significant difference in PFS was found across the two arms in postmenopausal women with PIK3CA-mutant ctDNA tumor (HR = 0.52, 95% CI: 0.39–0.69). Moreover, the risk of adverse events (RR = 1.09, 95%CI: 1.05–1.13), CTCAE≥3 (RR = 1.97, 95%CI: 1.49–2.60) and discontinuation due to adverse events (RR = 4.91, 95%CI: 3.37–7.15) were also significantly different between two treatment groups. Sensitivity analysis showed PLOMA-3 trial was an important factor of heterogeneity.DiscussionEven though the combination of targeted therapy plus fulvestrant improved PFS and increased ORR in advanced breast cancer patients, the toxicities of combination therapy were also higher than fulvestrant monotherapy. Further studies related to inhibitors targeting the specific signaling pathway or receptors are urgently needed, and more efforts concerning precision medicine of targeted therapy plus endocrine therapy should be taken to improve the clinical benefits.

Time to treatment failure of palbociclib and letrozole as second-line therapy or beyond in hormone receptor-positive advanced breast cancer.

The management of endocrine therapy resistance is one of the most challenging facets of advanced breast cancer treatment. Palbociclib is an inhibitor of cyclin-dependent kinases 4 and 6 approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer in combination with fulvestrant in postmenopausal women with disease progression following endocrine therapy. However, treatment responsiveness of tumors to palbociclib after multiple lines of endocrine therapy is not clearly established. The purpose of this study was to determine the efficacy of palbociclib and letrozole in patients pretreated with one or more lines of endocrine therapy. This was a single-center, retrospective cohort study of all postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer patients who received palbociclib and letrozole as a second-line endocrine therapy or beyond (and no prior cyclin-dependent kinases 4 and 6 inhibitor therapy) between February 1, 2015, and July 31, 2016. The primary objective was to evaluate time to treatment failure of palbociclib in combination with letrozole as a second-line of therapy or beyond. Fifty-three patients meeting eligibility criteria were included in the analysis. For the primary outcome, the median time to treatment failure of palbociclib and letrozole was 6.3 months (95% CI 3.1-7.4 months). Progression-free survival of palbociclib and letrozole therapy was 6.4 months (95% CI 4.9-8.3 months). Palbociclib and letrozole therapy is a viable, effective treatment option for metastatic breast cancer patients who were not exposed to cyclin-dependent kinases 4 and 6 inhibitors as a first-line endocrine therapy. The benefits of palbociclib and letrozole therapy were seen without excessive toxicity, and although neutropenia was common, it may be managed with dose reduction.