Bone-only Disease Research Articles

The role of Cabazitaxel in patients with castration-resistant and osseous metastases prostate cancer. A Hellenic Cooperative Oncology Group Phase II Study.: Cabazitaxel in mCRPC patients with osseous metastases

BackgroundCabazitaxel is an effective treatment in metastatic castration-resistant prostate cancer (mCRPC) patients previously exposed to docetaxel and novel hormonal treatments. Understanding the molecular biology of mCRPC disease and taking into account the several approved treatment options, biomarkers are needed to guide decision making including cabazitaxel treatment. MethodsCababone was a phase II translational study that attempted to identify predictors of cabazitaxel efficacy. mCRPC with documented bone metastases were enrolled prospectively and treated with cabazitaxel 25mg/m2 every three weeks. Prostate cancer biopsies, bone marrow aspirates and blood samples were collected for translational research. ResultsSixty patients were enrolled and 59 received treatment according to protocol. Six-month progression free survival (PFS) rate was 47% (95% CI: 33% - 59%) and 12-month Overall Survival (OS) rate was 70% (95% CI: 56% - 80%). Patients with reactive hematopoiesis had improved PFS and OS with cabazitaxel treatment. Mutations in HRR genes were detected in 7 patients. ConclusionsNo differences in cabazitaxel efficacy were noted according to mutational status of HRR genes analyzed. No new safety issues were detected. In conclusion, CabaBone confirmed efficacy of cabazitaxel in mCRPC patients including the subgroup of patients with HRR mutations. Reactive hematopoiesis in bone marrow biopsies was related to improved survival warranting further investigation of bone biomarkers as predictors of cabazitaxel efficacy. Micro-AbstactCabaBone is a phase II translational study that evaluated the role of bone microenvironment and HRR genes mutations in the efficacy of cabazitaxel in mCRPC patients with bone-only disease. Study confirmed efficacy of cabazitaxel in patients independent of the presence of HRR gene mutations. Reactive hematopoiesis in bone marrow was recognized as a possible predictive and prognostic biomarker of cabazitaxel efficacy.

Characterization of molecular response and progression in patients with metastatic HR+/HER2- breast cancer receiving endocrine therapy and CDK4/6 inhibitors using a high-sensitivity tumor-informed assay.

3052 Background: Tumor-informed circulating tumor DNA (ctDNA) assays, designed to track patient (pt) specific variants identified by tumor sequencing, offer enhanced sensitivity compared to traditional assays focused on driver genes. This approach enables precise ctDNA quantification, facilitating early detection of molecular progression and innovative strategies in metastatic breast cancer (mBC). Methods: HR+/HER2- mBC pts receiving standard endocrine therapy + CDK4/6 inhibitors (CDKi) were enrolled in a prospective observational cohort (2018–2023). Plasma samples were collected at baseline (BL), within 30 days (d) and ~q3 months with restaging scans. Archival tumor WES was used to design personalized panels for ctDNA monitoring. The primary endpoint was time to treatment failure (TTF). Results: Of 51 pts analyzed (median age 60 years [range 38-88], 1/2L [75/20%], visceral disease 63%, palbo-/ribo-/abemaciclib 76/22/2%), tumor-informed panels were successfully designed for 43 (1 failed WES, 7 failed QC), detecting BL ctDNA in 39 (91%). The median BL estimated variant allele fraction (eVAF) was 0.5% (0.006–17.9) and was associated with liver metastases but no other covariates (e.g. bone-only disease, history of 1ry endocrine resistance [ER]). Higher BL eVAF predicted shorter TTF (HR 1.14 CI 95% 1.05–1.23, p<0.01). Most pts had eVAF decreases below BL in the first 30 d (78%) and before the first scan (89%; median 90 d, 23–158). Early increases above BL did not significantly predict TTF, with 3/8 cases showing prolonged responses. ctDNA clearance was observed in 11/39 (28%) pts at a median of 172 d (14–410) and predicted longer TTF (HR 0.06, CI 95% 0.01–0.45, p<0.01; median TTF not reached vs 14.5 mo for pts with and without clearance), with treatment failure (TF) rates of 0% vs 40%, and 8% vs 80%, at the 1- and 2-year landmarks, respectively. Clearance was not associated with any clinical covariate (i.e. disease sites, therapy line, CDKi, history of 1ry ER). For any sample irrespective of the trajectory, higher eVAF ratios to BL predicted shorter lead times to TF, though with poor correlation (r2 0.08, p=0.01). eVAF ratios to BL >1, >0.5 and <0.5 at any timepoint had median lead times to TF of 76 d (Q1–Q3 25–135), 133 d (41–360), and 326 d (174–471). A complete analysis of ctDNA dynamics and operating parameters will be presented along with RECIST 1.1 evaluation and WES-based genomic subgroups. Conclusions: ctDNA levels and changes on therapy are prognostic and high sensitivity tumor-informed assays expand the proportion of pts who can be monitored. ctDNA clearance identified pts with better outcome and might inform pt follow up and interventional strategies. Reappraisal of existing early response cutoffs, with limited precision for individual decision making, may be necessary with more sensitive assays.

International phase 3 clinical trial evaluating PF-07220060 plus fulvestrant in patients with HR+/HER2− advanced/metastatic breast cancer with progression after a prior CDK4/6 inhibitor.

TPS1129 Background: Substantial improvement in survival outcomes has been achieved with cyclin-dependent kinase (CDK) 4/6 inhibitors plus endocrine therapy (ET) in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced/metastatic breast cancer (BC); however, resistance to this therapy ultimately occurs. PF-07220060 is an oral, highly potent, selective, next generation inhibitor of CDK4 with sparing of CDK6. A first-in-human phase 1/2a study evaluated PF-07220060 (300/400 mg BID) plus ET in patients with HR+/HER2− advanced/metastatic BC who progressed on a prior CDK4/6 inhibitor plus ET (n = 26). At the data cutoff date of November 1, 2022, in patients with measurable disease (n = 21), 6 (29%) had confirmed objective response (OR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and 11 (52%) had a clinical benefit response (CBR). Of all patients (n = 26), median progression-free survival (PFS) was 24.7 weeks, and 8 (31%) patients continued treatment without progression for 60 or more weeks (1). Methods: This international (29 countries; 356 proposed sites), phase 3, open-label, randomized, parallel-group clinical trial will evaluate whether PF-07220060 plus fulvestrant improves clinical outcomes compared with the investigator-chosen therapies in adult female and male patients with HR+/HER2− advanced/metastatic BC with progression after prior therapy of CDK4/6 inhibitor plus a nonsteroidal aromatase inhibitor.Key eligibility criteria include advanced/metastatic BC with measurable disease or non-measurable bone-only disease, documented HR+/HER2− status, and progressive disease/recurrence during or within 12 months after the last dose of prior CDK4/6 inhibitor given in the advanced or adjuvant setting, respectively. One additional prior line of approved treatment in the advanced setting targeting ESR1, PIK3CA, AKT1, PTEN, or BRCA is allowed. Approximately 500 patients will be randomly assigned (1:1) to receive PF-07220060 (orally and continuously in a 28-day cycle) plus fulvestrant (intramuscular injection on days 1 and 15 of cycle 1 and then on day 1 of each cycle thereafter) or investigator’s choice of fulvestrant alone or everolimus plus exemestane, which must be declared before randomization. The primary endpoint is PFS by blinded independent central review, which is defined as the time from the date of randomization to the date of first documented disease progression, as determined per RECIST v1.1, or death due to any cause, whichever occurs first. Secondary objectives include overall survival, OR, duration of response, CBR, safety, patient-reported outcomes, and pharmacokinetics. 1. Yap. JCO. 2023;41:3009. Clinical trial information: NCT06105632 .

Abstract PO5-05-05: Clinical outcomes of CDK4/6 inhibitors in patients with bone only metastatic breast cancer

Abstract Background: CDK4/6 inhibitors (CDK 4/6i) have significantly advanced the treatment of hormone receptor-positive (HR+) metastatic breast cancer in the last decade. Several clinical trials including PALOMA, MONALEESA, and MONARCH have shown improved progression-free survival (PFS) rates when CDK4/6i were combined with endocrine therapy (ET). These results led to recommending their use in combination with ET as the first line of therapy in the metastatic settings. Bone metastasis is the most common site of disease in patients with HR+ metastatic breast cancer, about 40% of whom have bone as the only site of metastasis (bone-only disease [BoD]). While previous studies have shown that BoD can have a unique clinical course and a more favorable prognosis compared to non-BoD metastasis, most of the aforementioned CDK 4/6i clinical trials have not shown significant improvements in PFS in BoD subset of patients. Here we aimed to investigate the survival outcomes of BoD patients at a single institution center and evaluate CDK 4/6i activity in preclinical models of bone metastasis in breast cancer. Patients and methods: Patients with HR+, HER2-negative metastatic breast cancer from a retrospective CDK4/6i study at Washington University School of Medicine were included in this analysis. We selected all the patients who received CDK4/6i in the first- or second-line settings from June 2014 to March 2020. Outcomes were collected through June 10, 2023. The Kaplan-Meier method with log rank test and multivariable cox model were used for survival analysis. Results: 114 female patients (n=75 first line, n=39 second line, n=20 African American, n=94 Caucasian) were included in this study. All patients received Palbociclib as the first exposure to CDK4/6 inhibitor in combination with ET for at least two months. Median age was 60 years (range, 28-87) and forty-seven patients (41%) were in the BoD group. Survival outcomes for BoD group were compared to the rest of patients who had either bone and visceral or visceral only metastatic lesions (BV group). Our results demonstrated a significantly reduced median PFS in BoD group compared to BV group (13.1 months [95%CI:8-18.2] vs 19.6 months [95%CI:6.8-32.4], p=0.01) respectively. There was no significant difference in overall survival between BoD and BV groups (36.6 months [95%CI:32.2-41] vs 41.7 months [95%CI 36.1-47.2] p=0.74) respectively. In multivariate analysis regarding the associated risk factors with PFS, after adjusting for age and race, BoD had a HR of 1.62 (95%CI:1.04-2.54) for PFS. Among the 75 patients who received CDK4/6i as their first line of therapy, BoD (n=32 patients [42.7%]) also showed an inferior (p=0.05) median PFS (20 months [95%CI 12.9-27]) compared to BV group (n=43 patients [57.3%], median PFS=28.4 months [95%CI: 16.3-40.4]). To investigate potential treatment resistance mechanisms in bone metastases, we used the triple negative 4T1 and the ER+ luminal B PyMT Bo1 breast tumor cell line derived mammary gland models in immunocompetent mice. Single agent CDK4/6i, ribociclib, decreased primary mammary gland tumor burden. This effect was abrogated when CD8+ T-cells were depleted. In the bone colonization model using these cell lines, ribociclib had little effect on bone tumor burden. Arg1+ immune suppressive macrophages were significantly decreased in the primary mammary tumor but not in the bone tumor after ribociclib administration, suggesting a relative treatment resistance and immune suppression in the bone tumor microenvironment compared to the primary mammary gland. Conclusion: CDK4/6i play a significant role in the treatment of patients with HR+ metastatic breast cancer. Our single institution, retrospective study and preclinical data suggests that CDK4/6i may not be as effective for the treatment of tumors residing in the bone microenvironment, warranting future studies to understand the mechanisms of CDK4/6 inhibitors action in bone versus visceral metastases. Citation Format: Mahta Mardani, Suleyman Noordeen, Katherine Clifton, Cynthia Ma, Jingqin Luo, Jing Xi, Nusayba Bagegni, Foluso Ademuyiwa, Rama Suresh, Ashley Frith, Andrew Davis, Ron Bose, Lindsay Peterson, Shana Thomas, Yu Tao, Takayuki Kobayashi, Jingyu Xiang, Yalin Xu, Xinming Su, Katherine Weilbaecher. Clinical outcomes of CDK4/6 inhibitors in patients with bone only metastatic breast cancer [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 PO5-05-05.

Abstract PO1-05-02: CDK4/6 inhibitors in advanced breast cancer (aBC). Preliminary results of the CDK4/6i choice and sequence of treatments in a series of 174 patients. GOIRC-04-2019 retro/prospective observational study

Abstract Background: The sequence of treatments in aBC after a CDK4/6 inhibitor (i) is not defined yet. Fulvestrant (FUL), everolimus (E) combinations, and chemotherapy (CT) represents the main treatment options in Europe. Neither of these options has proven to be superior to the others. We conducted a retro/prospective, observational, non-randomized study, to evaluate the impact of subsequent treatments options after a 1st or 2nd line CDK4/6i in real-world clinical practice. Preliminary result in the retrospective series are presented. Methods: All patients (pts) who met the criteria to receive CDK4/6i plus aromatase inhibitors (AIs) or FUL, from market availability, were enrolled. 400 pts will be included; data from 200 pts will be collected retrospectively and 200 prospectively. Results: To date, 293 pts receiving CDK4/6i have been enrolled and the outcomes of 174 are available for a preliminary analysis. Characteristics of pts were as follow: M/F 1/173; ductal carcinoma 69%, lobular carcinoma 24%; de novo disease 28.6% In the relapse group, 46.5% pts were endocrine sensitive; 22% were endocrine resistant (7.9% and 14.1% secondary). 29.3% had bone-only disease, 46% visceral metastases only; 36% were Her2 score 0 and 64% score 1-2. 77% received CDK4/6i in 1st line, 23% in 2nd line. In pts receiving 2nd line CDK4/6i, prior therapies (tx) were as follow: 34.5% taxanes, 43% other CT, 15% FUL, 8% E, 8% FUL. In the 1st line, 46% received palbociclib (P), 37% ribociclib (R) 21% abemacicib (A). In the second line P76%, R10%, A14%. The subsequent treatments in the 49 pts who progressed after 1st line CDK4/6i was: 26% AIs/FUL +/-E, 74% CT. In the 28 pts who progressed after a 2nd line CDK4/6i tx: 20% FUL+/- E, 80% CT. The median lines of post CDK4/6i was 3 for both group (range 1-8 and 1-7). Median progression free survival (mPFS) after 1st line CDK4/6i tx was 31 months (mo) (95% CI 21-39) and 22 mo (65% CI 14-21) after 2nd line CDK4/6i tx. mPFS per CDK4/6i 1st line was as follow: P 23 mo, R 39.9 mo, A 23.2 mo. In 2nd line mPFS was: P 20 mo, R 14 mo, A 5 mo. No differences were observed between the three CDK4/6i but, if considering 1st and 2nd line together there was a difference in favor of R (p=0.009). Across five variables (ductal vs lobular; Her 2 score 0 vs 1/2, ki 67 < 20 vs >20, de novo vs recurrence, bone only vs other sites, type of CDK4/6i) no differences were observed in mPFS, except for bone only disease in 1st line setting (mPFS 46.7 vs 22,9 mo, p=0.007) Median PFS in second line in the group who received 1st line CDK4/6i, was 5 mo in pts receiving CT and 7 mo in pts treated with FUL/E whereas, for pts receiving further tx after 2nd line CDK4/6i tx, was 7 mo in CT and 4 mo with FUL/E (p=ns). Following the Sonia trial results, an analysis of PFS2 has been performed and in pts receiving CDK4/6i vs other therapies in 1st line (57 vs 91 pts), PFS2 was 24 mo vs 35 mo (p=0.014). Conclusion: The sequence of treatments after a CDK4/6i is far to be defined. In this preliminary analysis conducted in pts treated mainly in the years 2017-2019, CT represents the main choice after CDK4/6i failure. These data show the picture of the initial approach in the daily practice in an evidence-absent scenario. The increasing skill in the management of the CDK4/6i has changed in the last 5 years and we will proceed to complete the enrollment, in order to evaluate the difference in the choice of CDK4/6i and the sequence of tx in the prospective part of the study. Citation Format: Luca Moscetti, Fabio Canino, Salvatore Natalizio, Isabella Sperduti, Elena Barbieri, Federico Piacentini, Claudia Omarini, Laura Cortesi, Monica Barbolini, Antonino Musolino, Antonio Frassoldati, Federica Caggia, Gabriele Zoppoli, Massimo Dominici, Angela Toss. CDK4/6 inhibitors in advanced breast cancer (aBC). Preliminary results of the CDK4/6i choice and sequence of treatments in a series of 174 patients. GOIRC-04-2019 retro/prospective observational study [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 PO1-05-02.

Abstract PO2-20-03: VERITAC-3: A randomized phase 3 study, with a lead-in, of first-line vepdegestrant + palbociclib vs letrozole + palbociclib in estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer

Abstract Background: Vepdegestrant (ARV-471) is a selective, orally administered PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader. In the phase 2 portion (VERITAC) of a first-in-human phase 1/2 study (NCT04072952), vepdegestrant 200 mg once daily (QD) was well tolerated and had clinical activity in heavily pretreated patients with ER+/human epidermal growth factor receptor 2–negative (HER2-) advanced breast cancer and was selected as the recommended phase 3 dose (RP3D) for vepdegestrant monotherapy. A phase 1b cohort of the phase 1/2 study is evaluating the safety and clinical activity of vepdegestrant plus palbociclib in patients with ER+/HER2- breast cancer after prior endocrine-based therapy; prior cyclin-dependent kinase (CDK)4/6 inhibitor therapy was permitted. Preliminary results showed encouraging activity for the combination based on clinical benefit rate (CBR; rate of confirmed complete response, partial response, or stable disease ≥24 weeks); an increase in palbociclib exposure was observed relative to historical palbociclib pharmacokinetic data and was accompanied by a higher incidence of grade 3/4 neutropenia compared with prior palbociclib and endocrine therapy combination studies, which was managed by monitoring and standard palbociclib dose modifications. The global, randomized phase 3 VERITAC-3 study (NCT05909397) will compare the efficacy and safety of vepdegestrant plus palbociclib vs letrozole plus palbociclib as first-line treatment for patients with ER+/HER2- advanced breast cancer. An open-label study lead-in (SLI) will evaluate the safety and tolerability of vepdegestrant 200 mg QD plus 2 doses of palbociclib (100 mg QD and 75 mg QD) in patients with ER+/HER2- advanced breast cancer to select the RP3D of palbociclib for this combination. Trial Design: Approximately 50 and 1130 patients will be enrolled in the SLI and the phase 3 parts of the study, respectively. Eligible patients (aged ≥18 years) must have histologically or cytologically confirmed ER+/HER2- locoregionally recurrent or metastatic breast cancer, with no prior treatment in the advanced setting, and no prior treatment in any setting with CDK4/6 inhibitors, vepdegestrant, fulvestrant, elacestrant, or other investigational agents (including novel endocrine therapy, selective ER degraders, selective ER covalent antagonists, and complete ER antagonists). Patients with measurable disease per RECIST v1.1 or nonmeasurable bone-only disease are eligible. Patients with disease recurrence during or ≤12 months after completion of adjuvant endocrine therapy are excluded. For the SLI, patients are randomized 1:1 to receive vepdegestrant 200 mg QD in combination with palbociclib 100 mg QD or 75 mg QD and are treated in 28-day cycles with vepdegestrant given continuously and palbociclib given for 21 days followed by 7 days off treatment. The objective of the SLI is to identify the RP3D of palbociclib in combination with vepdegestrant, which will be determined through the primary outcome measures of incidence of grade 4 neutropenia, study drug dose reduction, and study drug discontinuation within the first 4 cycles of treatment. Secondary outcome measures include safety, antitumor activity (objective response rate, CBR, and duration of response), and plasma concentrations of study drugs. In the planned phase 3 portion of the trial, patients will be randomized to vepdegestrant plus palbociclib or letrozole plus palbociclib. The primary efficacy endpoint of the phase 3 portion is progression-free survival based on blinded independent central review. Enrollment began June 2023 and is ongoing. Citation Format: Seth Wander, Erika Hamilton, Mario Campone, Michael Danso, Sara Hurvitz, Hiroji Iwata, Colombe Chappey, Derek Yang, Julia Perkins Smith, Yuan Liu, Yuanyuan Zhang, Sibyl Anderson, Michelino de Laurentiis. VERITAC-3: A randomized phase 3 study, with a lead-in, of first-line vepdegestrant + palbociclib vs letrozole + palbociclib in estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer [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 PO2-20-03.

Combination of metronomic capecitabine and letrozole in metastatic hormone receptor positive, HER2 negative breast cancer: a randomized phase II trial

First line endocrine therapy is the gold standard for advanced estrogen receptor positive, human epidermal growth factor receptor 2 negative breast cancer. Adding CDK4/6 inhibitors has improved progression free survival. Metronomic Capecitabine has proven to be safe to combine with endocrine therapy with promising efficacy. We conducted a phase II randomized, open label, single centre clinical trial on patients with metastatic ER positive and HER 2 negative breast cancer. Eligible patients were randomized (1:1) to arm A: metronomic dose of capecitabine (500 mg/m2 BID) combined with letrozole (2.5 mg OD) or arm B: letrozole single agent. The primary endpoint was progression free survival. The study was terminated early due to poor accrual and 60 eligible patients out of the planned 204 were randomized. This clinical trial is registered on ClinicalTrials.gov (MD-127-2019, NCT04571437). Between February 2019 and April 2022, 60 patients were randomized. This is the first report of the study, after a median follow-up of 18.6 months. The median age at diagnosis was 47 years with only 41.7% of patients post-menopausal. Half of our patients had bone-only disease, 45% had visceral metastasis (liver and lung) and 63% presented with endocrine sensitive disease. The estimated median PFS for the whole population was 16.2 months. Median PFS for capecitabine arm was 17.7 months versus 14.6 months for letrozole alone (p = 0.078). Overall response rate was 70% for capecitabine/letrozole arm and 56.6% for letrozole only. Clinical benefit rate was 90% in the capecitabine/letrozole arm versus 73.3% in the letrozole arm. Overall survival data is still immature after this short follow up duration. Adverse event assessment showed acceptable all grade and high grade toxicity profile consistent with the established adverse events of both capecitabine and letrozole. Anaemia (28.3%) and hand & foot syndrome (43.8%) were significantly more common in the capecitabine/letrozole arm. Capecitabine combined with letrozole have showed a trend towards improvement in progression free survival with potential more benefit to certain sub-groups and the combination showed acceptable safety profile consistent with the established known safety profile of both letrozole and capecitabine.

Differences between whole body magnetic resonance imaging (WB-MRI) and chest/abdomen/pelvis computed tomography (CT)/bone scan (CT/B) in patients staged as having metastatic hormone-sensitive prostate cancer (mHSPC): A retrospective comparative study within a single trust in the UK.

37 Background: Diagnostic imaging for metastases detection in HSPC varies across different countries with increasing use of WB-MRI and PSMA-PET. However, CT/B has still been the most used modality in the real world and recent registration clinical trials in this disease setting. Methods: We performed a cross-sectional retrospective descriptive study comparing WB-MRI with CT/B used as baseline staging modalities in patients diagnosed with mHSPC between February 2017 and August 2023 in two hospitals belonging to the same NHS trust in the UK routinely using one of the two. The study aimed at the detection of differences between the two modalities in the identification of metastatic sites and CHAARTED volume/LATITUDE risk, and the relative impact on patients’ received therapies and outcomes. Results: Of 213 patients diagnosed with mHSPC, 121 had baseline WB-MRI, 86 CT/B and 7 choline or PSMA PET. Compared to CT/B, patients staged by WB-MRI were diagnosed with significantly higher bone-only (47 vs 24%, p=0.002) and lower lymph-node only disease (11 vs 27%, p=0.005); higher high-volume (49 vs 21%, p<0.001) and -risk disease (48 vs 17%, p<0.001); higher de-novo metastatic disease (91 vs 66%, p<0.001); had previously received less radical surgery (2 vs 13%, p=0.003) or radiotherapy (7 vs 24%, p<0.001); received more frequently ADT plus Docetaxel (65 vs 44%, p=0.005). Treatment and outcome results in the overall cohorts’ populations and according to disease volume/risk will be presented. Conclusions: In a homogenous cohort of patients, we found a relevant discrepancy between the use of WB-MRI and CT/B in the identification of high-volume/risk and de-novo disease in mHSPC related to a higher detection rate of bone-only disease by the WB-MRI. This may prompt clinicians to offer different systemic therapies according to the disease burden and could also have a role in avoiding overtreatments for the under-staged disease.

Circulating Tumor Cells Prediction in Hormone Receptor Positive HER2-Negative Advanced Breast Cancer: A Retrospective Analysis of the MONARCH 2 Trial.

The MONARCH 2 trial (NCT02107703) showed the efficacy of abemaciclib, a cyclin-dependent kinase 4 & 6 inhibitor (CDK4/6i), in combination with fulvestrant for hormone receptor-positive, HER2-negative metastatic breast cancer (MBC). The aim of this analysis was to explore the prediction of circulating tumor cells (CTCs) stratification using machine learning for hypothesis generation of biomarker-driven clinical trials. Predicted CTCs were computed in the MONARCH 2 trial through a K nearest neighbor (KNN) classifier trained on a dataset comprising 2436 patients with MBC. Patients were categorized into predicted Stage IVaggressive (pStage IVaggressive, ≥5 predicted CTCs) or predicted Stage IVindolent (pStage IVindolent, <5 predicted CTCs). Prognosis was tested in terms of progression-free-survival (PFS) and overall survival (OS) through Cox regression. Patients classified as predicted pStage IVaggressive and predicted pStage Stage IVindolent were, respectively, 183 (28%) and 461 (72%). After multivariable Cox regression, predicted CTCs were confirmed as independently associated with prognosis in terms of OS, together with ECOG performance status, liver involvement, bone-only disease, and treatment arm. Patients in the pStage Stage IVindolent subgroup treated with abemaciclib experienced the best prognosis both in terms of PFS and OS. The treatment effect of abemaciclib on OS was then explored through subgroup analysis, showing a consistent benefit across all subgroups. This study is the first analysis of CTCs modeling for stage IV disease stratification. These results show the need to expand biomarker profiling in combination with CTCs stratification for improved biomarker-driven drug development.

Long term survival in patients with bony oligometastatic breast cancer treated with curative intent: An institutional case series.

e12574 Background: Despite recent advances in treatment, metastatic breast cancer is widely recognized as a generally incurable condition. However, oligometastatic disease remains a poorly characterized condition with few clinical trials exploring treatments and outcomes. The term itself lacks a formal definition but is often used to refer to breast cancer displaying ≤5 metastatic sites, not necessarily in the same organ. Surgical management of discrete metastases has failed to demonstrate long-term benefit, while radiotherapy for isolated bone metastases has shown promise in some retrospective studies resulting in prolonged disease-free interval. Metastatic breast tumors overexpressing HER2 represent a category where systemic therapy may offer some prolonged remission or even cure. Methods: We are conducting a retrospective review of breast cancer patients with oligometastatic disease, as defined by ≤5 sites of disease, treated at Fred Hutch Comprehensive Cancer Center (FHCC) from 2000 to 2022; we will characterize FHCC provider practices, therapies delivered, goals of treatment, and long-term outcomes. This larger ongoing effort will be reported in a separate publication. Among a cohort of patients initially identified and undergoing record review, we reviewed all patients with bone-only disease and report their outcomes here. Results: We initially identified 17 cases of oligometastatic breast cancer currently undergoing treatment at FHCC. Of these, we noted that five patients had bone-only metastases and displayed marked similarities in treatment and outcome. All presented with de novo metastatic disease, and all five had ≤2 sites of metastasis, all in the axial skeleton. Four had HER2+ tumors; of these, three were also hormone-receptor positive. The remaining patient had triple-negative disease. All were treated with curative intent, with radiation to isolated bone metastases delivered concurrently with adjuvant radiation to breast/axilla. All are living today, with a median 56 months of follow up. One remains on a systemic metastatic regimen with a CDK4/6 inhibitor, while the rest are off therapy or are completing a standard adjuvant regimen. Conclusions: Oligometastatic breast cancer represents a heterogeneous entity that may in some instances be curable, but we lack sufficient data to identify which patients may benefit from therapy with curative intent. Standard curative treatment combined with radiotherapy to isolated bone metastases produced long-term survival in five current FHCC patients, which is consistent with other reports on patients with a low burden of bone-dominant metastatic disease. Further research is needed to validate curative approaches to therapy for this understudied population.

70P Invasive lobular breast cancer (ILC), an overlooked subtype in clinical trials

ILC represents ∼15% of all breast cancers (BC). Clinical, histological and molecular differences between ILC and BC of non-special type support the idea of ILC as a separate entity. Unfortunately, evidence on treatment efficacy for ILC is often lacking. We aimed to map out the lack of documentation and representation of patients with ILC in clinical drug trials (CT), trials investigating gene expression profiles (GEPs) and molecular screening programs (MS). Phase III and IV CT for novel BC treatments were identified on clinicaltrials.gov and Pubmed by use of keywords linked to treatment strategies, GEPs and MS and ‘breast cancer’. CT were included if a manuscript was available on 15.01.2023. Inclusion and exclusion criteria were reviewed to see if patients with ILC or non-measurable disease were excluded. Documentation of ILC was assessed and if reported, percentage of ILC, central pathology for ILC and ILC subgroup analyses were evaluated. In total, 80 CT were included of which 14 were neoadjuvant, 11 adjuvant and 55 metastatic. One CT restricted inclusion to patients with NST. Non-measurable disease was an exclusion criterium in 20% of the CT (14.3% neoadjuvant and 25.2% metastatic) and non-measurable disease with the exception of bone-only disease was excluded in 30.9% of the metastatic CT. Inclusion of patients with ILC was documented in 11/80 CT (13.8%: 35.7% neoadjuvant, 9.1% adjuvant, 9.1% metastatic). Inclusion rates varied between 2.0 and 16.3%. Only 2/11 CT had specific sub-analyses on ILC and no CT reported central pathology for ILC. The initial manuscript of 6/7 of the GEPs and 1/3 of the MS was lacking ILC information. Secondary retrospective analyses for ILC are available for 5/6 remaining GEPs. ILC is greatly overlooked in the majority of CT with poor representation, documentation and lack of specific sub-analyses. Eligibility criteria and definitions of treatment response do not reflect the unique biology and clinical course of ILC. Thus, conclusions about efficacy with respect to ILC cannot accurately be drawn. It is critical that these gaps in inclusion and study of ILC are closed. ILC deserves much more attention from both clinical investigators and pharmaceutical industries.

A Retrospective Multicenter Analysis of the Incidence of Bone-Only Disease at PSMA PET/CT in Castration Resistant Prostate Cancer Patients.

PSMA PET/CT has unprecedented accuracy for localization of initial or recurrent prostate cancer (PC), which can be applied in a metastasis-directed therapy approach. PSMA PET/CT (PET) also has a role in the selection of patients for metastasis-directed therapy or radioligand therapy and therapy assessment in CRPC patients. The purpose of this multicenter retrospective study was to determine the incidence of bone-only metastasis in CRPC patients who underwent PSMA PET/CT for restaging, as well as identifying potential predictors of bone-only PET positivity. The study analyzed data from 179 patients from two centers in Essen and Bologna. Results showed that 20.1% of the patients had PSMA uptake only in the bone, with the most frequent lesions located in the vertebrae, ribs, and hip bone. Half half of the patients showed oligo disease in bone and may benefit from a bone-metastasis-directed therapy. Initial positive nodal status and solitary ADT were shown to be negative predictors of osseous metastasis. The role of PSMA PET/TC in this patient population needs to be further explored in terms of its role in the evaluation and adoption of bone-specific therapies.

Palbociclib Adherence and Persistence in Patients with Hormone Receptor Positive/Human Epidermal Growth Factor Receptor 2 Negative (HR+/HER2-) Metastatic Breast Cancer

To assess adherence and persistence with palbociclib therapy in patients with HR+/HER2- metastatic breast cancer (mBC) in a US real-world setting. This retrospective study evaluated palbociclib dosing, adherence, and persistence using commercial and Medicare Advantage with Part D claims data from the Optum Research Database. Adult patients with mBC who had continuous enrollment 12 months prior to mBC diagnosis and initiated first-line palbociclib with aromatase inhibitor (AI) or fulvestrant between 02/03/2015 and 12/31/2019 were included. Demographic and clinical characteristics, palbociclib dosing and dose changes, adherence (medication possession ratio [MPR]), and persistence were measured. Adjusted logistic and Cox regression models were used to examine demographic and clinical factors associated with adherence and discontinuation. Patients (n = 1066) with a mean age of 66 years were included; 76.1% received first-line palbociclib+AI and 23.9% palbociclib+fulvestrant. Most patients (85.7%) initiated palbociclib at 125 mg/day. Of the 34.0% of patients with a dose reduction, 82.6% reduced from 125 to 100 mg/day. Overall, 80.0% of patients were adherent (MPR), and 38.3% discontinued palbociclib during a mean (SD) follow-up of 16.0 (11.2) and 17.4 (13.4) months, for palbociclib+fulvestrant and palbociclib+AI, respectively. Annual income below $75,000 was significantly associated with poor adherence. Older age (age 65-74 years (hazard ratio [HR] 1.57, 95% CI, 1.06, 2.33), age ≥75 years (HR 1.61, 95% CI: 1.08, 2.41)) and bone-only metastatic disease (HR 1.37, 95% CI, 1.06, 1.76) were significantly associated with palbociclib discontinuation. In this real-world study, >85% of patients started palbociclib at 125 mg/day and 1 in 3 had dose reductions during the follow-up. Patients were generally adherent and persistent with palbociclib. Older age, bone-only disease, and low-income levels were associated with early discontinuation or non-adherence. Further studies are needed to understand the associations of clinical and economic outcomes with palbociclib adherence and persistence.

HR+/HER2- de novo metastatic breast cancer: a true peculiar entity?

De novo metastatic breast cancer (dnMBC) accounts for ~6-10% of all breast cancers and for ~30% of MBC with increasing incidence over time. Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) tumours are the most frequent subtype with a similar incidence to that observed amongst recurrent MBC (rMBC). Higher frequency of PI3KCA and ARID2 mutations and a lower frequency of ESR1 mutations and of genes involved in DNA damage, as compared with rMBC, have been reported in HR+/HER2- dnMBC; however, these are not correlating with prognosis, whilst tumour mutational burden is inversely correlated with outcome. Bone represents the most frequent metastatic site, being the single site in up to 60% of patients with dnMBC. HR+/HER2- dnMBC has been generally reported to have better outcomes than rMBC, with a median overall survival ranging from 26 months to nearly 5 years in patients with favourable features such as age <40 years and bone-only disease, but not when compared with patients with late recurring disease (≥2-5 years). Analyses of the de novo cohorts within randomized clinical trials and large real-world series report a better outcome after treatment with CDK4/6 inhibitors and endocrine agents as compared to rMBC. Despite the limitations of retrospective studies and controversial results of the randomized trials, locoregional treatment of the primary tumour after response to systemic therapy appears to confer a survival benefit, particularly in patients with favourable prognostic factors. Altogether genomic, biological and clinical findings highlight HR+/HER2- dnMBC as a peculiar entity as compared with rMBC and deserve a dedicated treatment algorithm. This article is part of the Tackling clinical complexity in breast cancer Special Issue: https://www.drugsincontext.com/special_issues/tackling-clinical-complexity-in-breast-cancer/.

Abstract P1-05-13: Clinical impact of whole-body magnetic resonance imaging on subsequent management in luminal/HER2-negative breast cancer patients

Abstract Background: Routine imaging can be inaccurate, especially in metastatic breast cancer (MBC) with bone-only disease or mainly bone disease. This analysis investigates how the use of whole-body magnetic resonance imaging (WB-MRI), in addition to routine computed tomography (CT) and bone scintigraphy (BS), can influence treatment decisions in patients with known MBC. Methods: In a prospective observational study, in our Institute, we performed WB-MRI as baseline and follow-up examination in addition to routine imaging (CT, BS) in luminal/HER2-negative BC patients with prevalence of bone disease potentially candidate to CDK 4/6 inhibitors. All examinations were interpreted by two experienced radiology specialists. Using the results of the examination, a multidisciplinary oncology committee (MOC) reported on the treatment strategy. A positive impact on clinical management was considered if the examination determined a modification in the treatment strategy compared to the MOC decision before WB-MRI. Results: Thirty consecutive luminal breast cancer patients in a metastatic setting at standard imaging were recruited. All these patients underwent CT and BS followed by WB-MRI study. At standard imaging, fourteen patients (46.7%) presented with bone-only disease, while eight patients (26.6%) did not show bone lesions. In 18 of 30 cases (60%) WB-MRI led to a modification of the therapeutic approach. Due to the detection of new metastatic lesions or progression of known metastatic sites, reported on WB-MRI alone, the therapeutic decision changed in 6 (20%) and 3 (10%) patients, respectively. In one patient (3%) the therapeutic decision changed because of both findings. Nine patients (30%) started a new therapeutic line due to evidence of progressive disease on WB-MRI, while 4 patients (13.3%) underwent radiotherapy and 1 patient received orthopaedic counselling for high risk WB-MRI-assessed bone lesions. In 8 patients (26.6%) the disease was re-classified as early breast cancer based on WB-MRI assessment. Conclusions: WB-MRI could play a role in the clinical assessment of luminal MBC. Further studies are needed to better address the potential use of WB-MRI in the assessment and monitoring of bone only/bone predominant luminal MBC and/or in equivocal cases. Citation Format: Filippo Merloni, Michela Palleschi, Alice Rossi, Andrea Prochowski Iamurri, Caterina Gianni, Samanta Sarti, Francesca Mannozzi, Federica Fiori, Giandomenico Di Menna, Lorenzo Cecconetto, Marianna Sirico, Chiara Casadei, Sara Bleve, Lorenzo Gasperoni, Roberto Casadei, Luca Tontini, Antonino Romeo, Domenico Barone, Ugo De Giorgi. Clinical impact of whole-body magnetic resonance imaging on subsequent management in luminal/HER2-negative breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-13.

Abstract P5-02-23: Association of Neutrophil-to-Lymphocyte Ratio and Absolute Lymphocyte Count with Clinical Outcomes for Patients with Advanced Breast Cancer in the MONARCH 2 Trial

Abstract Background: Pretreatment neutrophil-to-lymphocyte ratio (NLR) and absolute lymphocyte count (ALC) are putative prognostic factors in patients with advanced breast cancer (ABC). Little information is available on the prognostic value of these immune status markers in patients treated with abemaciclib (ABE). In this study, we investigated the relationship between baseline NLR and ALC and clinical outcomes using data from the phase 3 MONARCH 2 (M2) trial. Methods: The M2 study compared ABE/fulvestrant to placebo (PBO)/fulvestrant in patients with estrogen-receptor positive, human epidermal growth factor receptor 2-negative ABC that had progressed on prior endocrine therapy. The current post hoc analyses used baseline laboratory data and outcome data from the June 20, 2019, cutoff date (median follow-up: 47.7 months). For both baseline NLR and baseline ALC, patients were divided into high and low categories, defined by a cutoff of 2.5 for NLR and 1.5 × 109/L for ALC. The association of baseline NLR and ALC with investigator-assessed progression-free survival (PFS) and overall survival (OS) was explored using Cox models stratified by treatment and described using Kaplan-Meier estimates. After assessing the prognostic value of baseline NLR and ALC for PFS and OS using a univariate analysis, a multivariate model was used to determine whether baseline NLR and ALC were independently prognostic considering additional baseline and disease characteristic factors. Results: Data were available for 426 and 219 patients in the ABE and PBO arms, respectively. Median baseline NLR was 2.5 and 2.4 in the ABE and PBO arms, respectively. Median baseline ALC was 1.4 × 109/L in both arms. The numbers of patients categorized into the high and low categories were well balanced for analysis of both NLR and ALC. Univariate analyses showed that baseline NLR (&amp;lt; 2.5, ≥2.5) was a prognostic factor for PFS and OS (2-sided p&amp;lt; 0.0001). Patients with low baseline NLR consistently had better PFS and OS than those with high baseline NLR, and the treatment effect of ABE against PBO was consistently observed regardless of NLR category (Table 1). Univariate analyses showed that baseline ALC (&amp;lt; 1.5 × 109/L, ≥1.5 × 109/L) was also a prognostic factor for PFS and OS (2-sided p=0.0116 and 0.0032, respectively). PFS and OS were better for patients with high baseline ALC than for those with low baseline ALC, and the treatment effect of ABE against PBO was observed regardless of ALC category (Table 1). For PFS, the multivariate model was adjusted for Eastern Cooperative Oncology Group performance status (ECOG PS), tumor grade, presence of liver metastasis, and bone-only disease. For OS, the multivariate model was adjusted for sensitivity to endocrine therapy, ECOG PS, presence of liver metastasis, and bone-only disease. When adjusting for these additional prognostic factors, baseline NLR, but not baseline ALC, remained statistically significant in the multivariate model (2-sided p&amp;lt; 0.0001). Conclusions: These exploratory analyses suggest that while both baseline NLR and ALC are prognostic of clinical outcomes, only baseline NLR is independently prognostic of PFS and OS. Low baseline NLR was associated with better PFS and OS outcomes, but the benefit of adding ABE to fulvestrant was similar regardless of baseline NLR status. Table 1. Summary of outcomes by treatment arm for NLR and ALC categories ALC, absolute lymphocyte count; CI, confidence interval; NLR, neutrophil-to-lymphocyte ratio; NR, not reached; OS, overall survival; PFS, progression-free survival. Citation Format: Eriko Tokunaga, Yasuo Miyoshi, Koji Dozono, Tsutomu Kawaguchi, Masakazu Toi. Association of Neutrophil-to-Lymphocyte Ratio and Absolute Lymphocyte Count with Clinical Outcomes for Patients with Advanced Breast Cancer in the MONARCH 2 Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-23.

Abstract P2-11-12: Pattern of distant relapse according to intrinsic molecular subtype in patients with HER2-positive breast cancer: a combined analysis of ShortHER, CherLOB, and two institutional cohorts

Abstract Background: All intrinsic molecular subtypes are represented among HER2-positive breast cancer, with implications on clinical outcome and treatment sensitivity. The impact of molecular subtypes on the pattern and site of relapse is largely unexplored. Methods: 677 patients with HER2-positive early breast cancer from the Shorther trial (n=437), the CherLOB trial (n=84) and two Institutional cohorts (Istituto Oncologico Veneto IRCCS Padova n=39 and Hospital Clinic Barcelona n=117) were included. Only patients with available PAM50 intrinsic molecular subtyping were considered. We analyzed the incidence of distant relapse (at any site and at specific sites) as the first event. Cumulative incidence was estimated according to competing risk analysis (Fine and Gray’s method). Competing risk regression was used to calculate the subdistribution Hazard Ratios (subHR) and their 95% Confidence Interval (CI). Results: The distribution of molecular subtypes was: 130 LumA (19%), 75 LumB (11%), 347 HER2-e (51%), 46 Basal (7%), 79 Normal (12%). Median follow up was 8.4 years (95%CI 8.2-8.6). The 10-yr cumulative incidence rates of distant relapse as first event were: LumA 7.9%, LumB 14.8%, HER2-e 14.7%, Basal 15.5%, Normal 10.4% (HER2-e vs LumA: SubHR 2.21, 95%CI 1.05-4.64, p=0.037). Table 1 shows the 5-yr and 10-yr cumulative incidence rates of distant metastases at specific sites (as first event) according to intrinsic subtype. HER2-e enriched and Basal tumors were more prone as compared to other subtypes to develop brain and lung metastasis as first event, respectively. Isolated brain metastases without extracranial disease occurred only in patients with HER2-e tumors. All brain metastases as first event occurred within 5 years from diagnosis. Bone-only disease as first event was less frequent in HER2-e and Basal subtype (subHR HER2-e vs LumA: 0.32, 95%CI 0.10-10.4. p=0.058). Next, we analyzed the frequency of site-specific first metastasis among patients who experienced a distant metastasis as first event (n=77). Lung metastases were more frequent in Basal tumors (LumA 25.0%, LumB 20.0%, HER2-e 24.4%, Basal 71.4%, Normal 0.0%, p=0.037) and bone metastases were more frequent in Luminal tumors (LumA 100.0%, LumB 60.0%, HER2-e 31.1%, Basal 42.9%, Normal 57.1%, p=0.006). Among 45 HER2-e patients with a first distant relapse, 25.6% were diagnosed with a brain metastasis and 15.6% had brain-only disease. Conclusions: Molecular subtypes influence the metastatic behaviour of clinically HER2-positive breast cancer. These results, if further validated, may have implication in planning personalized monitoring strategies. Table 1. 5-yr and 10-yr cumulative incidence rates of distant metastasis at specific sites (as first event) according to intrinsic subtype. Citation Format: Maria Vittoria Dieci, Giancarlo Bisagni, Stefania Bartolini, Antonio Frassoldati, Daniele Giulio Generali, Federico Piacentini, Gaia Griguolo, Enrico Tagliafico, Fara Brasó-Maristany, Nuria Chic, Francesca Porra, Roberto Vicini, Roberto D’Amico, Sara Balduzzi, Aleix Prat, PierFranco Conte, Valentina Guarneri. Pattern of distant relapse according to intrinsic molecular subtype in patients with HER2-positive breast cancer: a combined analysis of ShortHER, CherLOB, and two institutional cohorts. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-12.

Abstract P3-01-14: Real-world treatment patterns of Palbociclib plus an aromatase inhibitor or aromatase inhibitor alone for metastatic breast cancer in the Flatiron database

Abstract Background: CDK4/6 inhibitor in combination with an aromatase inhibitor (AI) or fulvestrant as initial endocrine therapy are standard of care for patients with HR+/HER2– advanced/metastatic breast cancer (mBC). This analysis describes treatment patterns including dosing patterns and time to subsequent treatment in patients receiving first line Palbociclib (PB)+AI therapy compared to AI alone, for HR+/HER2– mBC in the US routine clinical setting. Methods: This was a retrospective analysis of Flatiron Health’s nationwide longitudinal electronic health records from over 280 cancer clinics representing more than 3 million actively treated cancer patients in the US. Between February 2015 and March 2020, 2888 postmenopausal mBC women and men aged ≥18 years started first-line PB+AI or AI therapy. Patients were followed from start of therapy to September 2020, death, or last visit, whichever came first. PB treatment patterns were captured as starting dose and dose adjustments from medical records during the observation period. Comparative time to subsequent therapy (TTNT) or chemotherapy (TTC) was defined as length of time from the start of treatment to next line of anticancer therapy/chemotherapy, death from any cause, last visit, or end of study, whichever came first. Cox proportional-hazards models were used to estimate the relative effectiveness of PB+AI vs AI. Stabilized inverse probability treatment weighting (sIPTW) and propensity score matching (PSM) statistical methods were used to balance of baseline demographics and clinical characteristics. Results: Of the 2888 eligible pts (1324 with PB+AI and 1564 with AI), median age was 70.0 years, 67.8% were white, 34.8% had de novo mBC, 29.4% had lung or liver involvement, 38.7% had bone-only disease. Median follow-up was 25.0 months in the PB+AI arm and 23.3 months in the AI alone arm. Of the 1342 patients receiving PB, therapy was started at 125 mg, 100 mg, and 75 mg/day in 83.8%, 10.9%, 3.6%, respectively (1.7% undocumented PB dose) with dose changes in 41.1%, 36.8%, 31.3% of patients in each starting dose category with dosing information. After sIPTW median TTNT was 18.4 months (95%CI: 16.3-20.3) in the PB +AI group and 8.3 months (95%CI: 7.2-10.0) in the AI group; HR=0.56 (95%CI: 0.51-0.62), p&amp;lt; 0.0001. After sIPTW median TTC was 37.4 months (95%CI: 33.7-40.7) PB+AI group and 29.2 months (95%CI: 26.8-33.5) in the AI group; HR=0.77 (95%CI: 0.69-0.86), p&amp;lt; 0.0001. Results for the PSM analyses were similar. The table presents full results in detail. Conclusions: These treatment patterns analyses in a heterogeneous mBC patients from real world US clinical practice, provide support for first line PB+AI treatment for HR+/HER2– mBC. The majority of patients initiated therapy at the 125 mg/daily dose (84%). Importantly, these analyses also report meaningful differences in the delay to next line of therapy and chemotherapy in the PB+AI compared to AI therapy arm. Table. Median time to next line of therapy or chemotherapy Citation Format: Hope Rugo, Xianchen Liu, Benjamin Li, Lynn McRoy, Connie Chen, Rachel M. Layman, Adam M. Brufsky. Real-world treatment patterns of Palbociclib plus an aromatase inhibitor or aromatase inhibitor alone for metastatic breast cancer in the Flatiron database [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-01-14.

Abstract GS3-06: GS3-06 Palbociclib After CDK4/6i and Endocrine Therapy (PACE): A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab for Endocrine Pre-treated ER+/HER2- Metastatic Breast Cancer

Abstract Background CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) have a well-established role in the management of hormone receptor-positive (HR+)/HER2- metastatic breast cancer (MBC). The benefit of continuing CDK4/6i beyond progression in combination with a different ET has not been confirmed. Preclinical data suggest synergy between CDK4/6i and PD-L1 inhibition. The PACE trial prospectively evaluates whether continuation of the CKD4/6i palbociclib beyond progression on prior CDK4/6i and aromatase inhibitor (AI), with a change in ET to fulvestrant, improves outcomes beyond change to fulvestrant alone, as well as explores the activity of the palbociclib, fulvestrant, and avelumab triplet. Methods PACE is a multicenter randomized open-label investigator-initiated phase II trial, open at 11 U.S. sites. Eligible patients (pts) had HR+/HER2- evaluable MBC with prior progression on AI and any CDK4/6i after &amp;gt; 6 months (mo) of therapy in the MBC setting, or during/within 12 mo in the adjuvant setting, with no more than 1 prior line of chemotherapy for MBC. Pts were randomized 1:2:1 to fulvestrant alone (F); fulvestrant and palbociclib (F+P); or fulvestrant, palbociclib, avelumab (F+P+A), with tumor assessments every 8 weeks. Blood for circulating tumor DNA (ctDNA) analysis was collected at baseline, at times of tumor assessments, and at progression. The primary objective was to evaluate progression-free survival (PFS) with F+P vs F; secondary objectives included PFS with F+P+A vs F, objective response rate (ORR) in all arms, and safety. A sample size of 220 patients was planned to provide 80% power to detect an improvement in PFS with HR 0.6154 with F+P vs F (6.5 vs 4 mo; α(1)=0.05). Results A total of 220 pts were randomized from 9/2017-2/2022 (F: n=55, F+P: n=111, F+P+A: n=54); median age 57 years (range 25-83), 85% non-Hispanic (7.7% non-Hispanic black), 8.6% Hispanic, 6.4% unknown. 40% had de novo MBC, 60% had visceral disease, and 14% bone-only disease. 16% had 1 prior line of chemotherapy for MBC, 90% had received prior palbociclib, 4.5% ribociclib, 4.1% abemaciclib, 1.4% palbociclib and ribociclib. Pts entered the trial after a median 19 mo of prior CDK4/6i plus AI (interquartile range 12-31 mo). A total of 10 (5%) pts received protocol therapy as first line ET for MBC, 169 (77%) as second line, and 41 (17%) as beyond second line. 88% entered the trial directly after progression on CDK4/6i. After a median follow-up of 24 mo, 18 pts remained on protocol treatment. PFS was not improved with F+P vs F (median 4.6 vs 4.8 mo; HR=1.11, 90% CI 0.79-1.55; 2-sided p=0.62). Median PFS was 8.1 mo with F+P+A (HR=0.75 vs F, 90% CI 0.50-1.12; 2-sided p=0.23). ORR was 7.3% (90%CI 1.5-13.0) with F, 9.0% F+P (4.5-13.5%) and 13.0% F+P+A (5.4-20.5%). No new safety signals have been observed. Analysis of ctDNA panel sequencing encompassing 70 genes from 184 baseline samples, including correlation with known and hypothesized resistance genes, will be presented. Conclusions For ER+/HER2- breast cancer, combining palbociclib with fulvestrant beyond progression on prior CDK4/6i and AI did not significantly improve PFS compared with using fulvestrant alone. The observed longer PFS when a PD-L1 inhibitor was added to fulvestrant plus palbociclib is an intriguing signal in this ER+ population. Translational studies of blood and tumor tissue are ongoing and will be presented. Citation Format: Erica L. Mayer, Yue Ren, Nikhil Wagle, Reshma Mahtani, Cynthia Ma, Angela DeMichele, Massimo Cristofanilli, Jane Meisel, Kathy D. Miller, Trevor Jolly, Elizabeth Riley, Rubina Qamar, Priyanka Sharma, Sonya Reid, Natalie Sinclair, Meredith Faggen, Caroline Block, Naomi Ko, Ann Partridge, Wendy Y. Chen, Michelle K. DeMeo, Victoria Attaya, Amanda Okpoebo, Yuan Liu, Eric Gauthier, Harold Burstein, Meredith Regan, Sara Tolaney. GS3-06 Palbociclib After CDK4/6i and Endocrine Therapy (PACE): A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab for Endocrine Pre-treated ER+/HER2- Metastatic Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS3-06.

Abstract OT3-08-01: A phase 1 trial of LOXO-783, a potent, highly mutant-selective, brain-penetrant allosteric PI3Kα H1047R inhibitor in PIK3CA H1047R-mutant advanced breast cancer (aBC) and other solid tumors (PIKASSO-01, trial in progress)

Abstract Background: Phosphoinositide 3-kinase alpha (PI3Kα) H1047R mutations are activating oncogenic events that occur in ~15% of breast cancers (BC). Available PI3Kα inhibitors target both wild-type (WT) and mutant PI3Kα and, as a result, their efficacy may be limited by on-target WT PI3Kα-mediated toxicities, including hyperglycemia, skin rash, and diarrhea. LOXO-783 is an oral, potent and highly mutant-selective, brain-penetrant allosteric PI3Kα H1047R inhibitor. Preclinically, LOXO-783 is highly selective for PI3Kα H1047R over WT PI3Kα and other PI3K isoforms and induces single-agent tumor regressions in ER+, HER2- PI3Kα H1047R-mutant BC models without causing hyperglycemia or increases in plasma insulin/C-peptide. LOXO-783 also demonstrates brain penetration in vivo with dose-dependent tumor growth inhibition in brain metastasis models. This trial investigates LOXO-783 alone and in combination with other anticancer therapies in patients with PIK3CA H1047R-mutant aBC and other solid tumors. Trial Design: This global, first-in-human phase 1a/b study of LOXO-783 includes dose escalation of LOXO-783 monotherapy followed by dose expansion of LOXO-783 alone and in combination with other anticancer therapies (Table). Monotherapy dose escalation will be evaluated using a modified toxicity probability interval-2 (mTPI-2) design. In dose expansion (Parts A-E), each combination cohort will include a safety lead-in of 3-6 patients. Men and premenopausal women with ER+ aBC must receive concomitant treatment with a GnRH agonist. An optional pharmacodynamic (PD) biomarker sub-study will be conducted at select dose levels during dose escalation in patients with ER+, HER2- aBC with soft tissue disease amenable to safe repeat tumor biopsies. Eligibility criteria: Eligible patients must have PIK3CA H1047R-mutant aBC or other solid tumors with measurable disease or non-measurable bone-only disease (aBC patients only). In dose escalation, patients may have received up to 5 prior regimens. In dose expansion, prior therapy requirements are outlined in the Table below. Key exclusion criteria include prior inhibitor(s) of PI3K/AKT/mTOR (except in dose escalation or in select patients with prior intolerance of these inhibitors), colorectal cancer, endometrial cancer with concurrent PI3K/AKT/mTOR and/or RAS/RAF alterations and diabetes mellitus (DM) requiring medication (except in Part C). Study objectives: Recommended phase 2 dose (RP2D) determination; safety and tolerability assessment, PK and PD evaluation, objective response rate and clinical benefit rate assessment per RECIST v1.1. Recruitment is ongoing (PIKASSO-01, NCT05307705). Table. Dose Expansion (Phase 1b) Citation Format: Dejan Juric, Komal Jhaveri, Muralidhar Beeram, Erika Hamilton, Vincent Chau, Matthew P. Hanley, Shiyao Liu, Lillian M. Smyth, Funda Meric-Bernstam. A phase 1 trial of LOXO-783, a potent, highly mutant-selective, brain-penetrant allosteric PI3Kα H1047R inhibitor in PIK3CA H1047R-mutant advanced breast cancer (aBC) and other solid tumors (PIKASSO-01, trial in progress) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-08-01.