Standard Endocrine Therapy Research Articles

Efficacy and safety results by menopausal status in monarchE: adjuvant abemaciclib combined with endocrine therapy in patients with HR+, HER2-, node-positive, high-risk early breast cancer.

Abemaciclib is the first and only cyclin-dependent kinases 4 and 6 inhibitor approved for adjuvant treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), node-positive, and high-risk early breast cancer (EBC), with indications varying by geography. Premenopausal patients with HR+, HER2- tumors may have different tumor biology and treatment response compared to postmenopausal patients. We describe the efficacy and safety of abemaciclib plus endocrine therapy (ET) for the large subgroup of premenopausal patients with HR+, HER2- EBC in monarchE. Randomized patients (1:1) received adjuvant ET with or without abemaciclib for 2 years plus at least 3 additional years of ET as clinically indicated. Patients were stratified by menopausal status (premenopausal versus postmenopausal) at diagnosis. Standard ET (tamoxifen or aromatase inhibitor) with or without gonadotropin-releasing hormone agonist was determined by physician's choice. Invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) by menopausal status were assessed at data cutoff on 1 April 2021 (median follow-up of 27 months). Among randomized patients, 2451 (43.5%) were premenopausal and 3181 (56.4%) were postmenopausal. The choice of ET for premenopausal patients varied considerably between countries. Treatment benefit was consistent across menopausal status, with a numerically greater effect size in premenopausal patients. For premenopausal patients, abemaciclib with ET resulted in a 42.2% and 40.3% reduction in the risk of developing IDFS and DRFS events, respectively. Absolute improvement at 3 years was 5.7% for IDFS and 4.4% for DRFS rates. Safety profile for premenopausal patients was consistent with the overall safety population. Abemaciclib with ET demonstrated clinically meaningful treatment benefit for IDFS and DRFS versus ET alone regardless of menopausal status and first ET, with a numerically greater benefit in the premenopausal compared to the postmenopausal population. Safety data in premenopausal patients are consistent with the overall safety profile of abemaciclib.

Rationale and trial design of NATALEE: a Phase III trial of adjuvant ribociclib + endocrine therapy versus endocrine therapy alone in patients with HR+/HER2- early breast cancer.

Ribociclib has demonstrated a statistically significant overall survival benefit in pre- and postmenopausal patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) advanced breast cancer. New Adjuvant Trial with Ribociclib [LEE011] (NATALEE) is a trial evaluating the efficacy and safety of adjuvant ribociclib plus endocrine therapy (ET) versus ET alone in patients with HR+/HER2- early nonmetastatic breast cancer (EBC). NATALEE is a multicenter, randomized, open-label, Phase III trial in patients with HR+/HER2- EBC. Eligible patients include women, regardless of menopausal status, and men aged ⩾18 years. Select patients with stage IIA, stage IIB, or stage III disease (per the anatomic classification in the AJCC Cancer Staging Manual, 8th edition) with an initial diagnosis ⩽18 months prior to randomization are eligible. Patients receiving standard (neo)adjuvant ET are eligible if treatment was initiated ⩽12 months before randomization. Patients undergo 1:1 randomization to ribociclib 400 mg/day (3 weeks on/1 week off) +ET (letrozole 2.5 mg/day or anastrozole 1 mg/day [investigator's discretion] plus goserelin [men or premenopausal women]) or ET alone. Ribociclib treatment duration is 36 months; ET treatment duration is ⩾60 months. The primary end point is invasive disease-free survival. The 36-month treatment duration of ribociclib in NATALEE is extended compared with that in other adjuvant cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor trials and is intended to maximize efficacy due to longer duration of CDK4/6 inhibition. Compared with the 600-mg/day dose used in advanced breast cancer, the reduced ribociclib dose used in NATALEE may improve tolerability while maintaining efficacy. NATALEE includes the broadest population of patients with HR+/HER2- EBC of any Phase III trial currently evaluating adjuvant CDK4/6 inhibitor treatment. ClinicalTrials.gov identifier: NCT03701334 (https://clinicaltrials.gov/ct2/show/NCT03701334).

Adjuvant palbociclib for ER+ breast cancer (PALLAS Trial (ABCSG-42/AFT-05/PrE0109/BIG-14-13): A preplanned analysis of the stage IIA cohort

390216 Background: CDK4/6 inhibitors have become standard of care for advanced hormone receptor positive, HER2-negative (HR+/HER2-) breast cancer in combination with endocrine therapy (ET), with one approved for high-risk patients (pts) in the adjuvant setting. The PALLAS Trial investigated the addition of palbociclib to adjuvant ET in pts with stage II-III breast cancer. Stage IIA patients were specifically enrolled to evaluate the potential benefit of using palbociclib with adjuvant ET pts diagnosed at lower risk who may have more indolent disease. Methods: In the prospective, randomized, phase III PALLAS trial, pts with HR+/HER2- early breast cancer were randomly assigned to receive adjuvant ET for at least 5 years with or without 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle). ET was of provider’s choice. Stage IIA enrollment was capped at 1,000 patients. While the primary end point of the overall study was invasive disease-free survival (iDFS) for the entire cohort, there was a preplanned analysis of recurrence and survival endpoints in the stage IIA cohort. Outcomes were compared between arms using stratified log-rank tests and Cox models (stratification factors: chemotherapy and age ≤ 50). Results: Among 5,796 pts enrolled at 406 centers in 21 countries worldwide between 9/1/2015 and 11/30/2018, a total of 1,010 stage IIA pts were enrolled. The protocol-defined number of events occurred at a median follow-up of 50 months for this subgroup (43.1 months for the overall study). Median age within this subgroup was 54 (range 29-85 yrs), and 410 (40.6%) were pre/perimenopausal, 506 (50.1%) T2/N0 (vs T0-1/N1), 272 (26.9%) grade 3 (vs. grade1/2), and 561 (55.5%) received chemotherapy. iDFS events occurred in 31 of 503 (6.2%) pts who received palbociclib plus ET and in 45 of 507 (8.9%) pts who received ET alone, resulting in a statistically nonsignificant difference in iDFS at 4 years (92.9% vs. 92.1%; hazard ratio, 0.75; CI, 0.48 to 1.19; P = .23). Nonsignificant differences were also observed for invasive breast cancer-free, distant recurrence-free, and locoregional cancer-free survival. No significant differences in iDFS were observed in subgroups including age group, receipt of chemotherapy, tumor grade, and clinical risk (T1/N1 vs. T2/N0).Conclusions: In this preplanned analysis of the stage IIA cohort of the PALLAS trial, the addition of adjuvant palbociclib to standard ET did not improve outcomes over ET alone, suggesting no benefit from the agent in reducing the incidence of early relapse in pts with lower-stage HR+/HER2- breast cancer. Future analyses will incorporate genomic risk and other molecular patterns from the extensive transPALLAS correlative program. Additional follow-up (10-year minimum) is also underway to assess the impact of palbociclib exposure on late recurrence in HR+ disease. Clinical trial information: NCT02513394.

SC98 - A prospective observational study of patients with metastatic castration-resistant prostate cancer progressing after standard hormonal therapy suitable for abiraterone acetate plus prednisone treatment

SC98 - A prospective observational study of patients with metastatic castration-resistant prostate cancer progressing after standard hormonal therapy suitable for abiraterone acetate plus prednisone treatment

Super-enhancer-controlled positive feedback loop BRD4/ERα-RET-ERα promotes ERα-positive breast cancer.

Estrogen and estrogen receptor alpha (ERα)-induced gene transcription is tightly associated with ERα-positive breast carcinogenesis. ERα-occupied enhancers, particularly super-enhancers, have been suggested to play a vital role in regulating such transcriptional events. However, the landscape of ERα-occupied super-enhancers (ERSEs) as well as key ERα-induced target genes associated with ERSEs remain to be fully characterized. Here, we defined the landscape of ERSEs in ERα-positive breast cancer cell lines, and demonstrated that bromodomain protein BRD4 is a master regulator of the transcriptional activation of ERSEs and cognate ERα target genes. RET, a member of the tyrosine protein kinase family of proteins, was identified to be a key ERα target gene of BRD4-regulated ERSEs, which, in turn, is vital for ERα-induced gene transcriptional activation and malignant phenotypes through activating the RAS/RAF/MEK2/ERK/p90RSK/ERα phosphorylation cascade. Combination therapy with BRD4 and RET inhibitors exhibited additive effects on suppressing ERα-positive breast cancer both in vitro and in vivo, comparable with that of standard endocrine therapy tamoxifen. Furthermore, combination therapy re-sensitized a tamoxifen-resistant ERα-positive breast cancer cell line to tamoxifen treatment. Taken together, our data uncovered the critical role of a super-enhancer-associated positive feedback loop constituting BRD4/ERα–RET–ERα in ERα-positive breast cancer, and suggested that targeting components in this loop would provide a new therapeutic avenue for treating ERα-positive breast cancer in the clinic.

Efficacy and Safety of Darolutamide in Patients with Nonmetastatic Castration-resistant Prostate Cancer Stratified by Prostate-specific Antigen Doubling Time: Planned Subgroup Analysis of the Phase 3 ARAMIS Trial

BackgroundPatients with nonmetastatic castration-resistant prostate cancer (nmCRPC) have a high risk of progression to metastatic disease, particularly if their prostate-specific antigen doubling time (PSADT) is ≤6 mo. However, patients remain at a high risk with a PSADT of >6 mo. ObjectiveTo evaluate the efficacy and safety of darolutamide versus placebo in patients stratified by PSADT >6 or ≤6 mo. Design, setting, and participantsA planned subgroup analysis of a global multicenter, double-blind, randomized, phase 3 trial in men with nmCRPC and PSADT ≤10 mo was conducted. InterventionPatients were randomized 2:1 to oral darolutamide 600 mg twice daily or placebo, while continuing androgen-deprivation therapy. Outcome measurements and statistical analysisThe primary endpoint was metastasis-free survival (MFS). Secondary endpoints were overall survival (OS) and times to pain progression, first cytotoxic chemotherapy, and symptomatic skeletal events. Quality of life (QoL) was measured using validated prostate-relevant tools. Safety was recorded throughout the study. Results and limitationsOf 1509 patients enrolled, 469 had PSADT >6 mo (darolutamide n = 286; placebo n = 183) and 1040 had PSADT ≤6 mo (darolutamide n = 669; placebo n = 371). Baseline characteristics were balanced between subgroups. Darolutamide significantly prolonged MFS versus placebo in both subgroups (unstratified hazard ratio [95% confidence interval]: PSADT >6 mo, 0.38 [0.26–0.55]; PSADT ≤6 mo, 0.41 [0.33–0.52]). OS and other efficacy and QoL endpoints favored darolutamide with significant improvement over placebo in both subgroups. The incidence of adverse events, including events commonly associated with androgen receptor inhibitors (fractures, falls, hypertension, and mental impairment), and discontinuations due to adverse events were low and similar to placebo. Limitations include small subgroup populations. ConclusionsIn patients with nmCRPC and PSADT >6 mo (maximum 10 mo), darolutamide provided a favorable benefit/risk ratio, characterized by significant improvements in MFS, OS, and other clinically relevant endpoints; maintenance of QoL; and favorable tolerability. Patient summaryIn patients with prostate cancer that has stopped responding to standard hormonal therapy (indicated by an increase in prostate-specific antigen [PSA] levels), there is a risk that the cancer will spread to other parts of the body. This risk is highest when the time it takes for the PSA level to double (ie, “PSA doubling time” [PSADT]) is less than 6 mo. However, there is still a risk that the cancer will spread even if the PSADT is longer than 6 mo. In a group of patients whose PSADT was more than 6 mo but no more than 10 mo, treatment with darolutamide slowed the cancer spread and allowed them to live longer than patients who received placebo (inactive drug). Darolutamide treatment did not cause many side effects and helped maintain patients’ quality of life without disruptions.

LBA14 Impact of age, recurrence score (RS) and ovarian function suppression (OFS) on endocrine response to short preoperative endocrine therapy (ET): Analysis of ADAPT and ADAPTcycle trials

Benefit of chemotherapy (CT) addition to ET remains controversial in premenopausal (pre) patients (pts) with 0-3 positive LNs (N0-1) and RS ≤25. In ADAPT, excellent outcome was observed in young N0-1 pts and ET response after short-term preoperative ET and RS 12-25 with ET alone. Here, we investigate impact of age, RS, and OFS on ET response, in ADAPT and its validation in the first part of ongoing phase III ADAPTcycle trial. In ADAPT, pts with clinical high-risk HR+/HER2- EBC received 3w of induction standard ET prior to surgery or core biopsy, and then ET-alone if N0-1 and RS 0-11 or 12-25 ± post-endocrine Ki67post≤10%, or CT if Ki67post>10%. In ADAPTcycle (n=5000 to screen), N0-1 pts with RS>25 and Ki67post≤10% and N2-3 pts with RS≤25 and ET-response are randomized to (neo)adjuvant CT or AI+ribociclib. 5938 pts included (ADAPT, n=3666; Acycle, n=2272): 1975 pts ≤50y/pre, 424 pts ≤40y. ET in ≤50y/pre pts included tamoxifen (98% ADAPT, 70.4% Acycle), TAM+OFS (15.2% Acycle) and AI+OFS (14.4% Acycle); >80% of >50y or post pts had AI. Baseline ER did not differ significantly between age groups ≤40, >40-50- and >50 ys. Mean baseline RS scores were higher in pts ≤40ys, but comparable between pts aged >40-50 and >50. ET-response rates varied substantially by type of ET, age, and RS in particular if no OFS in premenopausal pts. In ADAPT, ET-response was associated with improved iDFS in all age cohorts, independent of baseline Ki67.Table: LBA14Age subgroupRS 0-25 (ADAPT/A-Cycle) Endocrine Response Ki67post<= 10% (%)RS>25 (ADAPT/A-cycle) Endocrine Response Ki67post<= 10% (%)TamTAM+ OFS*AI+ OFS*AITAMTAM+ OFS*AI+ OFS*AI≤50 years and premenopausal45.1/ 37.6%65.0%76.5%14.3/ 19.5%48.0%77.8%≤40 years37.7/ 41.7%72.2%84.6%3.9/ 14.3%44.4%69.2%41-50 years46.8/ 36.8%61.9%74.617.8/ 21.8%52.2%82.6%>50 years old or postmenopausal61.7/ 49.7%****88.6/ 85.8%21.5/ 15.2%****44.6/ 64.7%* OFS data in ADAPTCycle only, in ADAPT, only 2% AI+OFS in pts ≤50 ys ** only few pts treated by OFS in >50 ys, pre group Open table in a new tab * OFS data in ADAPTCycle only, in ADAPT, only 2% AI+OFS in pts ≤50 ys ** only few pts treated by OFS in >50 ys, pre group ET-response after TAM or AI according to RS groups was similar in both trials, but adding OFS to TAM or AI substantially improves ET-response in pre pts ≤ 50y, rendering similar results as in AI-treated post pts. ET-response assessment provides clinically relevant information for CT-decision making in pre ≤50y N0-1 pts in addition to gene expression testing.

The regrouping of Luminal B (HER2 negative), a better discriminator of outcome and recurrence score.

Breast cancer (BC) remains the leading cause of cancer-related deaths worldwide. High recurrence risk Luminal BC receives adjuvant chemotherapy in addition to standard hormone therapy. Considering the heterogeneity of Luminal B BC, a more accurate classification model is urgently needed. In this study, we retrospectively reviewed the data of 1603 patients who were diagnosed with HER2-negative breast invasive ductal carcinoma. According to the expression level of PR and Ki-67 index, the Luminal B (HER2-negative) BCs were divided into three groups: ER+PR-Ki67low (ER-positive, PR-negative, and Ki-67 index <20%), ER+PR+Ki67high (ER-positive, PR-positive, and Ki-67 index ≥20%), and ER+PR-Ki67high (ER-positive, PR-negative, and Ki-67 index ≥20%). The cox proportional hazards regression model was used to evaluate the correlation between each variable and outcomes. Besides, discriminatory accuracy of the models was compared using the area under the receiver operating characteristic curve and log-rank χ2 value. The analysis results showed that there was a significant correlation between subtypes using this newly defined classification and overall survival (p < 0.001) and disease-free survival (DFS) (p < 0.001). Interestingly, patients in the ER+PR-Ki67high subgroup have the worst survival outcome in Luminal B (HER2-negative) subtype, similar to Triple-negative patients. Besides, the ER+PR+Ki67high has worse 5-year DFS compared with Luminal A group. There was a significant relationship between the regrouping subtype and the recurrence score index (RI) (p < 0.001). Moreover, the results showed that patients in ER+PR-Ki67high subtype were more likely to have high RI for distance recurrence (RI-DR) and local recurrence (RI-LRR). Our newly defined classification has a better discrimination ability to predict survival outcome and recurrence score of Luminal B (HER2-negative) BC patients, which may help in clinical decision-making for individual treatment.

Prostate Cancer Drug Therapy: What Have Clinicians Missed During the COVID-19 Pandemic.

Due to the COVID-19 pandemic, major congresses and many teaching opportunities as well as the usual visits from medical advisors of pharmaceutical firms have been postponed and canceled. The major trials of prostate cancer in the last 5 years in each state are shortly discussed providing a panoramic overview of the available evidence and data on prostate cancer treatment. Apalutamide, enzalutamide, and darolutamide have proven to have clinical benefits when added to androgen deprivation therapy for patients with nonmetastatic castration-resistant prostate cancer. In patients in the metastatic hormone-sensitive setting, next to docetaxel, abiraterone, enzalutamide, and apalutamide have been shown to significantly improve overall survival and progression-free survival in comparison to standard hormone therapy. In addition, docetaxel abiraterone and enzalutamide are widely used in the metastatic setting. For second-line therapy of metastasized prostate cancer patients who have received either docetaxel or abiraterone or enzalutamide, olaparib, cabazitaxel, radium, and lutetium therapy have been shown to be beneficial in selected patient groups.

Alpelisib therapy: from theory to practice

Before the development and implementation of the first PI3K inhibitor (alpelisib), the presence of a mutation in the PIK3CA gene had only prognostic value: it determined the unfavorable course of luminal HER2-negative metastatic breast cancer (testing for mutations was not part of routine screening methods). Achievements in the treatment of HR+HER2- mBC are primarily associated with the use of CDK4/6 inhibitors, which allowed not only a significant increase in the median progression-free survival while maintaining high quality of life, but also significantly increased overall survival of patients with luminal HER2-negative metastatic breast cancer. However, subgroup analyses demonstrate that the presence of the PIK3CA mutation is an independent factor in decreasing progression-free time and overall survival, even in patients treated with CDK4/6 inhibitors. Mutations of the PIK3CA gene are diagnosed in 30-40% of luminal metastatic breast cancer patients, they are associated with an increased risk of relapse and disease progression, are associated with a significant reduction in survival rates and treatment effectiveness, and determine the development of primary and secondary resistance to endocrine therapy. Standard endocrine therapy with fulvestrant combined with alpelisib has significantly improved treatment outcomes in patients with HR+HER2-metastatic breast cancer with the PIK3CA mutation who previously received treatment for advanced disease or had progression during adjuvant therapy. This combination is now included in all major international guidelines and is a priority therapy option. Testing for PIK3CA mutations is the current diagnostic standard in luminal HER2-negative mBC. The review presents an update of the main clinical trials with alpelisib, treatment results from real clinical practice, and also considers aspects of use in pretreated patients with different medical history. The article outlines the main recommendations for the prevention and correction of adverse events, and presents our own experience of using alpelisib in a patient with a classic course of breast cancer with a PIK3CA mutation.

Abstract 1639: Human immune system mouse model of ER+ metastatic breast cancer

Abstract In a recent clinical trial in heavily pretreated estrogen receptor alpha-positive (ER+) metastatic breast cancer (MBC), ~23% of patients reached the primary endpoint of clinical benefit of &amp;gt;24 weeks on Fulvestrant plus the anti-androgen Enzalutamide. ESR1 mutant biopsies had more T regulatory cells (t test p&amp;lt;0.021) and macrophages (p&amp;lt;0.003) than ESR1 wild type (WT), which had more TP53 mutations and higher levels of cytotoxic T effector cells (p&amp;lt;0.01). In addition, PD-L1 increased in post- vs. pre-treatment biopsies (paired t test p&amp;lt;0.002). This increase in PD-L1 post-treatment warrants testing if the addition of a checkpoint inhibitor to the Fulvestrant-Enzalutamide combination will enhance therapy efficacy in ER+ MBC resistant to standard endocrine therapy. However, the lack of immune competent ER+ breast cancer pre-clinical models is a major barrier to these studies. Human immune system (HIS) mouse models were developed as a platform in which to test immune checkpoint inhibitors in other human cancers, and one HIS model was recently shown to support the growth and immune infiltration of ER+ patient-derived xenograft (PDX) primary tumors. We tested whether HIS mice are a robust model in which to define ER+ tumor-immune microenvironment interactions at metastatic sites. We implanted NCG mice (NOD-Prkdcem26Cd52Il2rgem26Cd22/NjuCrl) humanized by engraftment of human umbilical cord blood-derived CD34+ (huCD34+) stem cells with the estrogen-independent HCI-013EI (013EI) PDX, derived from an ER+, invasive lobular MBC which harbors the Y537S ESR1 mutation. Mice were monitored for tumor latency and growth rate, and primary tumors and organs were collected for immunohistochemistry, single-cell RNA sequencing (scRNAseq), and phasor-fluorescence lifetime imaging microscopy (FLIM). The ER mutated PDX 013EI had a longer tumor latency in HIS (median 77 days) vs. age-matched immune deficient control mice (27.5 days, log-rank p=0.043). Once formed, 013EI tumors in HIS mice grew slower than those in controls (mixed-effects analysis, p=0.035). HIS mice had visible lung, liver, and/or gastrointestinal tract metastases despite small primary tumors. Lung metastases from HIS mice retain ER expression and are infiltrated by human CD4+, CD8+, and CD68+ immune cells. Initial scRNAseq analysis also suggests infiltration by diverse immune cell populations in primary tumors from HIS mice. Initial phasor-FLIM for NADH autofluorescence suggests that 013EI tumors are highly glycolytic in HIS mice. In conclusion, our results show that huCD34+ HIS mice effectively support growth, metastasis, and immune infiltration of an ESR1 mutant MBC PDX. Ongoing studies will further define the tumor-immune microenvironment in this and ESR1 WT MBC PDX, focusing on immune cell infiltration, PD-L1 expression, steroid receptor status, metabolic signaling and changes in these parameters following novel combinations of endocrine, immunotherapy and metabolic agents. Citation Format: Ayodeji Olukoya, Shaymaa Bahnassy, Nicole S. Spoelstra, Lu Jin, Suman Ranjit, Anthony Elias, Jennifer K. Richer, Rebecca B. Riggins. Human immune system mouse model of ER+ metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1639.

Phase 3 ENABLAR-2 study to evaluate enobosarm and abemaciclib combination compared to estrogen-blocking agent for the second-line treatment of AR+, ER+, HER2- metastatic breast cancer in patients who previously received palbociclib and estrogen-blocking agent combination therapy.

TPS1121 Background: Targeting the androgen receptor (AR) may be the next important endocrine therapy for advanced breast cancer. The AR has been demonstrated to be a tumor suppressor when activated. Enobosarm is an oral selective AR targeting agonist that activates the AR in breast cancer. Preclinical studies in CDK4/6 inhibitor resistant PDX models demonstrated combinatorial synergistic activity of enobosarm plus CDK 4/6 inhibitors. An open-label, Phase 2 study, was conducted in 136 women with heavily pretreated ER+ HER2- metastatic breast cancer that were randomized to oral daily enobosarm at a dose of 9 or 18 mg. The efficacy evaluable (EE) group were patients that were AR positive (&gt; 10% AR nuclear staining). In the EE population with measurable disease at baseline, 10 patients had received prior endocrine therapy + a CDK 4/6 inhibitor. Subsequent treatment with enobosarm resulted in a clinical benefit rate of 50% and the best overall response rate (ORR) was 30% (2CRs and 1 PR). Of the 10 patients, 7 had AR nuclear staining ≥40%. None of the patients with AR nuclear staining &lt; 40% responded to enobosarm. Although a small subset of the study, it appears that enobosarm has activity in patients who had ≥40% AR staining and who had progressed on standard endocrine therapy with a CDK 4/6 inhibitor. Overall, treatment with enobosarm was well tolerated with significant positive effects on quality-of-life measurements. Methods: The ENABLAR-2 trial is an ongoing Phase 3, randomized, open-label, efficacy and safety study in patients with AR+ ER+ HER2- MBC with AR nuclear staining of ≥40%, who have progressed after one line of systemic therapy comprising estrogen blocking agent and palbociclib. The planned sample size is 186 patients randomized 1:1 to enobosarm + abemaciclib OR fulvestrant if the first line of therapy for MBC was a non-steroidal AI plus palbociclib, until disease progression, toxicity, or loss of clinical benefit. If first line therapy for metastatic breast cancer was fulvestrant plus palbociclib, then the patient will be randomized 1:1 to either enobosarm + abemaciclib OR an AI. Randomization will be stratified by AR% nuclear staining, ≥60% versus &lt; 60%, as well as by estrogen blocking agent such that each cohort will have the same number of subjects previously receiving fulvestrant + palbociclib in first line therapy. The key objectives are to determine the safety and efficacy of enobosarm and abemaciclib combination versus an alternative estrogen blocking agent with the primary endpoint of PFS. Secondary endpoints include ORR, duration of response, overall survival, change from baseline in Short Physical Performance Battery (SPPB), change in EORTC Quality of Life Questionnaire (EORTC-QLQ) and change in body composition as measured by DEXA. Clinical trial information: NCT05065411.

Final results from a phase III randomized clinical trial of adjuvant endocrine therapy ± chemotherapy in women ≥ 70 years old with ER+ HER2- breast cancer and a high genomic grade index: The Unicancer ASTER 70s trial.

500 Background: Benefit of adjuvant chemotherapy (CT) in addition to endocrine therapy (ET) remains controversial for patients (pts) aged ≥ 70 years with oestrogen receptors-positive (ER+) HER2-negative (HER2-) breast cancer (BC). In a large prospective trial, we first assessed the tumour genomic grade index (GGI) in all pts, and second, randomized pts with a high GGI between CT + ET vs. ET alone. Methods: Eligible pts were women ≥ 70 years with ER+ HER2- primary BC or isolated local relapse, irrespective of other characteristics, for whom adjuvant systemic treatment was considered. G8 score, Charlson comorbidity index (CCI) and 4-year mortality Lee score were collected at baseline. GGI was centrally performed by RT-PCR on FFPE samples. Pts with low GGI were not recommended to receive CT and were followed in an observational cohort. Pts with high (+ equivocal) GGI were randomized 1:1 to CT + ET vs. ET alone, using G8, pN and centre for stratification. Investigators chose between 3 CT regimens: 4 cycles of doxorubicin/cyclophosphamide, non-pegylated liposomal doxorubicin/cyclophosphamide or docetaxel/cyclophosphamide, given q3w with G-CSF. Standard ET consisted of 5 years of aromatase inhibitor, tamoxifen or a sequence based on tolerance. Based on CALGB 49907 results, the primary objective was to demonstrate an overall survival (OS) benefit for CT (4-year assumptions 87.5 vs 80%, HR=0.60) in the intent to treat (ITT) population. With 171 events, the trial had 90% power to demonstrate a difference with a bilateral test α=0.05. Secondary objectives included BC specific survival (BCSS), invasive disease-free survival (iDFS), event-free survival (EFS), competing events, cost-effectiveness and Q-TWiST analysis, geriatric dimensions, willingness and quality of life. Results: Between 04/2012 and 05/2016, 1,969 pts from 61 French and 12 Belgian centres were enrolled. Of them, 1,089 (55%) were randomized between CT + ET and ET alone. Median follow-up was 5.8 years at the data cut-off (17/12/2021) with 180 OS events observed. Median age was 75 (70-92), G8 score, CCI and Lee score being &gt;14, ≤ 2, and ≤ 8 in 60%, 62% and 84% of pts, respectively. Tumours were ≥ pT2, pN+, isolated local relapses, with histological grade III, in 56%, 46%, 11% and 39% of cases, respectively. No significant OS difference was observed between arms (HR 0.85 [0.64-1.13], p=0.2538); 4-year OS was 90.5% in the CT + ET arm and 89.7% in the ET alone arm. The forest plot could not identify any subgroup deriving significant benefit from CT. ITT and per protocol analysis of secondary objectives (BCSS, iDFS, EFS) showed similar results. Conclusions: In this large phase III trial, we did not find a statistically significant OS benefit with the addition of CT to ET after surgery for ER+ HER2- BC with a high GGI. Analysis of the other outcome measures will be presented. Clinical trial information: NCT0156405.

Adjuvant dynamic marker-adjusted personalized therapy comparing endocrine therapy plus ribociclib versus chemotherapy in intermediate-risk HR+/HER2- early breast cancer: ADAPTcycle.

TPS609 Background: The WSG ADAPT trial program focusses on individualization of (neo)-adjuvant decision-making in EBC in a subtype-specific manner. Clinical feasibility of the WSG ADAPT trial goals - early response assessment and subtype-specific therapy tailoring to those patients (pts) who are most likely to benefit - has recently been confirmed by the 5-years survival data of the ADAPT HR+/HER2- clinical trial. Methods: WSG-ADAPTcycle is a prospective, multi-center, interventional, two-arm, (neo)adjuvant, non-blinded, randomized, controlled phase III trial (NCT04055493) investigating whether treatment with the CDK4/6 inhibitor ribociclib (600mg/day) together with ET is superior to standard-chemotherapy (CT) in intermediate-risk HR+/HER2- EBC. Definition of intermediate-risk is either based on Oncotype DX and endocrine responder status (measured by Ki67-response after 2-4 weeks of induction endocrine therapy (ET)) or on low-intermediate baseline Ki67 and high estrogen receptor (ER)/progesterone receptor (PR)-expression (Dowsett et al. NPJ Breast Cancer 2020). Co-primary endpoints are DFS and dDFS. It is planned to screen 5600 pts and to randomize 1670 pts (1002 to ribociclib + ET; 668 to standard CT followed by ET). Study start was in July 2019 (88 sites, enrollment period 42 months) and until date of submission, 3079 pts have been screened and 811 randomized (490 ribociclib / 321 CT). Pre-/postmenopausal pts with histologically confirmed invasive HR+/HER2- EBC with high clinical risk (cT2-4 or Ki-67 20% or G3 or cN+) are eligible if they fulfil the ADAPT intermediate-risk criteria: Recurrence Score (RS) ≤25 plus several risk factors and poor ET responder, RS &gt;25 and ET-responder in p/cN0-1 pts, or RS ≤25 with c/pN2-3 in ET-responder. Direct randomization of premenopausal patients (irrespective of ET-response) with c/pN0 and RS 16-25 or c/pN1 with RS 0-25 is allowed according to investigator´s decision; however, based on the ADAPT results, ET+ovarian function suppression alone is strongly recommended in ET-responders. Treatment duration is 2 years for the ribociclib + aromatase inhibitor (AI) (premenopausal: AI + GnRH)-arm and 16-24 weeks for the CT-arm; neoadjuvant or adjuvant treatment is allowed. The minimum 5-year follow-up phase includes standard adjuvant ET. ePROs are collected using CANKADO; ECG monitoring is performed using a novel eHealth method. Translational analyses: Tumor tissue will be collected prior to ET, after at least 3 weeks of ET, if residual tumor is diagnosed (neoadjuvant treatment), and at recurrence, to identify potential resistance markers. Exploratory tissue biomarker research will be conducted to assess alterations in molecular markers. In addition, ctDNA/ctRNA from optional blood samples will be assessed for mutations and gene expression relevant for HR+/HER2- EBC. Clinical trial information: NCT04055493.

Influence of local treatment on the biology of advanced prostate cancer : Treatment of the primary tumor may delay hormone resistance of metastases

HintergrundIn den letzten 15 Jahren zeigt sich ein Trend hin zu einem längeren Überleben beim metastasierten Prostatakarzinom. Neben dem durch neue Medikamente bedingten Fortschritt deuten retrospektive Daten auch auf einen möglichen positiven Effekt einer früheren Primärtumorbehandlung hin.FragestellungKann eine Primärtumorbehandlung im Falle einer späteren Metastasierung die Prognose der betroffenen Patienten verbessern und wenn ja, über welche Mechanismen?Material und MethodeWir werteten die klinischen Langzeitergebnisse von 115 Patienten aus, die bei T4-Prostatakarzinomen nach induktiver Hormontherapie an unserer Klinik prostatektomiert worden waren. Weiterhin erfolgte eine kritische Durchsicht und Diskussion der zur oben genannten Fragestellung vorhandenen Literatur.ErgebnisseVon den 115 Patienten hatten 84 im weiteren Verlauf ein biochemisches Rezidiv erlitten, waren also definitiv durch die radikale Prostatektomie nicht geheilt. Das tumorspezifische und das Gesamtüberleben dieser 84 Patienten lag nach 150 Monaten bei 61 % bzw. 44 %. Bemerkenswert war die Beobachtung, dass diese Patienten ein überraschend gutes und langes Ansprechen auf eine Hormontherapie zeigten. Von den 84 Patienten waren nach durchschnittlich 95 Monaten Nachbeobachtungszeit noch 47 am Leben. 31 von ihnen, also ungefähr zwei Drittel, standen immer noch unter einer Standardhormontherapie. Nur 13 hatten eine Resistenz gegen die primäre Hormontherapie entwickelt und entsprechend eine tertiäre Hormontherapie erhalten, auf die sie teilweise aber auch wieder langfristig sensibel blieben.SchlussfolgerungenDie Primärtumorentfernung, zumindest unter den beschriebenen Begleitumständen, scheint die Entwicklung einer Hormonresistenz beim metastasierten Prostatakarzinom hinauszögern und in Einzelfällen sogar ganz verhindern zu können.

Abstract OT2-11-09: Lidera breast cancer: A phase III adjuvant study of giredestrant (GDC-9545) vs physician’s choice of endocrine therapy (ET) in patients (pts) with estrogen receptor-positive, HER2-negative early breast cancer (ER+/HER2- EBC)

Abstract BACKGROUND ETs that target ER activity and/or estrogen synthesis are the mainstay of ER+ BC treatment. Despite best management, up to 20% of pts with ER+/HER2- eBC develop resistance (in some cases due to the acquisition of tumor mutations in ESR1 that can drive estrogen-independent transcription and proliferation) and still have high recurrence rates on standard ETs. New treatment alternatives for ER+/HER2- eBC are needed to reduce risk of recurrence and improve survival, tolerability, quality of life, and adherence. Giredestrant is a highly potent, nonsteroidal oral selective ER antagonist and degrader (SERD). It achieves robust ER occupancy and is active against tumors that retain ER-sensitivity or have ESR1 mutation(s). Giredestrant has been demonstrated to be more potent in vitro and achieves higher ER occupancy in vivo than fulvestrant, the only currently approved SERD. Early phase clinical studies have demonstrated that single-agent giredestrant (30 mg daily) has promising clinical and pharmacodynamic activity, and is well-tolerated in the ER+/HER2- eBC and metastatic BC settings. TRIAL DESIGN This is a phase III, global, randomized, open-label, multicenter study evaluating the efficacy and safety of adjuvant giredestrant vs physician’s choice of adjuvant ET in pts with medium- and high-risk stage I-III histologically confirmed ER+/HER2- eBC. Pts are randomized 1:1 to oral 30 mg daily giredestrant or physician’s choice of standard ET (tamoxifen, anastrozole, letrozole, or exemestane, given according to prescribing information). Stratification factors are risk (medium vs high, based on anatomic [tumor size, nodal status] and biologic features [grade, Ki67, gene signatures if available]); geographic region (US/Canada/Western Europe vs Asia-Pacific vs rest of the world); prior chemotherapy (no vs yes); and menopausal status (pre-/perimenopausal vs postmenopausal). Beginning on Day 1 of Cycle 1, pts will be treated with giredestrant or physician’s choice of standard ET for at least 5 years. Continuing physician’s choice of standard ET after 5 years is at discretion of the investigator and per local standard of care. ELIGIBILITY Female/male pts with medium-/high-risk stage I-III ER+/HER2- eBC; prior curative surgery; completion of (neo)adjuvant chemotherapy (if administered) and/or surgery &amp;lt;12 months prior to enrolment; no prior ET (up to 4 weeks of [neo]adjuvant ET is allowed). For men and pre-/perimenopausal women, a luteinizing hormone-releasing hormone agonist will be given per local prescribing information (mandatory for pts in the giredestrant arm). AIMS Primary endpoint: Invasive disease-free survival (IDFS). Secondary endpoints: Overall survival; IDFS (STEEP definition, including second non-primary BC); disease-free survival; distant recurrence-free survival; locoregional recurrence-free interval; safety; pharmacokinetics; pt-reported outcomes. In addition, this study aims to improve health equity in research and expand clinical trial access. The study will also use/develop digital healthcare solutions, which will enable better understanding of patients’ needs and their adherence to ET. STATISTICAL METHODS The primary endpoint analysis will use a stratified log-rank test at an overall 0.05 significance level (two-sided). An interim analysis and a futility analysis are planned, and an independent data monitoring committee will be in place. ACCRUAL Target enrollment is 4100 pts globally once the study is open for enrollment. CONTACT INFORMATION For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Clinicaltrials.gov number NCT04961996. Citation Format: Aditya Bardia, Peter Schmid, Nadia Harbeck, Mothaffar F Rimawi, Sara A Hurvitz, Sherene Loi, Shigehira Saji, Kyung Hae Jung, Gustavo Werutsky, Daniil Stroyakovskii, Vanesa López-Valverde, David Tesarowski, Chenglin Ye, Michael Davis, Tanja Badovinac Crnjevic, Pablo Diego Perez-Moreno, Charles E Geyer, Jr. Lidera breast cancer: A phase III adjuvant study of giredestrant (GDC-9545) vs physician’s choice of endocrine therapy (ET) in patients (pts) with estrogen receptor-positive, HER2-negative early breast cancer (ER+/HER2- EBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-11-09.

Abstract P1-07-09: Results of treatment with inhibitors of cycline-dependent kinase CDK4/6 in patients with breast cancer in the presence of different types mutation in the PIK3CA gene

Abstract The aim of this work is frequency evaluation of mutations in the PIK3CA gene in a group of hormone positive breast cancer patients, evaluation of different types of PIK3CA mutation influence on the effectiveness of hormonal therapy in treatment of CDK4/6 inhibitors. Materials and methods. We analyzed the treatment results in patients with metastatic breast cancer ER/PR positive, HER2-neu negative amplification who received treatment in 2019-2021. Patients under study were tested for PIK3CA mutations as part of the program “Improvement of molecular genetic diagnostics in the Russian Federation in order to increase the effectiveness of anticancer treatment” including testing of mutations: C420R (Exon 7), E542K (Exon 9), E545A (Exon 9), E545G (Exon 9), E545K (Exon 9), Q546E (Exon 9), Q546R (Exon 9), H1047L (Exon 20), H1047R (Exon 20), H1047Y (Exon 20) and E545D (Exon 9). The material for the study was tumor tissue. Results and discussion. 128 patients with ER/PR positive HER2-neu negative breast cancer have been tested. Of the one hundred and twenty eight patients thirty nine (30,5%) showed a pathogenic mutation in the PIK3CA gene, seventy three patients (57%) showed no mutations and the result from sixteen patients (12,5%) was not obtained due to inadequate quality of tumor tissue. Thirty five patients (27,3%) showed luminal A subtype of tumor, eighty five (66,4%) - luminal B subtype, and we failed to determine tumor subtype in eight patients (6,3%). Among 39 patients with mutations one (2,6%) mutation detected C420R (Exon 7), seven (17,9%) - E542K (Exon 9), one (2,6%) - E545A (Exon 9), ten (25,6%) - E542K (Exon 9), two (5,1%) - H1047L (Exon 20), eighteen (46,2%) - H1047R (Exon 20). The average age of onset tumor in patients with mutations is 54,8±2,2 years, in patients with no mutations - 51,2±2,5 years. 56 patients received therapy of inhibitors of cycline-dependent kinase CDK4/6 in combination with Letrosol or Fulvestrant.21 patients received therapy of inhibitors of cycline-dependent kinase CDK4/6 as a first line treatment, 19 patients as a second line treatment, 13 patients as a third line treatment and 3 patients as a forth and more line treatment. 37 patients out of 56 completed therapy due to progressive disease, 19 patients continue the treatment. Progression free survival in patients without mutations to patients with mutations who received therapy of inhibitors of cycline-dependent kinase CDK4/6 is 14 months against 9 months. The comparison of group of patients with mutations in 9 and 20 Exons showed improvement of PFS in a group of patients with mutation in 20 Exon: 11 months against 6 months. PFS was higher in patients without mutations in comparison with patients with mutation in 9 Exon: 15 months against 6 months, the PFS difference was insignificant in comparison of patients with mutation in 20 Exon and patients without mutations: 12 months against 14. Median time of remission in patients who received treatment in an adjuvant setting with standard hormonal therapy - Tamoxifen or aromatase inhibitors Anastrazol or Letrozol is 41 months against 50 months in groups of with mutations and without respectively. Comparison of remission medians also didn’t show any significant difference in a group of mutations in Exons 9 and 20 with a group of no mutations: 60 months against 50 months and 24 months against 50 months. Conclusion. The worst effect is in patients with the mutation in Exon 9 PIK3CA gene compared to patients with the mutation in Exon 20 while treated with anti CDK4/6 drugs. Age of onset didn’t influence the detection of mutations in PIK3CA gene. Patients with mutation in Exon9 had less PFS compared to patients without any mutations but the difference is not statistically significant. Citation Format: Alexander Sultanbaev, Ainur Nasretdinov, Konstantin Menshikov, Shamil Musin, Nadezda Sultanbaeva. Results of treatment with inhibitors of cycline-dependent kinase CDK4/6 in patients with breast cancer in the presence of different types mutation in the PIK3CA gene [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-07-09.

Abstract OT2-14-01: CAPItello-292: A phase Ib/III study of capivasertib, palbociclib and fulvestrant, versus placebo, palbociclib and fulvestrant, for endocrine therapy-resistant HR+/HER2− advanced breast cancer

Abstract Background: More than two-thirds of advanced breast cancer (ABC) is hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-). Endocrine therapy (ET) is the core treatment for patients with HR+/HER2- ABC, most commonly an aromatase inhibitor (AI), tamoxifen, or the selective estrogen receptor degrader (SERD), fulvestrant. ET is increasingly also combined with a cyclin-dependent kinase (CDK) 4/6 inhibitor, and this has become the first-line standard of care for HR+/HER2- ABC in many countries. However, despite the fact that combination therapy prolongs life compared with ET alone, most patients eventually develop therapy resistance and HR+/HER2- ABC is considered incurable. Overcoming therapy resistance is a major challenge, partially because it is associated with several different mechanisms. The phosphoinositide 3-kinase/protein kinase/phosphatase and tensin homologue (PI3K/AKT/PTEN) pathway regulates cell growth, proliferation and survival. Increased PI3K/AKT/PTEN pathway activity has been observed as one of the key mechanisms driving resistance to the combination therapy of ET and CDK4/6 inhibitors. Capivasertib is a potent selective inhibitor of all three AKT isoforms that suppresses PI3K/AKT/PTEN pathway activity. Capivasertib has demonstrated synergistic anticancer activity with standard ET agents in in vitro and in vivo experimental models. Moreover, the Phase II FAKTION trial found that patients with AI-resistant HR+/HER2- ABC had longer progression-free survival (PFS) when capivasertib was added to fulvestrant therapy, compared with fulvestrant alone. CAPItello-292 is a Phase Ib/III trial examining the safety, tolerability and clinical benefit of adding AKT inhibition (with capivasertib) to combined CDK4/6 inhibition (with palbociclib) and ET (with fulvestrant) for patients with ET-resistant HR+/HER2- ABC. Trial design: CAPItello-292 (NCT04862663) is enrolling patients with HR+/HER2- locally advanced or metastatic breast cancer whose disease progressed or recurred while receiving ET or within 12 months of completing an ET (neo)adjuvant regimen. The Phase Ib trial will identify the recommended Phase III dose (RP3D) for combined capivasertib, palbociclib and fulvestrant therapy. Up to 72 patients will be enrolled for the Phase Ib part. The initial regimen will be capivasertib (320 mg twice daily; 4 days on, 3 days off through each 28-day cycle), palbociclib (125 mg once daily for 21 days of each 28-day cycle) and fulvestrant (500 mg once every 28 days, plus a loading dose on day 15 of the first cycle). In the Phase III part, approximately 628 patients will be randomized 1:1 to receive either the RP3D of the triplet or placebo plus palbociclib and fulvestrant until disease progression, unacceptable toxicity or withdrawal of consent. The Phase III primary endpoint is PFS. Secondary endpoints include safety, tolerability and overall survival, as well as PFS of patients whose tumors have PIK3CA/AKT1/PTEN alterations. The first site for the study was activated in mid-May 2021. As of July 2021, two patients have been dosed in the first cohort. Funding and acknowledgements: CAPItello-292 is funded and overseen by AstraZeneca. AstraZeneca funded medical writing support provided by Rose Goodchild, PhD, of Oxford PharmaGenesis, Oxford, UK. This abstract was previously presented at the 2021 European Society for Medical Oncology (ESMO) Annual Meeting, 3019TiP, Erika Hamilton et al. - Reused with permission. Citation Format: Hope S Rugo, Gaia Schiavon, Lynda M Grinsted, Elza C De Bruin, Maria Teresa Catanese, Erika Hamilton. CAPItello-292: A phase Ib/III study of capivasertib, palbociclib and fulvestrant, versus placebo, palbociclib and fulvestrant, for endocrine therapy-resistant HR+/HER2− advanced breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-14-01.

Abstract P3-14-03: The DNA damage repair landscape in Black women with breast cancer

Abstract Black women have 42% higher mortality rate from estrogen receptor positive (ER+) breast cancer than white women. Molecular mechanisms underlying worse outcome in black women are understudied. Recently, downregulation of specific DNA damage repair (DDR) genes was shown to causally induce resistance to standard care endocrine therapy by dysregulating cell cycle regulation, and to associate with poor outcome in white women with ER+ breast cancer. However, frequency and patterns of DDR dysregulation in Black women with ER+ breast cancer and impact on survival outcomes remains untested. By assessing RNA expression of 104 DDR genes across three tumor, and two normal breast, datasets, here, we map for the first time, global patterns of DDR gene expression regulation specific to Black women, both in tumors and in the normal breast. We identify a specific subset of 8 candidate DDR genes that are dysregulated at the RNA level in tumors from Black women. Of note, a novel DDR regulation signature where genes from the homologous recombination pathway are upregulated and genes from SSBR pathways (mainly base excision repair) are coincidently downregulated is almost uniquely detectable in tumors from Black women (8% incidence relative to 1% in tumors from white women, p=0.01). Moreover, this coincident DDR signature associates with dysregulated cell cycle gene expression (p&amp;lt;0.001). In accordance, patients whose tumors demonstrate this coincident DDR signature also have significantly worse survival outcomes across datasets (hazard ratio of 9.5, p&amp;lt;0.001). Overall, these results constitute the first systematic analysis of differences in DDR gene expression regulation between Black and white women and identify a specific DDR signature associated with poor outcome in tumors from Black women. These results provide new grounds for refining biomarker profiles and improving precision medicine for underserved populations. Citation Format: Aloran Mazumder, Athena Jimenez, Rachel E Ellsworth, Sophia George, Stephen J Freedland, Matthew N Bainbridge, Svasti Haricharan. The DNA damage repair landscape in Black women with breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-03.

Abstract OT1-12-05: Phase II neoadjuvant trial evaluating trastuzumab deruxtecan with or without anastrozole for HER2-low, HR+ early stage breast cancer

Abstract Background Although patients with clinical response of hormone receptor-positive (HR+)/HER2-negative breast cancer (BC) frequently respond to neoadjuvant therapy, fewer than 10% of patients achieve a pathologic complete response (pCR) with standard chemotherapy or endocrine therapy, even in combination with targeted agents such as CDK4/6 inhibitors. Thus, finding more effective therapies for this disease remains an area of unmet need. HER2 amplification is a known driver of endocrine resistance and HER2 may be expressed at a low level (IHC 1+ or 2+) in up to 60% of HR+ BC. Trastuzumab deruxtecan (DS-8201a, T-DXd) is a novel HER2-targeting antibody drug conjugate (ADC) that is FDA approved for HER2-positive metastatic BC and has demonstrated promising clinical efficacy in HER2-low BC with an objective response rate of ~37%. The aim of TALENT (TRIO-US B-12) is to evaluate the clinical activity and toxicity of neoadjuvant T-DXd either alone or in combination with endocrine therapy in patients with HR+/HER2-low early BC. Methods TRIO-US B-12 TALENT (NCT04553770) is an ongoing randomized, multicenter, open-label, two-stage, phase II neoadjuvant trial for participants with early stage, HR+, HER2-low expressing (1+ or 2+ by IHC) BC. Eligible participants include men and women with previously untreated, operable invasive BC greater than 2.0 cm (cT2) in size. Pts with recurrent or metastatic BC, or inflammatory BC are excluded. Pts are randomized 1:1 to receive six cycles of T-DXd (5.4 mg/kg IV q21 days) either alone or in combination with anastrozole AI (1 mg PO QD). Men and pre/peri menopausal women randomized to the AI arm also receive standard of care GnRH agonist. Stratification factors include HER2 expression (1+ or 2+) and menopausal status (men stratified as post-menopausal). Tumor tissue is taken at baseline, cycle 1 day 17-21, and at surgery. Blood samples are taken at four time points for biomarker analysis. The primary endpoint is pCR rate (breast and lymph node) at definitive surgery. In stage I, 58 participants will be randomized (29/arm). If ≥2 participants in an arm achieve pCR, that arm will expand (stage II) to enroll an additional 15 participants (total of 44/arm). A pCR rate of &amp;gt;10% (5/44) would be considered favorable, warranting further evaluation of the treatment in a larger trial. Other endpoints include safety, changes in Ki67 expression, Residual Cancer Burden index, biomarker analysis (including serial cfDNA analysis), and health-related quality of life. As of June 2021, sixteen participants have enrolled. Conclusions To our knowledge this is the first and only ongoing study evaluating T-DXd with or without endocrine therapy for HR+, HER2-low breast cancer in the neoadjuvant setting. The study will shed light on clinical activity and biomarkers, which may guide larger confirmatory studies for patients with HR+, HER2-low early breast cancer. Citation Format: Sara Hurvitz, Aditya Bardia, Merry L. Tetef, Nicholas P. McAndrew, Steven Applebaum, Aashini K. Master, Maggie L. DiNome, Minna K. Lee, Evangelia Kirimis, David D. Kim, Lisa S. Wang, Kyle Greene, Vu Phan, Nihal Abdulla, David Chan, Laura M. Spring, Christine Kivork, James Chauv. Phase II neoadjuvant trial evaluating trastuzumab deruxtecan with or without anastrozole for HER2-low, HR+ early stage breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-12-05.