Line Chemotherapy For Metastatic Breast Cancer Research Articles

Abstract PS12-02: Exploration of ctDNA Dynamics in the PACE Trial: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab for HR+/HER2- Metastatic Breast Cancer

Abstract Background The PACE trial for HR+/HER2- metastatic breast cancer (MBC) prospectively evaluated whether continuation of the CKD4/6 inhibitor (CDK4/6i) palbociclib (P) beyond progression on prior CDK4/6i and aromatase inhibitor (AI), with a change in endocrine therapy (ET) to fulvestrant (F), improved outcomes beyond change to F alone, as well as explored the activity of a palbociclib, fulvestrant, and avelumab (P+F+A) triplet. The primary analysis did not show improvement in progression-free survival (PFS) with F+P versus F alone. In this analysis, an evaluation of serial translational PACE samples was performed to gain insights into the mutational landscape of HR+/HER2- MBC after prolonged exposure to CDK4/6i, evaluate early mutational dynamics with ongoing therapy, and identify potential genetic markers predictive of treatment response. Additionally, the identification of acquired mutations at the time of tumor progression could provide valuable information about mechanisms of treatment resistance. Methods PACE is a multicenter randomized open-label investigator-initiated phase II trial. Eligible patients (pts) had HR+/HER2- evaluable MBC with prior progression on AI and any CDK4/6i after > 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 F alone, F+P, or F+P+A, with tumor assessments every 8 weeks. Correlative samples including circulating tumor DNA (ctDNA) were collected at baseline (BL), times of tumor assessments (C3D1), and end of study/progression (EOT). Targeted NGS (Guardant360) to evaluate mutations (somatic single nucleotide variants and indels) was performed. Kaplan-Meier survival curves were used for assessing PFS and the log-rank test for comparisons. McNemar’s test with continuity correction was used to test the changes in the frequency of mutations. Results Of the 220 randomized pts, 211 contributed ctDNA samples (200 at BL, 129 at C3D1, 146 at EOT). Characteristics of the correlative science population were similar to the intention to treat population. At BL, the most common mutations observed were ESR1 (57%), TP53 (38%), PIK3CA (36%), GATA3 (20%) ATM (12%) and Rb1 (12%). The presence of a PIK3CA mutation vs WT-PIK3CA at BL was associated with shorter PFS in the F alone arm (p=0.001) but not in the F+P or F+P+A arms. ESR1 mutations present at baseline were D538G (34%), Y537S (21%), Y537N (15%), E380Q (10%) and L536H (4%). At C3D1, the most common mutations observed were ESR1 (47%), TP53 (33%), PIK3CA (26.1), GATA3 (18.1), ATM (13%) and PTEN (8.6%). Including only BL and C3D1 matched samples (N=124), the prevalence of ESR1 mutations decreased after 2 cycles of treatment (57% at BL vs 44% at C3D1), predominantly observed in the F+P+A arm. For those in any arm with at least 6 months of disease stability on study (N=53), the presence of an ESR1 D538G mutation decreased during therapy, with 38% having a mutation at BL, 24% at C3D1, and no pts gaining ESR1 D538G at C3D1. The prevalence of PIK3CA mutations also decreased on treatment (32% at BL to 24% at C3D1), with the greatest decrease in the F+P arm. A predictive model correlating early genomic dynamics and associations with outcome will be presented. Conclusions The PACE trial offers one of the largest clinical trial cohorts describing the genomic landscape of HR+/HER2- MBC post-CDK4/6 exposure. Results from this correlative study provide a comprehensive mutational landscape post-CDK4/6i, demonstrate associations between mutations and clinical outcomes, and suggest the potential value of early ctDNA dynamics in this setting. Citation Format: Rinath Jeselsohn, Jingxin Fu, Yue Ren, Reshma Mahtani, Cynthia Ma, Angela DeMichele, Massimo Cristofanilli, Jane Meisel, Kathy Miller, Yara Abdou, Elizabeth Riley, Rubina Qamar, Priyanka Sharma, Sonya Reid, Naomi Ko, Yuan Liu, Harold Burstein, Michelle DeMeo, Sara Tolaney, Erica Mayer. Exploration of ctDNA Dynamics in the PACE Trial: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab for HR+/HER2- 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 PS12-02.

Harnessing olaparib, palbociclib, and endocrine therapy: A phase I/II trial of olaparib, palbociclib and fulvestrant in patients with BRCA mutation-associated, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (HOPE).

TPS1126 Background: Hormone receptor-positive (HR+) metastatic breast cancer (MBC) in patients (pts) with germline or somatic BRCA1 or BRCA2 (g/s BRCA1/2) mutations has dual drivers: hormone receptor signaling and homologous recombination deficiency. The PALOMA-3 trial showed superiority of fulvestrant (F) with palbociclib (P) compared to F alone. The OlympiAD trial showed the poly-ADP ribose polymerase inhibitor (PARPi) olaparib (O) to be superior to chemotherapy in BRCA1/2-associated MBC. However, treatment resistance inevitably develops; targeting dual therapeutic drivers concurrently may delay or circumvent resistance. O and P have overlapping hematologic toxicity and the safety of combined O, P and F is unknown. The tolerability of O + P is particularly relevant given the emergence of potentially less myelosuppressive PARPi. Methods: HOPE (NCT03685331) is a phase I/II trial to evaluate safety and efficacy of O, P and F in pts with g/s BRCA1/2-associated, HR+ MBC. Eligible pts have an ECOG performance status 0-1, measurable/evaluable breast cancer, any/no prior endocrine therapy, and 0-2 lines of chemotherapy for MBC. Prior platinum is allowed for curative intent if completed at least 12 months prior to MBC diagnosis, or for MBC if no progression during therapy. Prior PARPi and CDK4/6i are permitted on phase I, and are permitted during phase II if there was no progression on them. Treatment (28-day cycles) consists of: O orally twice daily continuously; F 500mg intramuscularly on day 1 of each cycle plus load; and P orally once daily on days 1-21. Phase I begins with a 28-day safety run-in of O and F alone. O and P doses are based on dose level (DL): DL 0 (starting level), O 300mg, P 75mg; DL 1, O 300mg, P 100mg; DL 2, O 300mg, P 125mg; DL-1, O 250mg, P 75mg and DL-2, O 200mg, P 75mg. For phase II, O and P will be dosed at MTD. Pts have tissue collection at baseline and peripheral blood cfDNA analysis at baseline, at progression, and at all scan timepoints (every 3 cycles). Phase I primary endpoint is MTD. A 3+3 dose escalation design is used with a 30% rate of dose limiting toxicity (DLT) deemed acceptable, and 6 patients treated at a dose for it to be declared MTD. A minimum of 2 and a maximum of 18 patients will be enrolled on the phase I. Phase II primary endpoint is PFS using Kaplan-Meier methods and secondary efficacy endpoints are objective response rate and 24-week clinical benefit rate. Phase II will evaluate 54 subjects to provide 80% power to detect an increase in PFS from 7 months with O monotherapy to 10 months. Exploratory objectives include examination of baseline tissue for PARPi predictive biomarkers and measures of tumor immunogenicity as well as serial serum evaluation for reversion mutations. Enrollment is ongoing. Clinical trial information: NCT03685331 .

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 > 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 P3-07-08: Exposure-adjusted incidence rates (EAIRs) of adverse events (AEs) from the phase 3 TROPiCS-02 study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in HR+/HER2- metastatic breast cancer (MBC)

Abstract Background: SG is a Trop-2-directed antibody-drug conjugate approved by the FDA for patients (pts) with metastatic triple-negative breast cancer who received ≥2 prior chemotherapies (≥1 for MBC). In the phase 3 TROPiCS-02 study, SG demonstrated a 34% reduction in risk of progression or death vs TPC in heavily pretreated, endocrine-resistant HR+/HER2– MBC (Rugo H, et al. ASCO 2022. LBA1001). The safety profile was manageable, with neutropenia and diarrhea as the key AEs. Absolute incidence rate is the most used metric to summarize AEs in routine clinical safety analyses. However, when the treatment duration differs significantly between treatment arms, these rates may need adjustment to account for longer treatment exposure, which may incur a higher incidence of AEs. Given that the median treatment duration was longer for SG in TROPiCS-02, EAIRs were assessed in post hoc safety analyses. Methods: Pts with HR+/HER2– unresectable locally advanced or MBC and 2-4 prior chemotherapy regimens for MBC were randomized 1:1 to receive SG or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until unacceptable toxicity or disease progression. The primary endpoint was progression-free survival per RECIST 1.1 by central review. Safety was a secondary endpoint. Time-at-risk EAIR considers pts’ exposure of a specific AE in quantifying the risk of AE, defined as the number of pts who experienced at least 1 specific AE, divided by the total exposure time (pt-year of exposure [PYE]) in each arm. For pts who experienced specific AEs, exposure time was calculated from first dose date up to the first AE onset, and for pts who did not, from first dose up to data cutoff (if still on study treatment) or up to last dose (if discontinued study treatment). The 95% CI of the EAIR difference is a standard method to assess the statistical significance of AE incidence rate differences between arms. Results: Of 543 pts enrolled (median age, 56 y; visceral metastases, 95%; prior CDK4/6 inhibitor for MBC, 99%; median lines of chemotherapy for MBC, 3), 517 pts (SG, n=268; TPC, n=249) received ≥1 dose of study treatment. At data cutoff (Jan 3, 2022), 18 pts (7%) vs 4 pts (2%) remained on treatment in the SG vs TPC arms; median treatment duration was 4.1 months and 2.3 months, respectively. The absolute incidence, EAIRs (incidence per 1 PYE), and EAIR differences for the overall safety summary and most common grade ≥3 TEAEs are provided (Table). Overall, SG had higher absolute incidence rates vs TPC for grade ≥3 treatment-emergent AEs (TEAEs), serious AEs, and TEAEs leading to death, but the EAIRs were similar between arms, suggesting an association with duration of treatment exposure. When adjusted for exposure, the incidence of grade ≥3 diarrhea remained higher for SG vs TPC; however, the incidence of grade ≥3 neutropenia was similar between arms. Conclusions: The safety profile of SG was manageable in pts with heavily pretreated HR+/HER2– endocrine-resistant, unresectable locally advanced or MBC. Though there was a higher absolute incidence of TEAEs leading to death and grade ≥3 neutropenia with SG vs TPC, the EAIRs were similar. Taken together with the efficacy benefit with SG, this supports a favorable risk/benefit profile for SG compared with standard chemotherapy in this pt population with limited therapeutic options. Table. Overall Safety Summary and Summary of Common (Absolute Incidence ≥5%) Grade ≥3 TEAEs With Absolute Incidence, Exposure-Adjusted Incidence Rates (EAIRs),a and EAIR Differencesb,c Citation Format: Sara Tolaney, Peter Schmid, Aditya Bardia, Frederik Marmé, Delphine Loirat, Priyanka Sharma, Hao Wang, Olivia Fu, Wendy Verret, Hope Rugo. Exposure-adjusted incidence rates (EAIRs) of adverse events (AEs) from the phase 3 TROPiCS-02 study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in HR+/HER2- metastatic breast cancer (MBC) [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 P3-07-08.

Abstract PD13-07: PD13-07 Combination therapy with the AKT inhibitor, ipatasertib, endocrine therapy, and a CDK4/6 inhibitor for hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC): results from the phase I TAKTIC trial

Abstract Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) provide significant clinical benefit in patients with HR+/HER2- metastatic breast cancer (MBC) and have become a standard of care treatment. Prior insights from tumor profiling and preclinical analyses suggest that AKT1 activation can induce CDK4/6i resistance. We hypothesized that targeting AKT1 following CDK4/6i progression may be an effective therapeutic strategy and conducted a clinical trial to evaluate both doublet (ET+AKTi) and triplet (ET+AKTIi+CDK 4/6i) therapy in the ≥ 2nd line MBC setting. Methods: TAKTIC is an open-label phase Ib clinical trial (clinicaltrials.gov NCT03959891) evaluating the combination of the AKT inhibitor ipatasertib (ipat) with fulvestrant (Arm A), an aromatase inhibitor (Arm B), or the triplet combination (Arm C) with fulvestrant + palbociclib (palbo). The primary objective is to evaluate the safety (NCI CTCAE 5.0) and tolerability of ipat in combination with endocrine therapy +/- CDK4/6i. Secondary objectives include clinical efficacy, as determined by objective response rate (RECIST v1.1), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Key inclusion criteria include unresectable HR+/HER2- MBC; at least 1 prior therapy for MBC including any CDK4/6i; up to 2 prior lines of chemotherapy for MBC (no limit on prior endocrine therapy). Here, we present an updated interim analysis from all study arms. Results: The trial completed accrual with 77 pts enrolled from June 2019 – February 2022, including 19 on Arm A, 16 on Arm B, and 42 on Arm C. Median age was 62 (range 32-88) and 65/77 pts (84%) received prior CDK4/6i (median no. of prior lines = 3, range 1-13). 56/77 pts (73%) had measurable disease at baseline and 50/77 pts (65%) had visceral metastases in the liver/lung (68% Arm A, 44% Arm B, 71% Arm C). Pts enrolled on Arms A and B received ipat at 400mg in combination with fulvestrant or an aromatase inhibitor, respectively. In Arm C, 27/42 pts enrolled into the dose escalation phase and received ipat + palbo at varying doses in combination with fulvestrant. Two DLTs were observed in the 300mg ipat + 125mg palbo cohort (grade 4 neutropenia ≥ 7 days). ET+400mg ipat + 100mg palbo was determined to be the recommended phase 2 dose (R2PD), and the remaining 15/42 pts on Arm C were treated at this dose level in the expansion phase. Treatment was well tolerated in all arms. Grade 3 and 4 toxicities included neutropenia (39/77, 50.6%), leukopenia (15/77, 19.5%), diarrhea (11/77, 14/3%), transaminitis (7/77, 9.1%), lymphopenia (6/77, 7.8%), rash (6/77, 7.8%), and thrombocytopenia (3/77, 3.9%). As of 6/28/2022, 16/77 pts remain on treatment. The median treatment duration for all pts is estimated at 6 months (range 0.5-39). Among the 56 pts with measurable disease, 11 had partial response (PR) and 32 had stable disease (SD) as the best response. CBR, defined as percentage of pts who achieved PR or SD > 6 months, was 48% across the study (53% Arm A, 31% Arm B, 57% Arm C). The median PFS was 5.5 months (95% confidence interval [CI]: 3.8 – 7.4) and the median OS was 24.5 months (95% CI: 17.1 – 33.9). Conclusions: The combination of ipat with endocrine therapy +/- palbo is well tolerated in heavily pre-treated pts, with preliminary evidence of clinical activity. This trial demonstrates how molecular insights related to CDK4/6i resistance inform potential therapy combinations. Further studies are needed to evaluate AKTi-based combinations in pts with HR+ MBC. Citation Format: Seth A. Wander, Jennifer C. Keenan, Andrzej Niemierko, Dejan Juric, Laura M. Spring, Jeffrey Supko, Neelima Vidula, Steven J. Isakoff, Lianne Ryan, Sarah Padden, Elizabeth Fisher, Amber Newton, Beverly Moy, Leif Ellisen, Douglas S. Micalizzi, Aditya Bardia. PD13-07 Combination therapy with the AKT inhibitor, ipatasertib, endocrine therapy, and a CDK4/6 inhibitor for hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC): results from the phase I TAKTIC 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 PD13-07.

A phase IB and randomised phase IIA trial of CApecitabine plus Radium-223 (Xofigo™) in breast cancer patients with BONe metastases: CARBON trial results

BackgroundApproximately 70% of patients with metastatic breast cancer (MBC) develop bone metastases. Despite advances in systemic treatment options and the use of bone targeted agents in the management of bone metastases to reduce skeletal morbidity, there remains an unmet need for further treatment options. Radium-223 (Ra223) is an alpha-emitting radiopharmaceutical that is preferentially taken up into bone at sites of increased osteoblastic activity where it emits high-energy, short-range alpha-particles that could provide a targeted anti-tumour effect on bone metastases. Here we evaluate the safety, feasibility and efficacy findings of the combination of Ra223 with capecitabine chemotherapy in patients with MBC with bone involvement. MethodsCARBON is a multi-centre, open-label phase IB/IIA study evaluating the combination of Ra223 (55 kBq/kg day 1 given on 6 weekly schedule) and capecitabine (1000 mg/m2 bd days 4–17 every 21 days) in patients with bone metastases from MBC (± other disease sites). Other eligibility criteria included ECOG performance status 0–2, ≤2 lines of chemotherapy for MBC and current bisphosphonate or denosumab use for ≥ 6 weeks. The phase IB part of the trial (6 patients) was conducted to provide preliminary feasibility and safety of capecitabine + Ra223. Thereafter, 28 patients were randomised (2:1) to capecitabine + Ra223 or capecitabine alone to further characterise the safety profile and evaluate efficacy, the primary efficacy endpoint being the bone turnover marker (urinary n-telopeptide of type I collagen) change from baseline to end of cycle 5 and secondary endpoints of time to first symptomatic skeletal event, and disease progression at extra-skeletal and bone disease. ResultsIn addition to bone metastases, 10/23 [44%] and 13/23 [57%] capecitabine + Ra223 and 2/11 [18%] and 9/11 [82%] capecitabine alone patients had soft tissue and visceral disease sites respectively. More capecitabine + Ra223 patients had received prior chemotherapy for MBC: 11/23 [48%] vs 2/11 [18%]. The analysis populations comprise 34 patients (23 capecitabine + Ra223, 11 capecitabine); 2 patients randomised to capecitabine + Ra223 received capecitabine alone and are included in the capecitabine arm. Median number of cycles received was 8.5 in capecitabine + Ra223 (range 3–12) and 12 in the capecitabine arm (range 1–12). 94/95 prescribed Ra223 cycles were administered. No dose limiting toxicities were seen in phase IB and no patients developed grade ≥ III diarrhoea. Gastrointestinal, haematological and palmer-planter erthyrodysesthesia adverse events were similar in both arms. Although formal statistical comparisons were not made, changes in bone turnover markers, the times to extra-skeletal progression and bone disease progression, and the frequency of symptomatic skeletal events were similar across the two treatment arms. ConclusionCapecitabine + Ra223 at the planned dose was safe and feasible in MBC patients with bone metastases. However, no efficacy signals were seen that might suggest greater efficacy of the combination over capecitabine alone clinically or biochemically.

Abstract P2-07-04: Analysis of host inflammatory and estrogen biomarkers in JAKEE: A phase II trial of the JAK inhibitor ruxolitinib in combination with exemestane for estrogen receptor-positive metastatic breast cancer

Abstract Background: Circulating IL-6, an activator of JAK/STAT signaling, is associated with poor outcomes and aromatase inhibitor (AI) resistance in hormone-receptor positive (HR+) metastatic breast cancer (MBC). We previously presented clinical outcomes of JAKEE, a single arm, phase II, Simon two-stage clinical trial that tested Ruxolitinib (Rux), an oral selective inhibitor of JAK1/2, and exemestane (EXE) in 25 participants (pts) with HR+ MBC that relapsed/progressed on non-steroidal AI (NSAI); specifically, the primary endpoint of safety was met, but there were no complete or partial responses and 6/25 (24%) achieved stable disease (SD) for ≥6 cycles. We investigated whether host circulating inflammatory markers, IL-6 genotypes, and estrogen levels were associated with differential response to therapy.Methods: Responders (R) were defined as having achieved SD≥6 cycles. Flow cytometry was performed on baseline and on-treatment peripheral blood samples to assess downstream CD3+ T-cell phosphoSTAT3 inhibition by Rux. Serum concentrations of C-reactive protein (CRP), IL-6, serum amyloid A (SAA), Estrone (E1) and Estradiol (E2) were measured at baseline and serially on treatment. Sanger sequencing was performed to assess for three functional variants of the IL-6 promoter: −572G>C (rs1800796), −597G>A (rs1800797), and −174G>C (rs1800795), with high-risk polymorphisms being -597G/G and/or -174G/G. Non-parametric median testing was employed to test for differences in circulating markers by response groups given non-normal distribution, with a two-sided alpha of 0.05.Results: The cohort was heavily pre-treated: 28% received ≥2 lines of chemotherapy for MBC and 20% had CNS disease at enrollment. Among 17/25 pts with samples for pharmacodynamic assessment, Rux exhibited a 25% median inhibition (range 0-77%) of phosphoSTAT3. There was no differential effect in R vs non-responders (NR) (median inhibition 20% vs 29%, p=0.15). Frequency of high-risk IL-6 genotypes and distribution of baseline serum CRP, IL-6, SAA, E1 and E2 are depicted in the table. 15/25 (60%) harbored a high-risk IL-6 promoter polymorphism, with no significant difference in frequency between R and NR (50% vs 63%, p=0.65). 19 pts had samples for inflammatory biomarker analysis. 16/19 had baseline CRP≥10mg/L. While median levels of baseline CRP, SAA, and IL-6 were above upper limit of normal, there was no difference between R and NR (table). The proportion of pts with baseline undetectable E1 and E2 were similar between R and NR (E1: 36.9% vs 33.3%, p=1.0, E2: 52.6% vs 50%, p=1.0); notably, a significantly lower proportion with high-risk IL-6 genotype had undetectable baseline E1 (20% vs 60%, p=0.041), while no difference was noted for baseline E2, nor in the % change in E1 or E2 levels from baseline to cycle 4 by responder status.Conclusions: The JAKEE cohort represents an inflamed population with elevated circulating inflammatory markers and a high proportion with high-risk IL-6 genotypes. Examination of host inflammatory markers, IL-6 genotypes and estrogen levels did not reveal a differential response to the combination of Rux and EXE in patients with HR+ MBC that had progressed on prior NSAI. At tolerable dosing, Rux exhibited only a modest inhibition of phosphoSTAT3. Further work is needed to optimize strategies for targeting inflammation and JAK/STAT signaling in HR+ MBC. IL-6 GenotypeFrequencyFrequency by ResponderSignificanceHigh-Risk -174G/G and/or -597G/G15/25 (60%)Non-responder12/19 (63.2%)Responder3/6 (50%)p-value0.56Pretreatment Inflammatory Biomarkers [Upper limit of normal]Median (Range)Median Level by Responder GroupSignificanceCRP [8mg/L]SAA [10mg/L]IL-6 [2pg/mL]24.0 (0.2-146.8)12.8 (2.8-162.5)4.2 (1.8-11.5)Non-responder23.219.84.5Responder24.7 12.42.7p-value0.510.150.15Baseline Estrogen BiomarkersMedian (Range)Non-responderResponderp-valueEstrone (E1) (pg/mL)Estradiol (E2) (pg/mL)79.5.0 (0.2-1039.0)0.2 (0.2-44.1)79.8 0.247.8 4.20.410.91 Citation Format: Igor Makhlin, Nicholas McAndrew, E. Paul Wileyto, Amy Clark, Robin Holmes, Lisa N Bottalico, Grace R Jeschke, Kevin R Fox, Susan M Domcheck, Jennifer M Matro, Angela R Bradbury, Natalie Shih, Michael D Feldman, Elizabeth O Hexner, Jacqueline F Bromberg, Angela DeMichele. Analysis of host inflammatory and estrogen biomarkers in JAKEE: A phase II trial of the JAK inhibitor ruxolitinib in combination with exemestane for estrogen receptor-positive metastatic 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 P2-07-04.

Abstract P1-18-22: AKT inhibition in combination with endocrine therapy and a CDK4/6 inhibitor (CDK4/6i) in patients with hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC) and prior CDK4/6i exposure: A translational investigation

Abstract Background: The cyclin-dependent kinase 4/6 inhibitors, with endocrine therapy (ET), have become the standard of care for patients with HR+/HER2- MBC. Prior insight from tumor biopsies and preclinical analyses suggest that AKT1 activation can provoke CDK4/6i resistance, highlighting a potential therapeutic role for AKT inhibition (AKTi) in this setting. However, combinatorial inhibition can be associated with significant toxicity and identification of the optimal biological dose is often challenging. In this translational co-clinical study, we evaluated escalating doses of AKTi combination with CDK 4/6i in parallel patient-derived pre-clinical models as well as a phase 1b clinical trial. Methods: In an open-label phase Ib dose-escalation clinical trial (TAKTIC, NCT03959891), we evaluated the safety, tolerability and efficacy of escalating doses of the AKT1 inhibitor ipatasertib (ipat) in combination with palbociclib (palbo) and fulvestrant (fulv) for patients with HR+/HER2- MBC. Inclusion criteria include unresectable or metastatic disease, at least 1 prior therapy for MBC including any CDK4/6i, and up to 2 prior lines of chemotherapy for MBC (no limit on prior endocrine therapy). In addition, response to escalating doses of ipat and palbo (with fulv) were explored in vitro via an ATP-based viability assay in tumor cell lines derived from circulating tumor cells (CTC) isolated from patients with endocrine-refractory HR+ MBC. Results: In the dose-escalation portion of the phase 1b clinical trial, 23 patients received the triplet combination of ipat, palbo, and fulv (median number of prior lines = 4.3, range 1-7; 100% with prior CDK4/6i): 3 pts received ipat at 200mg + 125mg palbo, 15 pts received 300mg + 125mg palbo, and 5 pts received 400mg + 100mg palbo, all with fulv (500 mg). Among the 23 patients, 20 patients (86.9%) had disease control (4 partial response and 16 stable disease) as the best response, per RECIST. Grade 3/4 toxicities included neutropenia (n=20), lymphopenia (n=3), diarrhea (n=3), thrombocytopenia (n=2), transaminitis (n=2), and rash (n=2). Two DLTs were observed in the 300mg ipat + 125mg palbo cohort (grade 4 neutropenia ≥ 7 days), but none at 400mg + 100mg palbo. The combination of ipat and palbo demonstrated an additive effect in vitro, with increased sensitivity to lower doses of palbo in the presence of ipat. Based on the totality of data, 400mg ipat + 100mg palbo + fulv 500 mg was selected as the recommended phase II dose (RP2D) in the post-CDK4/6i setting. Conclusions: The triplet combination of endocrine therapy with AKTi and lower dose CDK4/6i appears to be well tolerated in heavily pre-treated pts, with preliminary evidence of clinical activity. Further study is needed to evaluate biomarkers associated with higher AKTi benefit in order to guide rational development of combination therapy for patients with HR+/HER2- MBC in the post-CDK4/6i setting. Overall, this translational study demonstrates how insight into the molecular mechanisms of CDK4/6i resistance and combinatorial modeling can be leveraged to develop actionable therapeutic regimens for patients with MBC. Citation Format: Seth A. Wander, Douglas S. Micalizzi, Taronish Dubash, Dejan Juric, Laura M. Spring, Neelima Vidula, Jennifer Keenan, Maureen Beeler, Elene Viscosi, Dante Che, Elizabeth L. Fisher, Rachel A. Hepp, Beverly Moy, Steven J. Isakoff, Leif W. Ellisen, Jeffrey G. Supko, Shyamala Maheswaran, Daniel A. Haber, Aditya Bardia. AKT inhibition in combination with endocrine therapy and a CDK4/6 inhibitor (CDK4/6i) in patients with hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC) and prior CDK4/6i exposure: A translational investigation [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 P1-18-22.

Abstract P2-14-03: A pilot study of paclitaxel plus pembrolizumab in patients with metastatic HER2-negative breast cancer (PePPy)

Abstract Background: Studies of immune checkpoint inhibitors combined with chemotherapy show activity in metastatic breast cancer (MBC). There is no data regarding sequencing of pembrolizumab (pem) in relation to chemotherapy in MBC patients (pts). We investigated the safety of a phased schedule vs concurrent schedule of paclitaxel (pac) and pembrolizumab (pem). Methods: Eligible pts had HR+HER2-negative or triple-negative (TN) MBC, ≥2 lines of hormone therapies and 0-3 prior lines of chemotherapy for MBC. Pts were randomized 1:1 to 2 cycles of pac 80 mg/m2 IV on D1 and D8 followed by pac and pem 200 mg/m2 IV on D1 of a 21-day cycle (Arm A; phased schedule) or pac and pem given together starting D1 of a 21-day cycle (Arm B; concurrent) and continuing until progression or toxicity. Primary objective was to continuously monitor overall grade 3 or 4 treatment-related adverse event (TRAE) rate for each arm and compare to relevant historical controls with Bayesian stopping rules. If the grade 3 or 4 TRAE rate convincingly exceeded 0.35 on either arm, enrollment to that arm would be halted. Secondary objectives were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Exploratory analyses assessed PD-L1 and tumor infiltrating lymphocytes (TILs) in the tumor and blood markers immunotyping. Results: Forty female pts were randomized (21 in Arm A and 19 in Arm B). Median age was 40 (range 28-76). Twenty pts were HR+HER2-negative; 20 pts had TNBC; 7 pts had de novo MBC. Median prior lines of chemotherapy was 1 (range 0 - 3); median no. of cycles was 7 (1-27); 7 pts in Arm A did not initiate pembrolizumab due to disease progression. The criteria for stopping enrollment based on Bayesian stopping rules were not met for either arm; 24% of subjects (5 of 21) on Arm A and 32% (6 of 19) on Arm B experienced stopping rule events. At the data cut-off of 2/16/21, with median follow-up of 10.1 months, overall ORR was 30% with 12 partial responses, and ORR in HR+HER2-negative and TNBC were 30% and 30%, respectively. Grade 3-4 TRAE rates were 24% in Arm A and 32% in Arm B. The most common grade 3-4 TRAES were peripheral sensory neuropathy (2 pts [10%] in Arm A; 3 pts [16%] in Arm B), decreased neutrophil count (1 pt [5%] in each Arm), and anemia (1 pt [5%] in each Arm). In the overall group, immune-related adverse events (irAEs) occurred in 28% of pts; 5% of these events were ≥ grade 3 in Arm A (gr 3 AST/ALT increased in 1 pt) and 5% in Arm B (gr 3 lipase increased in 1 pt). The most common irAE was hypothyroidism (6 pts, 15%). Tumor PD-L1 assay and TILs were performed in 39 pts and blood immunotyping on all pts. Seven pts (18%) had PD-L1 positive tumors (PDL-1 H-score ≥ 5, centrally tested) and 19 (48.7%) had significant immune infiltration (TILs score 2-3). Biomarker analysis is currently in progress. Updated data, including ORR, PFS and OS by arm, is expected to be presented. Conclusions: Both the phased and concurrent schedules of pac and pem were found to be safe and feasible. The combination’s safety profile was consistent with the known individual agent’s safety profile. Clinical activity was demonstrated in both metastatic HR+HER2-negative and TNBC pts. Clinical trial information: NCT03018080. Citation Format: Antoinette R. Tan, S. Jean Chai, Myra M. Robinson, Lane B. Hellner, Nagajyothi Gavini, Nanna Sulai, J. David Turner, Jennifer Atlas, David L. Graham, Raghava R. Induru, Kunal C. Kadakia, Geetha D. Vallabhaneni, Arielle L. Heeke, David M. Foureau, Julie G. Fisher. A pilot study of paclitaxel plus pembrolizumab in patients with metastatic HER2-negative breast cancer (PePPy) [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 P2-14-03.

Abstract OT2-18-01: Harnessing olaparib, palbociclib, and endocrine therapy (HOPE): Phase I/II trial of olaparib, palbociclib and fulvestrant in patients with BRCA1/2-associated, hormone receptor-positive, HER2-negative metastatic breast cancer

Abstract Background: Hormone receptor-positive (HR+) metastatic breast cancer (MBC) that occurs in the context of a germline or somatic BRCA1 or BRCA2 (BRCA1/2) mutation has dual drivers: hormone receptor signaling and homologous recombination deficiency. The PALOMA-3 trial studied the selective estrogen receptor downregulator fulvestrant and the CDK4 and CDK6 inhibitor (CDK4/6i) palbociclib in patients with HR+ MBC. Compared with fulvestrant and placebo, combination fulvestrant and palbociclib demonstrated significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival. The OlympiAD trial examined patients with HER2-negative MBC and a germline BRCA1/2 mutation who were treated with the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib or non-platinum chemotherapy. Olaparib resulted in improved PFS, double the response rate, and a lower risk of disease progression or death compared to chemotherapy. Despite these remarkable therapeutic advances, resistance to treatment inevitably develops and contributes to mortality in patients with MBC. Targeting dual therapeutic drivers concurrently may delay or circumvent resistance; however, olaparib and palbociclib have overlapping hematologic toxicity and the safety of combined olaparib, palbociclib and fulvestrant has not been determined. Methods: HOPE (NCT03685331) is a phase I/II clinical trial to evaluate the safety and efficacy of olaparib, palbociclib and fulvestrant in patients with HR+ MBC and a pathogenic or likely pathogenic germline or somatic variant in BRCA1/2. Eligible patients are biological males, postmenopausal females, or premenopausal females on ovarian suppression who have an ECOG performance status 0-1, measureable/evaluable breast cancer, any/no prior endocrine therapy, and 0-2 prior lines of chemotherapy for MBC. Prior platinum chemotherapy is allowed for curative intent treatment if completed at least 12 months prior to diagnosis of metastatic disease, or for MBC if there was no progression during therapy. Prior PARPi and prior CDK4/6i are permitted without restriction during phase I, and are permitted during phase II provided there was no progression on these therapies. Treatment (28-day cycles) consists of: olaparib 300mg by mouth twice daily continuously; fulvestrant 500mg intramuscularly on day 1 of each cycle and day 15 of the first cycle; and oral palbociclib once daily on days 1-21. For phase I, palbociclib dose is based on dosing cohort. Dose Levels (DL) are: DL 0 (starting level), 75mg; DL 1, 100mg; DL 2, 125mg. Phase I treatment begins with a 28-day safety run-in of fulvestrant and olaparib alone. For phase II, palbociclib will be dosed at MTD. Subjects will have archival tissue collection or fresh biopsy at baseline as well as research blood samples for cfDNA analysis at baseline, at progression, and at all scan timepoints (every 3 cycles). The phase I primary endpoint is determination of MTD. A 3+3 dose escalation design will be utilized with a 30% rate of dose limiting toxicity (DLT) deemed acceptable, and 6 patients treated at a dose for it to be declared MTD. This schema yields a minimum of 2 and a maximum of 18 patients on the phase I. For the phase II trial, the primary endpoint is PFS estimated using Kaplan-Meier methods and secondary efficacy endpoints are objective response rate and 24-week clinical benefit rate. The phase II trial will evaluate 54 subjects to provide 80% power to detect an increase in PFS from 7 months with olaparib monotherapy to 10 months. Exploratory objectives include examination of baseline tissue for PARPi predictive biomarkers and measures of tumor immunogenicity as well as serial serum evaluation for reversion mutations. Enrollment has begun. Citation Format: Alexandra Torres, Carey Kokkonen, Mary Oladeji, Kurt D'Andrea, Rosemarie Mick, Vivek Narayan, Michael Mallamaci, Gayle Ewing, Hayley Knollman, Nadine M. Tung, Mark Robson, Katherine L. Nathanson, Susan Domchek, Payal D. Shah. Harnessing olaparib, palbociclib, and endocrine therapy (HOPE): Phase I/II trial of olaparib, palbociclib and fulvestrant in patients with BRCA1/2-associated, hormone receptor-positive, HER2-negative metastatic 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 OT2-18-01.

Prospective Evaluation of a Circulating Tumor Cell Sensitivity Profile to Predict Response to Cisplatin Chemotherapy in Metastatic Breast Cancer Patients.

BackgroundCisplatin (cDDP) has regained interest for metastatic breast cancer (MBC) patients, given the platinum sensitivity in subtypes and better manageable toxicity. Here, the primary aim was to determine whether molecular characteristics of circulating tumor cells (CTCs) could identify patients responding to cDDP and to describe the outcomes to cDDP monotherapy in a large group of MBC patients pretreated with anthracycline- and taxane-based treatments.MethodsBased on cell line data, a CTC-cDDP-sensitivity profile was generated. Applying an A’Herns single-stage phase II design, further investigation was considered worthwhile if 5/10 patients with a favorable profile responded to cDDP. Patients received 70mg/m2 cDDP every three weeks, CTCs were enumerated and the CTC-cDDP-sensitivity profile was determined. In total, 65 heavily pretreated MBC patients (77% received ≥2 lines of previous chemotherapy for MBC) were eligible for the per-protocol analysis. Primary endpoint was response rate, secondary endpoints included best observed response, progression-free survival (PFS) and overall survival (OS).ResultsThe best observed response during cDDP therapy was a partial response in 7% and stable disease in 56% of the patients. None of the patients with a favorable CTC-cDDP-sensitivity profile had a response. The median baseline CTC count was 8 (range 0-3254). Patients with <5 CTCs had a better PFS and OS than patients with ≥5 CTCs (median PFS 4.5 months (95%CI 2.38-6.62) vs. 2.1 months [(95%CI 1.34-2.80)(p=0.009)] and median OS 13.1 months (95%CI 9.89-16.33) vs. 5.6 months [(95%CI 3.60-7.64)(p=0.003)]. No other factors than CTC count were associated with outcome to cDDP therapy, including triple-negative breast cancer versus ER-positive tumors.ConclusionsThe CTC-cDDP-sensitivity profile was unable to select patients responding to cDDP monotherapy. In an unselected group of heavily pretreated MBC patients, cDDP yields outcomes comparable to other chemotherapeutic regimens for heavily pretreated MBC patients. CTC count was the only factor associated with outcome in these patients.Clinical Trial Registration(https://www.trialregister.nl/trial/3885, identifier NTR4046)

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

Abstract Background: Sapanisertib (S) is an investigational, oral, and highly selective adenosine triphosphate (ATP)-competitive inhibitor of target of rapamycin complex 1/2 (TORC1/2). Simultaneous inhibition of ER and phosphoinositide 3kinase (PI3K)/serine/threonine-specific protein kinase (AKT)/mammalian target of rapamycin (mTOR) pathway with S may restore sensitivity to endocrine therapies in patients (pts) with breast cancer, who have progressed during or after aromatase inhibitor (AI) therapy. Here we report data from a phase 2 study of continuous once-daily or once-weekly S + fulvestrant (F) compared with single-agent F in pts with breast cancer. Methods: Postmenopausal women with ER+ and HER2- advanced or metastatic breast cancer following progression during/after AI therapy were randomized 1:1:1 to receive F (500 mg intramuscularly on day 1 of a 28-day cycle) alone (Arm A) or in combination with oral S either daily (4 mg; Arm B) or weekly (30 mg; Arm C) until progressive disease (PD), unacceptable toxicity, or consent withdrawal. Pts were stratified according to presence/absence of visceral metastases, previous sensitivity to hormonal therapy, and previous exposure to cyclin-dependent kinase (CDK) 4/6 inhibitors. Pts on Arm A could receive S at PD. Key exclusion criteria were: prior therapy with mTOR inhibitors, PI3K inhibitors, or F; &amp;gt;1 prior line of chemotherapy for MBC; recurrent disease or PD on &amp;gt;2 endocrine therapies for MBC. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR; any duration and at 24 weeks), overall survival (OS), and safety. Results: Between Aug 2016 and May 2018, 141 pts were randomized (Arm A: 46; Arm B: 47; Arm C: 48). One patient in Arm C was not treated. Median age was 58 years (range 33-84). Stratification was well balanced across arms; overall, 65% had visceral metastases, 84% had prior sensitivity to hormonal therapy, and 34% had received prior CDK 4/6 inhibitors. Pts received a median of 4 cycles (range 1-40) of F on Arm A, 5 cycles (range 1-33) of daily S + F on Arm B, and 4 cycles (range 1-39) of weekly S + F on Arm C. The last follow-up visit was in Nov 2019. The main reasons for treatment discontinuation included PD (76%, 60%, 53%; Arm A, B, and C, respectively) and adverse events (AEs; 4%, 32%, 36%; Arm A, B, and C, respectively). Of the pts in Arm A with confirmed PD, 18 crossed over to Arm B and C (9 each); crossover was analyzed separately. Efficacy data are shown in the table; median PFS was 3.5, 7.2, and 5.6 months in Arm A, B, and C, respectively. OS data were immature at the primary data cut-off. Three pts died during the study (2 and 1 in Arm A and B, respectively); all deaths were attributed to underlying disease. Most common any-grade AEs were: asthenia (24%), hyperglycemia, fatigue, and headache (22% each) in Arm A; hyperglycemia (57%) and nausea (49%) in Arm B; nausea (87%) and vomiting (70%) in Arm C. Conclusion: Daily or weekly treatment with S + F demonstrated modest clinical benefit in ER+/HER2- advanced or MBC pts who progressed during/after AI compared with single-agent F. The S + F combinations had increased toxicity leading to more treatment discontinuations compared with single-agent F. Table: PFS and response dataArm A Single-agent F (n = 46)Arm B S (QD) + F (n = 47)Arm C S (QW) + F (n = 48)Median PFS (95% CI), months3.5 (1.9-5.6)7.2 (3.9-10.6)5.6 (4.1-9.0)HR (95% CI)0.77 (0.47-1.26)0.88 (0.53-1.45)ORR*, n/N (%)5/46 (10.9)10/47 (21.3)†6/47 (12.8)CBR*, n/N (%)28/46 (60.9)35/47 (74.5)31/47 (66.0)CBR≥6 months*, n/N (%)15/46 (32.6)23/47 (48.9)12/47 (25.5)*Safety population †Including 2 complete responses Citation Format: José Á García-Saenz, Noelia Martínez Jáñez, Miguel Martin, Ainhara Lahuerta Martínez, Santiago González-Santiago, Nieves Ferrer, Manuel Ramos Vázquez, José Luis Alonso Romero, Antonio Antón, Eva Carrasco, Jingjing Chen, Rachel Neuwirth, E Jane Leonard, Dennis Slamon. Open-label, randomized, phase 2 study of sapanisertib (TAK-228/MLN0128) in combination with fulvestrant in postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor-2-negative (HER2-) advanced or metastatic breast cancer (MBC) that previously progressed during or after aromatase inhibitor therapy (NCT02756364) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-01.

Abstract PS14-02: A randomised phase IB/IIA study of CApecitabine plus Radium-223 in breast cancer patients with BONe metastases (CARBON) - Safety and preliminary efficacy findings

Abstract Background: Bone metastases (BMs) occur in approximately 70% of patients (pts) with metastatic breast cancer (MBC). Despite significant advances in the management of BMs with bone-targeted agents and the associated reduction in skeletal-related events, there remains an unmet need for further treatment options to improve median overall survival beyond 2-3 years. Radium-223 [R] dichloride is an alpha-emitting radiopharmaceutical that is avidly taken up, like calcium, into the bone where it emits high-energy, short-range alpha-particles resulting in a targeted anti-tumour effect on BMs. Combining R with current systemic therapy could potentially enhance efficacy in MBC with BMs. Methods: CARBON is a UK, open-label, multi-centre phase IB/IIA study evaluating the combination of capecitabine [C] (1000mg/m2 bd days 4-17, 12x21 day cycles) with R 55kBq/kg day 1 given on a 6-weekly schedule in pts with BMs from MBC (+/- other sites of disease) with ≥2 bone lesions on radionuclide bone scan and/or ≥1 lesion confirmed on plain radiographs, CT or MRI. Other eligibility criteria included ECOG PS 0-2, ≤ 2 lines of chemotherapy for MBC and current use of a bisphosphonate / denosumab for ≥6 weeks. To establish the feasibility and safety of C+R the phase IB opened in August 2016 registering 6 pts; the primary endpoint was dose-limiting toxicities (DLTs), defined as ≥grade 3 gastrointestinal toxicity lasting &amp;gt;48 hours or ≥grade 4 haematological toxicity lasting &amp;gt;7 days. Subsequently, between April 2017 and March 2019 28 pts were randomised (2:1) to C+R vs C in phase IIa to further characterise the safety profile, with frequency of CTC grade 3-4 toxicities and diarrhoea as primary endpoints. Preliminary evaluation of efficacy through assessment of bone turnover marker changes from baseline to end of cycle 5 and time to progression in bone and overall was made. Results: Baseline clinico-pathologic characteristics and prior treatments were well balanced between the arms; 13 C+R and 9 C pts had visceral metastases. There were 0 DLTs in the 6 phase IB pts, therefore the same C+R dose and schedule was studied in phase IIA. 2 pts randomised to C+R received C alone and are included in the C arm. The safety population consists of 34 pts (23 C+R, 11 C). Median number of cycles received was 8.5 (range 3-12) in C+R arm and 12 (range 1-12) in C arm. 38/307 (12%) treatment cycles were delayed (25 [13%] C+R arm, 13 [12%] C arm). 11 (48%) C+R and 6 (55%) C pts had a permanent C dose reduction. 94/95 (99%) prescribed R cycles were administered. 9 (39%) C+R and 9 (82%) C pts completed all 12 cycles. Other reasons for discontinuation were: progressive disease in 12 (52%) C+R and 0 in C pts; toxicity in 1 (4%) C+R and 1 (9%) C pt; clinician decision in 1 (9%) C pt; progressive disease and toxicity in 1 (4%) C+R pt. Only 25/575 (4%) reported AEs were grade 3-4 (n=21 in 11 [48%] C+R pts, n=4 in 4 [36%] C pts) with 0 episodes of grade 3-4 diarrhoea. Table 1 shows maximum grades of diarrhoea and haematological AEs experienced by arm. 18 SAEs occurred (n=11 in 8 C+R pts, n=7 in 2 C pts). 8 (44%) SAEs were grade 3 (C+R: 6, C: 2); none were related to diarrhoea. There were 0 SUSARs. Conclusion: In the first completed trial evaluating R with chemotherapy in MBC pts, the combination of C+R is safe and well-tolerated. Preliminary efficacy analyses including bone markers are ongoing and will be presented at the meeting. The creation of the data was supported in part by Bayer Plc and Yorkshire Cancer Research. Table 1: Maximum CTCAE grade (G) experienced - diarrhoea and haematological AEs.C+R (n=23)C (n=11)Not experiencedG1G2G3G4Not experiencedG1G2G3G4Diarrhoea7 (30%)14 (61%)2 (9%)006 (55%)4 (36%)1 (9%)00Neutropenia18 (78%)02 (9%)3 (13%)010 (91%)01 (9%)00Thrombocytopenia21 (91%)1 (4%)1 (4%)009 (82%)1 (9%)1 (9%)00Anaemia21 (91%)2 (9%)0008 (73%)1 (9%)2 (18%)00 Citation Format: Matthew Winter, Jessica Kendall, Sarah Brown, Emma Rathbone, Caroline Wilson, Sacha Howell, Chris Twelves, Carlo Palmieri, Anjana Anand, Iain MacPherson, Rob Coleman, Janet Brown. A randomised phase IB/IIA study of CApecitabine plus Radium-223 in breast cancer patients with BONe metastases (CARBON) - Safety and preliminary efficacy findings [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-02.

Abstract PS10-27: A phase II proof-of-concept study of palbociclib (P) rechallenge in patients (pts) with hormone receptor (HR)[+]/HER2[-] metastatic breast cancer (MBC) and clinical benefit to prior P-based treatment (BIOPER)

Abstract Background: The addition of a cyclin-dependent kinase 4-6 inhibitor (CDK4/6i) to letrozole or fulvestrant significantly improves progression-free survival (PFS) and overall survival (OS) in HR[+]/HER2[-] MBC pts. At present, the optimal endocrine treatment (ET) after progression on a CDK4/6i remains unknown. However, preliminary findings revealed drivers of adaptive resistance more frequently related to ET than to CDK4/6i. BIOPER explored the efficacy and safety of continuing the same CDK4/6i in combination with a different ET agent beyond progression on prior P-based regimen in HR[+]/HER2[-] MBC and assessed predictive biomarkers to identify those pts who are more likely to benefit from this strategy. Methods: BIOPER (NCT03184090) is a multicenter, non-controlled, phase II trial. Eligible pts included pre- and post-menopausal women aged ≥18 years with HR[+]/HER2[-] MBC that showed a confirmed progressive disease (PD) after having achieved clinical benefit (response or stable disease ≥24 weeks) on immediately prior P plus ET-based regimen. Up to two prior ET lines and not more than one line of prior chemotherapy for MBC were allowed. Pts received P (oral, 75/100/125 mg/day 3 weeks on/1 week off) combined with ET of physician’s choice (including tamoxifen, exemestane, fulvestrant, anastrozole, or letrozole) until PD or unacceptable toxicity. Co-primary endpoints were clinical benefit rate (CBR) -in terms of complete or partial response [PR] and stable disease lasting ≥24 weeks as per RECIST 1.1 (H0: CBR≤5% versus H1: CBR≥20%)- and tumor molecular alterations in the cyclin D-CDK 4/6-retinoblastoma pathway detected at baseline as markers of resistance and sensitivity to P rechallenge. Secondary endpoints included investigator-assessed PFS, objective response rate (ORR), OS, and safety using the Common Terminology Criteria for Adverse Events (AEs) 4.03. Results: Between June 15, 2017 and April 25, 2019, a total of 33 pts from 21 centers in 2 countries were enrolled. Among the 33 pts who were included in the safety set, 1 patient who did not achieve clinical benefit on prior P-based regimen was excluded from the efficacy analysis (n=32). The median age was 59.5 years (range 42-80 years) and all pts were post-menopausal. A total of 25 (78.1%) pts had visceral disease (56.3% of whom with liver metastases), 16 (50%) had ECOG 0, and 19 (59.4%) presented ≥3 metastatic sites. Of 32 pts, 15 (46.9%) received letrozole, 14 (43.8%) received fulvestrant, and 3 (9.4%) exemestane. The median PFS for the prior P-based regimen was 13.8 months (mo) (95% confidence interval [CI] 5.6-47.1 mo). The median number of prior ET and chemotherapy lines for MBC was 2 (range 1-4). By the data cutoff date, 26 PFS events occurred, 5 pts were still on treatment, and 1 patient discontinued treatment because of investigator’s decision. The CBR was 34.4% (95% CI 18.6-53.2%) reaching the prespecified primary endpoint. The ORR was 3.1% (95% CI 0.1-16.2%) with 1 patient with PR. The median PFS was 2.6 mo (95% CI 1.8-5.5 mo). With a median follow-up of 11.8 mo, the OS data were immature with a total of 8 deaths (25%). The incidence of all grade (G) and G 3 or 4 (G3-4) AEs were 90.9% and 48.5%, respectively. The most common G3-4 AEs were neutropenia (42.4%) and leukopenia (6.1%). No discontinuations due to AEs and treatment-related deaths occurred. A comprehensive molecular tumor profiling will be presented during the symposium. Conclusions: Prolonging CDK4/6 blockade beyond progression on prior P-based treatment achieved the prespecified clinical benefit among pts with HR[+]/HER2[-] MBC. This strategy is currently being evaluated in the randomized phase II PALMIRA trial. Further research is ongoing to identify patient subgroups who could benefit from this treatment strategy. Citation Format: Antonio Llombart-Cussac, Javier Cortés, Beatriz Bellosillo Paricio, Miguel Gil Gil, Giuseppe Curigliano, José Manuel Pérez-García, Laura Comerma Blesa, Manuel Ruíz Borrego, Enrique Espinosa, Lourdes Calvo, Begoña Bermejo, Meritxell Bellet, Federico Rojo Todo, Juan de la Haba, Vanesa Quiroga, Alessandro Minisini, Ana Santaballa, Miguel Sampayo, Andrea Malfettone, Joan Albanell. A phase II proof-of-concept study of palbociclib (P) rechallenge in patients (pts) with hormone receptor (HR)[+]/HER2[-] metastatic breast cancer (MBC) and clinical benefit to prior P-based treatment (BIOPER) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-27.

Abstract 3390: Predictive and prognostic value of circulating tumor DNA (ctDNA) compared to circulating tumor cells (CTC) in a prospective cohort of metastatic breast cancer patients: The UCBG COMET trial

Abstract Background: In metastatic breast cancer (MBC), monitoring circulating tumor DNA (ctDNA) can detect mutation associated with resistance to treatment and its variations reflect changes in tumor burden. We prospectively monitored CTC and ctDNA during first line chemotherapy for MBC. Methods: The French cohort COMET is a prospective study including first line HER2- negative pts receiving weekly paclitaxel and bevacizumab. Blood samples were obtained at baseline (BL) and before the second cycle of chemotherapy (C2). ctDNA was analyzed by targeted resequencing (custom panel 220kb) SNV (28 genes + 8 promoters and CNA (18 genes). Results: For ctDNA, out of 196 pts analyzed, 147 had at least one somatic mutation (SNV) detected in plasma (75%). Despite no complete overlap, 24 pts (12%) had no CTC nor ctDNA detected at baseline. Including Copy Number Variation analysis (CNV), the number of patients without detectable ctDNA at baseline could be reduced to 18 (9%). The average number of mutations per pt was 2.4 (range 1 to 9). Median Allelic Frequency (MAF) was 9.1%. Most commonly mutated genes were TP53 and GATA3 with 14% and 7% of all mutations, respectively. TP53 mutations were detected in 31 % of patients and were associated with a shorter progression-free and overall survival. PI3KCA mutations were detected in 23.2% of the pts, were correlated with presence of bone metastasis and had no prognostic value. ESR1 was mutated in 10.6% of the pts, restricted to the ER+ subgroup and had no impact on overall survival. At baseline, CTC and ctDNA levels were correlated (r = 0.40, p &amp;lt; 0.0001). CTC detection was correlated with TP53 mutations detection but not with mutations PI3KCA or ESR1. Only 68 pts (36%) had detectable ctDNA at C2 with a MAF of 2% (0.3%-40%). 52.8% of patients positive for ctDNA at D1C1 became negative at D1C2 and only one negative at baseline became positive at C2. Correlation rate with CTC was the same after one cycle of chemotherapy (r = 0.40). Median follow-up was 53 months and median OS was 32 months. At multivariate analysis, triple negative status, detectable ctDNA at C2, CTC ≥5 at C2 and grade 3 on primary tumor were independent prognostic for OS. Conclusion: Early decrease of CTC and/or ctDNA after one cycle of chemotherapy are independent predictive markers of favorable outcome. Compared to CTC, ctDNA allows monitoring of tumor burden during chemotherapy and specific detection of targetable mutations as PI3KCA, HER2 or BRCA. Citation Format: Jean-Yves Pierga, Amanda Silveira, Elodie Girard, Veronique Lorgis, Marie-Laure Tanguy, Benoit Albaud, Olivier Tredan, Coraline Dubot, Caroline Hego, William Jacot, Anthony Goncalves, Marc Debled, Christelle Levy, Jean-Marc Ferrero, Christelle Jouannaud, Marie-Ange Mouret-Reynier, Florence Dalenc, Sylvain Baulande, Jerome Lemonnier, Frederique Berger, Francois-Clement Bidard, Charlotte Proudhon. Predictive and prognostic value of circulating tumor DNA (ctDNA) compared to circulating tumor cells (CTC) in a prospective cohort of metastatic breast cancer patients: The UCBG COMET trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3390.

Phase Ib trial to evaluate safety and anti-tumor activity of the AKT inhibitor, ipatasertib, in combination with endocrine therapy and a CDK4/6 inhibitor for patients with hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC) (TAKTIC).

1066 Background: The cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), with an anti-estrogen, are the standard of care for HR+/HER2- MBC. Insights from patient biopsies and preclinical analysis suggest that AKT1 activation can provoke CDK4/6i resistance. We hypothesized that targeting AKT1 following CDK4/6i progression may provide clinical benefit. Methods: TAKTIC is an open-label phase Ib trial exploring the combination of the AKT1 inhibitor, ipatasertib (ipat), with an aromatase inhibitor (Arm A), fulvestrant (Arm B), or the triplet combination (Arm C) of fulvestrant + ipat + palbociclib (palbo). The primary objective is to evaluate the safety and tolerability of ipat in combination with endocrine therapy +/- CDK4/6i. Key inclusion criteria include unresectable HR+/HER2- MBC; at least 1 prior therapy for MBC including any CDK4/6i; up to 2 prior lines of chemotherapy for MBC (no limit on prior endocrine therapy). Here, we present an interim analysis from the triplet combination (Arm C). Results: As of 1/31/2020, 25 pts have enrolled, including 12 on Arm C, all of whom received prior CDK4/6i (median no of prior lines = 5.5, range 2-7). Along with fulvestrant, 3 pts received ipat at 200mg + 125mg palbo, 7 pts received 300mg + 125mg palbo, and 2 pts received 400mg + 100mg palbo. To date, 8/12 pts remain on treatment including 2 with partial response, 3 with stable disease, 3 with restaging studies pending and 4 with progressive disease. The triplet combination was well tolerated. Grade 3 toxicities included reduced WBC (8/12), reduced neutrophil count (11/12), reduced lymphocyte count (2/12) and single instances of transaminitis, rash, and reduced platelet count. The only grade 4 toxicity was reduced neutrophil count (4/12). There were no DLTs observed and no discontinuations due to toxicity. Mean steady state pharmacokinetic parameters for ipat were similar to historical data from single agent trials suggesting that combined treatment with palbo + fulvestrant did not affect the pharmacokinetics of ipat. Updated analysis will be presented at the meeting. Conclusions: The triplet combination of endocrine therapy with CDK 4/6i and AKTi appears to be well tolerated in heavily pre-treated pts, with a subset demonstrating signs of clinical benefit. The trial demonstrates how insights into the molecular mechanisms of CDK4/6i resistance could be leveraged into actionable therapeutic regimens for HR+/HER2- MBC. Clinical trial information: NCT03959891 .

Real-world clinical effectiveness and safety of olaparib monotherapy in HER2-negative gBRCA-mutated metastatic breast cancer: Phase IIIb LUCY interim analysis.

1087 Background: OlympiAD (NCT02000622) demonstrated the benefit of olaparib over standard of care in patients (pts) with HER2-negative (HER2-) metastatic breast cancer (MBC) and germline BRCA mutations (gBRCAm). LUCY (NCT03286842) aimed to provide additional data on the real-world effectiveness and safety of olaparib monotherapy in this setting. Methods: This Phase IIIb, open-label, single-arm study of olaparib 300 mg twice-daily, enrolled pts with HER2- gBRCAm MBC who had received a taxane and/or anthracycline in the (neo)adjuvant/metastatic setting, and ≤2 lines of chemotherapy for MBC. Hormone receptor-positive (HR+) pts had progressed on prior endocrine therapy (ET), and further ET was considered unsuitable. Primary endpoint: investigator-defined progression-free survival (PFS). Secondary endpoints: overall survival, time to first subsequent therapy or death (TFST), and investigator-assessed clinical response rate (CRR). The interim analysis was planned after 160 PFS events. Results: From Oct 2018-Sept 2019, 252 pts were enrolled (160 sites, 15 countries; mean age 46.2 [range 22-75] years; 73.4% ECOG PS 0). Median total treatment duration: 7.9 months (mo; range 0.2-20.0). Median PFS: 8.1 mo (95% confidence interval [CI] 6.9, 8.7; 166 events [65.9%]). Clinical trial information: NCT03286842 . Median TFST: 9.7 mo (95% CI 8.7, 11.1). CRR: 48.6% (95% CI 42.2, 55.0). Adverse events (AEs) in &gt;20% of pts (all grades): nausea, anemia, asthenia, vomiting, and fatigue. 24.6% of pts reported a grade ≥3 AE, including anemia (n=33 [13.1%]). 4.4% of pts had an AE leading to treatment discontinuation. Conclusions: Interim results in this real-world population of pts with HER2- gBRCAm MBC were consistent with the OlympiAD study, and support olaparib as a chemotherapy-free alternative treatment for pts with gBRCAm advanced BC. [Table: see text]

Abstract OT2-08-01: A phase 1b trial to evaluate safety and anti-tumor activity of the AKT inhibitor, ipatasertib, in combination with endocrine therapy with/without CDK 4/6 inhibitor for patients with hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC) (TAKTIC)

Abstract Background: The cyclin-dependent 4/6 inhibitors (CDK4/6i), in combination with an anti-estrogen, have emerged as the standard of care for patients with HR+/HER2- MBC. While only limited insight exists into the molecular factors that drive progression, emerging evidence suggests that activation of AKT1 may provoke resistance in a subset of patients. Overexpression of AKT1 also conveys resistance in HR+/HER2- breast cancer cells in vitro. AKT1 plays a well-established role in promoting tumor progression and metastasis. Targeting AKT1 following progression on CDK4/6i may provide durable clinical benefit in HR+/HER2- MBC. Trial Design: This is an open-label phase Ib trial with three arms - Arm A includes fulvestrant + ipatasertib and Arm B includes an aromatase inhibitor (AI) + ipatasertib. Arm C includes fulvestrant + ipatasertib + palbociclib. Arm A and B are dose-expansion cohorts while Arm C is a dose-escalation (standard 3+3 design) followed by subsequent dose-expansion. Eligibility Criteria: Key inclusion criteria include the presence of locally advanced/unresectable and metastatic HR+/HER2- breast cancer; postmenopausal status or pre/peri-menopausal status s/p oophrectomy or GNRH agonist; at least one prior therapy for MBC including any CDK4/6i; adequate performance status (ECOG 0-2); and adequate bone marrow and hepatic function. Stable CNS metastatic disease and up to two prior lines of chemotherapy for MBC are allowed (no limit on number of prior lines of endocrine therapy). Key exclusion criteria include prior use of fulvestrant (for Arm A); any prior intolerable toxicity with CDK4/6i (for Arm C); prior exposure to an AKT inhibitor in any setting; active CNS disease; concurrent use of specific CYP3A4 inhibitors or inducers; poorly controlled intercurrent illness; and pregnancy or active child-bearing potential. Specific Aims: The primary objective of this study is to evaluate the safety and tolerability of ipatasertib in combination with endocrine therapy (aromatase inhibitor or fulvestrant) with or without CDK4/6i in patients with HR+/HER2- MBC who have received prior CDK 4/6i. Secondary objectives include assessment of objective response rate (ORR), clinical benefit rate (CBR), and progression free survival (PFS). Exploratory objectives include next generation sequencing of solid tumor biopsies and cfDNA along with immunohistochemical analysis of tumor biopsies to identify genomic and protein-based predictors of response and resistance. Statistical Methods: Arms A and B constitute dose-expansion cohorts to confirm the safety/tolerability of ipatasertib use with anti-estrogens and evaluate preliminary efficacy. A dose-limiting toxicity (DLT) rate of &amp;lt;33% will constitute success for future doublet development. There will be an initial enrollment phase (n=6); if ≤ 2 DLTs occur, total enrollment will be pursued (n=15 for each arm). Arm C is a standard 3+3 phase I trial design to establish a recommended phase II dose (RP2D) and maximum tolerated dose (MTD). Once the doses are established, an expansion cohort will be pursued (n=15) to confirm safety of the triplet and evaluate preliminary evidence of efficacy. Present and Target Accrual: Anticipated accrual for Arms A+B will be n=15 (each). Arm C enrollment will be n=15-30 pending establishment of RP2D/MTD prior to dose expansion. Current enrollment n=4, since study activation in May 2019. Citation Format: Seth A. Wander, Dejan Juric, Laura M. Spring, Neelima Vidula, Maureen Beeler, Karleen Habin, Elene Viscosi, Lauren Scarpetti, Elizabeth Tripp, Rachel Hepp, Beverly Moy, Steven J. Isakoff, Leif W. Ellisen, Aditya Bardia. A phase 1b trial to evaluate safety and anti-tumor activity of the AKT inhibitor, ipatasertib, in combination with endocrine therapy with/without CDK 4/6 inhibitor for patients with hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC) (TAKTIC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-08-01.

Abstract OT2-03-03: Evaluation of talazoparib, a PARP inhibitor, in patients with somatic BRCA mutant metastatic breast cancer: Genotyping based clinical trial

Abstract Background: Metastatic breast cancer (MBC) accounts for most breast cancer deaths. In 2018, two Poly(ADP-ribose) polymerase (PARP) inhibitors, olaparib and talazoparib, were approved for the treatment of MBC patients with germline BRCA1 or 2 mutations based on the OlympiAD and EMBRACA trials (Robson, NEJM, 2017 and Litton, NEJM, 2018), which demonstrated improvement in progression-free survival (PFS) with PARP inhibitors compared to chemotherapy. These landmark findings have triggered much interest in studying PARP inhibitors in MBC, but germline BRCA mutations only account for 5-10% of breast cancer patients. A critical question is whether PARP inhibitors may also be beneficial in MBC with somatic BRCA1 or 2 mutations, similar to somatic BRCA mutant ovarian cancer where they are effective(George, Oncotarget, 2017). Liquid biopsies via circulating cell-free DNA (cfDNA) may unveil somatic mutations. We previously demonstrated (Vidula, SABCS, PD1-13, 2017) that a subset of MBC patients have detectable somatic cfDNA BRCA1 or 2 mutations, in the absence of germline BRCA mutations, highlighting the role of liquid biopsies for detection of somatic BRCA mutations in MBC. Based on our preliminary data, we hypothesize that we can utilize liquid biopsies to detect somatic BRCA1 or 2 mutations and guide therapy selection with a PARP inhibitor in patients with MBC. Methods: In this single arm phase II clinical trial we will evaluate the efficacy and safety of a PARP inhibitor, talazoparib, in patients with somatic BRCA mutant MBC (N=30). Patients will undergo cfDNA screening to identify cfDNA somatic BRCA1 or 2 deleterious mutations. Patients without known BRCA germline mutations who have cfDNA BRCA1 or 2 mutations will be enrolled at the Massachusetts General Hospital and University of California San Francisco. The study will enroll both patients with hormone receptor positive/HER2 negative breast cancer and triple-negative breast cancer whose disease has progressed on at least 1 prior line of endocrine therapy and at least 1 prior line of chemotherapy for MBC, respectively. Patients may have received any number of prior lines of therapy. Eligible patients will be treated with talazoparib 1 mg daily until progression (evaluated with serial CT chest/abdomen/pelvis and bone scan) or unacceptable toxicity. The primary endpoint is to determine PFS by RECIST 1.1. Patients will be enrolled in a two-stage design, providing 80% power to demonstrate that the treatment is associated with “success” (PFS &amp;gt; 12 weeks) in ≥53% patients (4% alpha). Secondary endpoints include objective response rate and safety/tolerability (NCI CTCAE v5.0). Serial cfDNA will be collected at baseline and during treatment to evaluate for changes in the BRCA cfDNA mutant allelic fraction in response to therapy. The impact of pre-existing resistance mutations in baseline cfDNA, particularly BRCA reversion mutations that can occur with prior platinum exposure (Weigelt, CCR, 2017), on outcomes will be studied. Paired liquid biopsies (pre- and post-treatment) will be compared to generate hypotheses about potential novel targets for future combination studies with talazoparib to improve response(exploratory objective). This study may help expand the applicability of talazoparib in MBC. This study was activated in July 2019. Funding support for the clinical trial is provided by a Pfizer ASPIRE award. (NCT03990896). Citation Format: Neelima Vidula, Nora Horick, Erin Basile, Sara Sutherland, Ruth Fax, Daniel Haber, Leif Ellisen, Hope S. Rugo, Aditya Bardia. Evaluation of talazoparib, a PARP inhibitor, in patients with somatic BRCA mutant metastatic breast cancer: Genotyping based clinical trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-03-03.

Randomized phase II study of eribulin mesylate (E) with or without pembrolizumab (P) for hormone receptor-positive (HR+) metastatic breast cancer (MBC).

1004 Background: Studies of checkpoint inhibitor monotherapy show only modest activity in HR+ MBC. We report data from the first randomized study comparing E plus P versus E alone in HR+/HER2- MBC. Methods: Eligible patients (pts) had HR+/HER2- MBC, ≥2 lines of hormonal therapies and 0-2 lines of chemotherapy for MBC. Pts were randomized 1:1 to E 1.4mg/m2 intravenously (IV) on d1 and d8 with P 200 mg/m2 IV on d1 of a 21-day cycle (Arm A) or E alone (Arm B). At time of progression, pts in arm B could crossover and receive P alone. Primary endpoint was progression-free survival (PFS). Key secondary endpoints were: objective response rate (ORR) and overall survival (OS). Exploratory analyses assessed the association between PFS and PD-L1 status, tumor-infiltrating lymphocytes (TILs), neutrophil-lymphocyte ratio (NLR), tumor mutation burden (TMB), and genomic alterations by next generation sequencing on archival tissue. Results: 88 pts initiated protocol therapy; the median age was 58, median prior lines of chemotherapy 1, prior lines of hormonal therapy 2. Median follow-up was 6.3 months. Median PFS and ORR were not different between Arms A and B (PFS 4.1 vs 4.2 months p = 0.38; ORR 25% and 34% respectively (p = 0.49). 14 patients initiated crossover treatment with pembrolizumab; 1 patient experienced a PR (ORR 7%). All-cause AEs occurred in 100% of pts (G3-4, 54.6%) including 2 treatment related deaths on Arm A, both from known AEs attributed to both drugs. PD-L1 assay was performed in 65 pts: 24 (36.9%) had PD-L1 positive ( &gt; 1% with 22C3, centrally tested) tumors. PD-L1 status, TILs, NLR, TMB, and genomic alterations were not associated with PFS (Table). Updated data, including OS and genomic results, will be presented. Conclusions: Among pts with HR+/HER2- MBC, the combination of E and P was not associated with longer PFS than E alone in the ITT or PD-L1+ population, though the PD-L1+ subgroup had very limited power to assess P benefit. Clinical trial information: NCT03051659. [Table: see text]