Supplementary Table S1. Selection Criteria; Supplementary Table S2. Recruiting Sites, Principal Investigators, and Patient Numbers; Supplementary Table S3. Study Members; Supplementary Table S4. List of antibodies used for immunohistochemistry analysis; Supplementary Table S5. Cutoff values for the quantitative assessment of biomarkers by immunohistochemistry; Supplementary Table S6. The 77-gene panel by the AVENIO ctDNA Expanded Kit used for targeted NGS on plasma samples; Supplementary Table S7. Representativeness of study participants; Supplementary Table S8. Association of baseline clinical and pathologic characteristics of trial participants included in the efficacy analysis with clinical benefit; Supplementary Table S9. Relative dose intensity and drug discontinuation; Supplementary Table S10. All causality AEs according to NCI-CTCAE version 4.0.3 occurring in at least 5% of the patients; Supplementary Table S11. Adverse events of special interest according to NCI-CTCAE version 4.0.3; Supplementary Table S12. Baseline clinical and pathologic characteristics of trial participants included in the retinoblastoma and signature subsets; Supplementary Table S13. Tumor best response according to RECIST version 1.1 of trial participants included in the retinoblastoma and signature subsets; Supplementary Table S14. Association of biomarkers and composite signatures with clinical benefit.

Summary of all adverse events according to NCI-CTCAE version 4.0.3.

Kaplan-Meier analyses of investigator-assessed progression-free survival and overall survival in the efficacy population.

The level of mutant and wild-type circulating DNA in baseline plasma samples by patient.

(A) Longitudinal ctDNA quantification during study treatment. (B) Variations of ctDNA during study treatment. (C, D) Kaplan-Meier analyses of investigator-assessed progression-free survival according to the ctDNA detection after 2 weeks and 12 weeks of study treatment.

Abstract Changes occurring in host-associated microbial communities (i.e., the microbiota) may modulate responses to checkpoint blockade immunotherapy. We previously showed that anti-programmed cell death protein 1, pembrolizumab, plus microtubule-targeting chemotherapy, eribulin, has encouraging antitumor activity in previously pre-treated hormone receptor (HR)-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer patients in the KELLY phase II study (NCT03222856). Faecal (58) and saliva (67) samples were prospectively collected at baseline, after three treatment cycles, and end of treatment from a subset of 28 patients included in this trial. Shotgun metagenomic and 16S ribosomal ribonucleic acid gene amplicon sequencing, and bioinformatics and statistical approaches were used to characterize faecal and oral microbiota profiles. Overall, treatment did not cause significant gut or oral microbiota perturbations, indicating limited drug-related microbial toxicity. Dominant gut microbiota genera included Bacteroidesand Faecalibacterium, with a common oral microbe, Prevotella, also present. Several typical oral microbes i.e., Prevotella and Streptococcus, were observed in both saliva and faecal samples, suggesting potential translocation along the oral-gut axis. Further analysis appeared to show that clinical benefit was driven, in part, by gut-associated Bacteroides fragilis and baseline oral-associated Streptococcus with an abundance ≥40%. We also observed that cell-free supernatant from Bacteroides fragilis NCTC 9343 stimulated lactate dehydrogenase release, in a dose-dependent manner from the MCF-7 (HR-positive/HER2-negative) breast cancer cell line. These data suggest that certain gut and oral microbiota members influence efficacy of new combinatory anti-breast cancer therapies, which may in part be mediated via microbial metabolites.

Aim: Changes in host-associated microbial communities (i.e., the microbiota) may modulate responses to checkpoint blockade immunotherapy. In the KELLY phase II study (NCT03222856), we previously demonstrated that pembrolizumab [anti-programmed cell death protein 1 (PD-1)] combined with eribulin (plus microtubule-targeting chemotherapy) showed encouraging antitumor activity in patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC) who had received prior treatments. Methods: A total of 58 fecal and 67 saliva samples were prospectively collected from a subset of 28 patients at baseline (BL), after three treatment cycles, and end of treatment. Shotgun metagenomics, 16S rRNA gene amplicon sequencing, and bioinformatics and statistical approaches were used to characterize fecal and oral microbiota profiles. Results: Treatment caused no substantial perturbations in gut or oral microbiota, suggesting minimal drug-related microbial toxicity. Bacteroides and Faecalibacterium were the dominant gut microbiota genera, while Prevotella and Streptococcus were present in both oral and gut samples, highlighting potential gut-oral microbial interactions. Additionally, clinical benefit (CB) appeared to be associated with gut-associated Bacteroides fragilis (B. fragilis ) and a BL oral abundance of Streptococcus ≥ 30%. Notably, B. fragilis NCTC 9343 supernatant induced dose-dependent lactate dehydrogenase (LDH) release from the MCF-7 (HR-positive/HER2-negative) BC cell line. Conclusion: These findings suggest that specific gut and oral microbiota may modulate the effectiveness of combinatory anti-BC therapies, potentially through the action of microbial metabolites.

Abstract Background The use of PPI among cancer patients (pts) is quite frequent. PAL is an oral, cyclin-dependent kinase 4 and 6 inhibitor recommended to be taken under fed conditions. PAL showed a reduced solubility when gastric pH is >4.5, a level commonly achieved by PPI. Observational, retrospective studies on concomitant PPI with PAL or ribociclib showed a shorter progression-free survival (PFS) among PPI users than nonusers. In the randomized, phase 2 PARSIFAL trial, PAL plus fulvestrant demonstrated no improvement in PFS and overall survival (OS) versus PAL plus letrozole as frontline treatment in HR+/HER2- ABC pts (Llombart-Cussac et al, JAMA Oncol 2021). Here we assessed the impact of PPI on PAL efficacy and safety in pts included in the PARSIFAL study. Methods Pts with endocrine-sensitive HR+/HER2- ABC and no prior therapy in advanced setting were randomly assigned to receive PAL (hard capsule formulation) plus either fulvestrant or letrozole. Pts with ≥1 PPI received over the entire PAL-based regimen were defined as PPI users, or PPI naïve (N-PPI) if no PPI was administered over the whole study treatment. We carried out two analyses considering early PPI users (E-PPI) –composed by pts who were receiving PPI since the PAL-based regimen initiation– and long-term PPI users (LT-PPI) –composed by pts who received PPI over the entire or ≥⅔ of the PAL-based regimen. PPI users defined as neither E-PPI nor LT-PPI were excluded from the analysis to avoid biases due to the PPI limited exposition. PFS, OS, and safety were compared among groups. Landmark analysis at 3, 6, 12, 18, 24, and 30 months (mo) was used for survival estimates conditional on surviving to certain time points and adjust for immortality bias in comparison between N-PPI and PPI users. Analyses were adjusted by stratification factors and patient characteristics. Results Of 486 pts included in the study, 325 (66.9%) were N-PPI. Among 161 (33.1%) PPI users, 64 (13.2%) were E-PPI and 91 (18.7%) were LT-PPI. Omeprazole was the most prescribed PPI in 80.7% (130 of 161) of PPI users. Median exposition to PPI for PPI users, E-PPI, and LT-PPI was 13.6, 15.9, and 19.4 mo, respectively. Compared with N-PPI, E-PPI and LT-PPI were older (median age, 60.5 vs 66.5 vs 67.0 years, respectively; P< 0.001) and had a worse functional status (ECOG PS of 0, 60.0% vs 34.0% vs 43.0%, respectively; P=0.002). Median follow-up for the whole population was 32 mo. Median PFS was 28.7 mo in N-PPI compared with 23.0 mo in E-PPI (HR 1.5; 95%CI 1.1–2.2; P=0.024) and 23.0 mo in LT-PPI (HR 1.4; 95%CI 1.0–1.9; P=0.035). Both PPI groups had poorer median PFS than N-PPI by landmark analysis at 3 and 12 mo. Subgroup analysis showed a consistent trend regardless of endocrine partner. Three-year OS rate was 81.1% in N-PPI compared with 63.5% in E-PPI (HR 2.2; 95%CI 1.3–3.7; P=0.003) and 62.0% in LT-PPI (HR 2.1; 95%CI 1.4–3.4; P=0.001). Both PPI groups had poorer 3-year OS rate than N-PPI by landmark analysis at 3, 6, 12, and 18 mo. Grade ≥3 hematological adverse events (AEs) occurred in 71.7% (233 of 325 pts) of N-PPI compared with 57.8% (37 of 64 pts; P=0.021) of E-PPI and 54.9% (50 of 91 pts; P=0.003) of LT-PPI. Dose reductions and delays due to hematological AEs were reported in 70.8% (230 of 325 pts) of N-PPI compared with 56.3% (36 of 64 pts; P=0.018) of E-PPI and 52.7% (48 of 91 pts; P=0.002) of LT-PPI. At 3 mo, 45.8% (149 of 325 pts) of N-PPI required a dose reduction or delay due to hematological AEs compared with 39.1% (25 of 64 pts; P=0.42) of E-PPI. Conclusions Early and sustained coadministration of PPI with PAL and endocrine therapy were associated with lower efficacy, hematological toxicities, and dose modifications. Despite the post-hoc nature of the study, these findings suggest pharmacokinetic interactions between PPI and PAL capsules. Further confirmatory studies including the tablet formulation of PAL, which is expected to assure its optimal absorption, are needed. Citation Format: Serena Di Cosimo, José Manuel Pérez-García, Meritxell Bellet Ezquerra, Florence Dalenc, Miguel Gil Gil, Manuel Ruiz Borrego, Joaquín Gavilá, Miguel Sampayo-Cordero, Elena Aguirre, Peter Schmid, Frederik Marmé, Joseph Gligorov, Andreas Schneeweiss, Joan Albanell, Pilar Zamora, Duncan Wheatley, Eduardo Martínez De Dueñas, Vicente Carañana, Kepa Amillano, Andrea Malfettone, Javier Cortés, Antonio Llombart-Cussac. PD13-10 Impact of Proton Pump Inhibitors (PPI) on Palbociclib (PAL) Outcomes in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer (HR+/HER2- ABC): Exploratory Analysis of the PARSIFAL 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 PD13-10.

De-escalation trials in oncology evaluate therapies that aim to improve the quality of life of patients with low-risk cancer by avoiding overtreatment. Non-inferiority randomized trials are commonly used to investigate de-intensified regimens with similar efficacy to that of standard regimens but with fewer adverse effects (ESMO evidence tier A). In cases where it is not feasible to recruit the number of patients needed for a randomized trial, single-arm prospective studies with a hypothesis of non-inferiority can be conducted as an alternative. Single-arm studies are also commonly used to evaluate novel treatment strategies (ESMO evidence tier B). A single-arm design that includes both non-inferiority and superiority primary objectives will enable the ranking of clinical activity and other parameters such as safety, pharmacokinetics, and pharmacodynamics data. Here, we describe the statistical principles and procedures to support such a strategy. The non-inferiority margin is calculated using the fixed margin method. Sample size and statistical analyses are based on the maximum likelihood method for exponential distributions. We present example analyses in metastatic and adjuvant settings to illustrate the usefulness of our methodology. We also explain its implementation with nonparametric methods. Single-arm designs with non-inferiority and superiority analyses are optimal for proof-of-concept and de-escalation studies in oncology.

BACKGROUND:Trastuzumab deruxtecan (T-DXd) has shown durable antitumor activity in pretreated patients with HER2-positive advanced breast cancer (ABC), but its efficacy has not yet been evaluated in patients with active brain metastases (BMs). DEBBRAH aims to assess T-DXd in patients with HER2-positive or HER2-low ABC and central nervous system involvement.METHODS:This ongoing, five-cohort, phase II study (NCT04420598) enrolled patients with pretreated HER2-positive or HER2-low ABC with stable, untreated, or progressing BMs, and/or leptomeningeal carcinomatosis. Here, we report findings from HER2-positive ABC patients with non-progressing BMs after local therapy (n = 8; cohort 1), asymptomatic untreated BMs (n = 4; cohort 2), or progressing BMs after local therapy (n = 9; cohort 3). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was 16-week progression-free survival (PFS) for cohort 1 and intracranial objective response rate (ORR-IC) for cohorts 2 and 3.RESULTS:As of October 20, 2021, 21 patients received T-DXd. In cohort 1, 16-week PFS rate was 87.5% (95%CI, 47.3-99.7; P < .001). ORR-IC was 50.0% (95%CI, 6.7-93.2) in cohort 2 and 44.4% (95%CI, 13.7-78.8; P < .001) in cohort 3. Overall, the ORR-IC in patients with active BMs was 46.2% (95%CI, 19.2-74.9). Among patients with measurable intracranial or extracranial lesions at baseline, the ORR was 66.7% (12 out of 18 patients; 95%CI, 41.0-86.7), 80.0% (95%CI, 28.4-99.5) in cohort 1, 50.0% (95%CI, 6.7-93.2) in cohort 2, and 66.7% (95%CI, 29.9-92.5) in cohort 3. All responders had partial responses. The most common adverse events included fatigue (52.4%; 4.8% grade ≥3), nausea (42.9%; 0% grade ≥3), neutropenia (28.6%; 19% grade ≥3), and constipation (28.6%; 0% grade ≥3). Two (9.5%) patients suffered grade 1 interstitial lung disease/pneumonitis.CONCLUSIONS:T-DXd showed intracranial activity with manageable toxicity and maintained the quality of life in pretreated HER2-positive ABC patients with stable, untreated, or progressing BMs. Further studies are needed to validate these results in larger cohorts.

Background: The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) significantly improved survival outcomes of HER2-low advanced breast cancer (ABC) patients (pts) compared to standard chemotherapy in the DESTINY-Breast04 trial. DEBBRAH is assessing the efficacy and safety of T-DXd in HER2[+] and HER2-low ABC pts with a history of brain metastases (BM) and/or leptomeningeal carcinomatosis (LMC); here, we report results of HER-low ABC pts. Methods: DEBBRAH (NCT04420598) is a multicenter, open-label, five-cohort, non-comparative, phase 2 study across 18 hospitals in 2 countries. A total of 39 pts aged ≥18 years with pretreated HER2[+] or HER2-low ABC with stable, progressing, or untreated BM and/or LMC, were enrolled in 5 cohorts: (1) HER2[+] ABC with non-progressing BM after radiotherapy and/or surgery; (2) HER2[+] or HER2-low ABC with asymptomatic untreated BM; (3) HER2[+] ABC with progressing BM after local treatment; (4) HER2-low ABC with progressing BM after local treatment; (5) HER2[+] or HER2-low ABC with LMC. Pts received 5.4 mg/kg T-DXd intravenously once every 21 days until disease progression, unacceptable toxicity, or consent withdrawal. Primary endpoint for cohorts 2 and 4 was intracranial overall response rate (ORR-IC) according to RANO-BM. Secondary endpoints included overall response (ORR) according to RECIST v1.1, progression-free survival (PFS), duration of response (DoR), clinical benefit rate (CBR); and safety and tolerability as per NCI-CTCAE v.5.0. Primary analysis is the estimation of ORR-IC (H0: ORR-IC ≤5%; H1: ORR-IC ≥40%) based on the one-sided binomial exact test. Sample size was planned to attain an 80% power at a nominal α level of 0.05 in each cohort. Results from cohort 2 should be considered descriptive since formal testing has to be performed in the whole cohort of pts with HER2[+] or HER2-low ABC and asymptomatic untreated BM. Results: From Oct 23, 2020, through Feb 15, 2022, 6 pts and 7 pts were allocated into cohorts 2 and 4, respectively. One patient with LMC included in cohort 4 was excluded from analysis. Median age was 54 (range 40–73) years. Median number of previous lines of therapy for advanced disease was 7 (range, 4-8) and 3 (range, 2-4) for cohorts 2 and 4, respectively. Median follow-up was 9.5 months (range, 1.6-15.7). At data cutoff (Apr 29, 2022), no patient of cohort 2 and 3 (50.0%) pts of cohort 4 remained on therapy. In cohort 2, ORR-IC was 66.7% (4 of 6 pts had intracranial partial response [PR]; 95% CI, 22.3–95.7). In cohort 4, ORR-IC was 33.3% meeting the primary endpoint (2 of 6 pts had intracranial PR; 95% CI, 4.3–77.7; P = .033). Overall, ORR-IC in all pts was 50% (6 of 12 pts; 95% CI, 21.1-78.9) and CBR was 66.7% (8 of 12 pts; 95% CI, 34.9-90.1). Combining pts with measurable intracranial or extracranial disease from cohorts 2 and 4, ORR, CBR and median DoR were 41.7% (5 of 12 pts; 95% CI, 15.2–72.3), 50.0% (6 of 12 pts; 95% CI, 21.1–78.9), and 7.2 months (95% CI, 2.5-16.4), respectively. Median PFS was 5.7 months (95% CI, 4.7-NA) among these pts. The most common treatment emergent adverse events (TEAEs) of any grade (G) were fatigue (58.3%; 8.3% G≥3) and nausea (50.0%; 0% G≥3). Two (16.7%; 0% G≥3) cases of interstitial lung disease/pneumonitis were reported. Serious unrelated TEAEs occurred in 2 (16.7%) of 12 pts; 1 case of general pain (G3) and 1 case of venous embolism (G5) that led to death. There were no drug-related deaths due to TEAEs. Conclusions: T-DXd showed a preliminary antitumor activity in pretreated HER2-low ABC pts with asymptomatic untreated or progressing BM after local treatment. The substantial response of BM to T-DXd in this setting is promising and warrants further investigation. Citation Format: José Manuel Pérez-García, Marta Vaz Batista, Patricia Cortez-Castedo, Manuel Ruiz Borrego, Juan Miguel Cejalvo, Juan de la Haba-Rodríguez, Laia Garrigós, Fabriccio Racca, Sonia Servitja, Salvador Blanch, Maria Gión, Mónica Nave, Adela Fernández, Alejandro Martínez-Bueno, Antonio Llombart-Cussac, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortés, Sofía Braga. Trastuzumab Deruxtecan in patients with Unstable Central Nervous System Involvement from HER2-Low Advanced Breast Cancer: The DEBBRAH 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 PD7-02.

Background: Olaparib (O) is approved for the treatment of HER2[-] patients (pts) with early or metastatic breast cancer and a germline BRCA mutation. Nevertheless, there is no evidence that HER2[+] tumors are resistant to PARPi. Preclinical data support that HER2[+] cells are sensitive to PARPi and strongly suggest that PARP inhibition augments the efficacy of trastuzumab (T). To test whether PARPi is synergistic with anti-HER2 therapy, the OPHELIA study has assessed the efficacy and safety of O in combination with T in pts with HER2[+] germinal BRCA-mutated advanced breast cancer (ABC). Methods: OPHELIA (NCT03931551) is an open-label, multicenter, single-arm, phase II trial. The study enrolled pts aged ≥18 years diagnosed of HER2[+] ABC with germinal deleterious mutations in BRCA1 or BRCA2 who had received at least one prior systemic regimen for advanced disease (including a pertuzumab- or trastuzumab emtansine based regimen). Pts received O (300 mg oral, twice daily) plus T (either loading dose of 8 mg/kg IV infusion, and subsequent 3-weekly doses of 6 mg/kg IV infusion; or 600 mg SC injection, on day 1 of every 21-day cycle) until disease progression, unacceptable toxicity, or consent withdrawal. Primary endpoint was investigator-assessed clinical benefit rate (CBR) for at least 24 weeks as per RECIST v.1.1. Secondary endpoints included overall response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS); and safety and tolerability as per NCI-CTCAE v.5.0. The primary analysis evaluated CBR (H0: ≤5%; H1: ≥30%) based on exact binomial test. Sample size was designed to attain a 90% power at 10% one-sided alpha level. Results: From Mar 25, 2019, through Mar 2, 2022, 5 pts (from a total of 42 pts evaluated) were enrolled at 17 sites in Spain. Median age was 37.0 (range 32–54) years, 1 (20.0%) patient was male, 4 (80.0%) pts carried germinal BRCA2 mutations, 4 (80.0%) pts had received ≥ 3 advanced disease treatments lines, and 4 (80.0%) pts presented ≥ 2 metastatic sites. At data cutoff (Mar 2, 2022), with a median follow-up of 18.7 months (min: 11.7; max: 22.1), 40.0% of pts remained on therapy. CBR at 24 weeks was 80.0% meeting the primary endpoint (4 of 5 pts; 95% CI, 28.4% to 99.5%, p< 0.001). ORR (1 complete and 2 partial responses) was 60.0% (95% CI, 17.4% to 94.7%), and median DoR was 3.8 months (95% CI, 2.5 to 8.3 months). Two (40.0%) pts had PFS events due to disease progression at 5.2 and 1.2 months, respectively. Rest of pts were treated for 5.5, 11.2, and 19.0 months. There were 2 (40.0%) deaths at 14.0 and 18.5 months. The most common non-hematological treatment emergent adverse events (TEAEs) of any grade (G) were fatigue (60.0%; 0% G≥3), nausea (60.0%; 0% G≥3), vomiting (40.0%; 0% G≥3), and back pain (40.0%; 0% G≥3). Anemia (40.0%; 20.0% G≥3) and lymphopenia (40.0%; 20.0% G≥3) were the most frequent hematological TEAEs. One (20.0%) patient discontinued treatment because of a drug-related TEAE (leukopenia). A dose reduction of O was reported in 1 (20.0%) patient. No treatment-related deaths were reported. Conclusions: HER2 overexpression in germline BRCA-mutated ABC is infrequent. The activity observed in these 5 pts indicates that O+T combination might be of help in this group of pts. We strongly believe that randomized data are not needed, and RWE studies might help us to understand the real activity of this combination. Toxicity was as expected. Citation Format: José E. Alés-Martínez, Judith Balmaña, Pedro Sánchez-Rovira, Francisco Javier Salvador Bofill, José Ángel García-Sáenz, Isabel Pimentel, Serafin Morales Murillo, Adela Fernández, Ainhara Lahuerta Martínez, Neus Ferrer, Pilar Zamora, Begoña Bermejo, Tamara Díaz-Redondo, María Helena Lopez-Ceballos, María Galán, Andrea Malfettone, Laura Calabuig, Miguel Sampayo-Cordero, José Manuel Pérez-García, Javier Cortés, Antonio Llombart-Cussac. Olaparib plus Trastuzumab in HER2[+] BRCA-Mutated Advanced Breast Cancer Patients: The OPHELIA Study [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 P4-07-29.

Background Palbociclib has gained a central role in the treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Despite its manageable toxicity profile, venous thromboembolism (VTE) or interstitial lung disease (ILD)/pneumonitis may infrequently occur. Therefore, we provide a comprehensive summary of the safety and tolerability of the combination of endocrine therapy and palbociclib among patients included in the randomized phase 2 PARSIFAL study. Materials and Methods Patients with endocrine-sensitive HR+/HER2- ABC and no prior therapy in an advanced setting (n = 486) were randomly assigned 1:1 to receive fulvestrant-palbociclib (FP) or letrozole-palbociclib (LP). Laboratory tests and the incidence of adverse events (AEs) were recorded at baseline and day 1 of each cycle. Progression-free survival (PFS) was estimated for patients with and without VTE. Results A total of 483 patients were analyzed. Neutropenia, leukopenia, anemia, asthenia, arthralgia, fatigue, and diarrhea were the most frequent AEs in both groups. Febrile neutropenia occurred in 3 (1.2%) patients of the FP group and in 1 (0.4%) patient in the LP group. Six (2.5%; 0.4% grade 3) patients in the FP group and 6 patients (2.5%; 0.4% grade 3) in the LP group experienced ILD/pneumonitis. Pulmonary embolism was reported in 12 (5.0%) patients in the FP group and 6 (2.5%) patients in the LP group. Advanced age at baseline was the only factor significantly associated with an increased risk of pulmonary embolism (P < .01). Conclusion The PARSIFAL data confirmed the favorable safety profile of both palbociclib regimens. VTE and ILD/pneumonitis were occasionally reported, and their early detection allowed patients to continue treatment effectively without detriment to efficacy.

1084 Background: A substantial benefit from adding an immune checkpoint inhibitor to chemotherapy (CT) was reported in mTNBC patients (pts) with PD-L1+ tumors. However, many pts still have a poor outcome. ATRACTIB is exploring the synergism between A (anti-PD-L1 antibody) and B (a VEGF-targeted antibody) with P in mTNBC irrespective of PD-L1 status. We report results from protocol-specified SIA. Methods: ATRACTIB is an open-label, single-arm, phase 2 trial (NCT04408118). Pts aged ≥18 years, with unresectable locally advanced or mTNBC, ECOG performance status of 0–1, who had received no prior systemic therapy or ≥12 months since (neo)adjuvant taxane-based CT are eligible. Pts receive A (840 mg IV, days 1, 15) with P (90 mg/m2 IV, days 1, 8, 15), and B (10 mg/kg IV, days 1, 15) on each 28-day cycle until disease progression, unacceptable toxicity, or patient withdrawal. Primary endpoint is investigator-assessed progression-free survival (PFS) as per RECIST v.1.1. Secondary endpoints include objective response and clinical benefit rates, overall survival, and safety. The trial was designed to detect a treatment effect in terms of median PFS (H0: ≤7 months; H1: ≥9.5 months) and 100 pts are needed to attain 80% power at a nominal one-sided α level of 5%. One SIA was planned for evaluating safety as per CTCAE v.5.0 on the first 20 pts who had completed a 3-month follow-up or reached the end of study. Results: From Oct 5, 2020, through Nov 21, 2021, 34 pts were enrolled at 13 sites in Spain and Germany and received at least 1 dose of study treatment. Median age was 57.5 (range 40–84) years, 23 (67.6%) pts had received prior CT for early disease, and 19 (56.0%) had visceral disease. At data cutoff (Sep 30, 2021), 25 (71.4%) pts were still receiving the drug regimen. Adverse events (AEs) led to drug discontinuation in 3 (8.8%) pts. Mean relative dose intensity was 90.2% for A, 96.5% for P, and 95.7% for B. P dose reduction was reported in 7 (20.6%) pts. Five (14.7) pts required a dose delay due to AEs (11.8% for A, 11.8% for P, and 8.8% for B). The most common AEs of any grade (G) were fatigue (47.1%; 8.8% G≥3), diarrhea (38.2%; 0% G≥3), and neurotoxicity (35.3%; 8.8% G≥3). Anemia (20.6%; 0% G≥3) and neutropenia (17.6%; 8.8% G≥3) were the most frequent hematological AEs. AEs of clinical interest (AECI) for B were hypertension (17.6%; 5.9% G≥3) and pulmonary embolism (2.9%; 0% G≥3). AECI for A were pneumonitis (2.9%; 0% G≥3), autoimmune hepatitis (2.9%; 2.9% G≥3), and alanine aminotransferase increased (2.9%; 2.9% G≥3). No treatment-related deaths were reported. Conclusions: The addition of A to P and B as 1L therapy for mTNBC shows a tolerable safety profile which is consistent with known safety profile of each agent without a significant synergistic toxicity. Based on the independent data monitoring committee recommendation, patient recruitment is ongoing. Clinical trial information: NCT04408118.

TPS209 Background: Multiple lines of evidence suggest a crosstalk between androgen receptor (AR) signaling and DNA damage repair (DDR) in prostate cancer. Co-targeting both pathways in mHNPC can result in a clinically relevant synergistic effect. ZZFIRST trial is evaluating the combination of TALA –a poly(ADP-ribose) polymerase inhibitor– and EZ –an AR signaling inhibitor– in mHNPC patients. Methods: This is a multicenter, open-label, randomized, investigator-initiated phase 2 clinical trial. Men aged ≥18 years with histologically confirmed mHNPC, an ECOG performance status of 0-1, and a prostate-specific antigen (PSA) ≥4 ng/mL at enrolment are eligible. Patients must have not received previous systemic treatment for locally advanced or mHNPC. A total of 54 patients will start treatment with EZ 160 mg/day for 2 28-day cycles in addition to standard androgen-deprivation therapy (ADT). Patients are then randomized and stratified based on homologous recombination gene alterations on a 1:2 ratio to either continue EZ 160 mg/day, or to receive EZ 160 mg/day plus TALA 0.5 mg/day. In both arms, patients will continue ADT throughout the trial. Treatment will continue until progressive disease (PD) or unacceptable toxicity. PSA will be determined every 4 weeks and radiological tumor extend will be assessed at screening and every 8 weeks for the 6 initial months of treatment and every 12 weeks thereafter until PD. Primary endpoint is PSA-complete response defined as the percentage of patients with PSA < 0.2 ng/mL at 12 months of therapy. Secondary endpoints include PSA-complete response at any time point and at month 7, PSA response ( < 4 ng/ml) at 7 and 12 months, PSA-progression-free survival (PSA-PFS), radiologic PFS, time to castration resistance based on PSA-PFS and rPFS, and overall survival. Safety will be assessed as per NCI-CTCAE 5.0. Exploratory endpoints include analysis of transcriptional changes in AR and DDR pathways and assessment of genomic signatures on tumor and liquid biopsies collected at baseline, 4 weeks, and PD. An imaging sub-study of whole-body diffusion weighted MRI will help to further study antitumor activity and drug resistance mechanisms. This trial was opened to accrual in July 2020. Currently 44 patients have been enrolled (with 37 randomized by cycle 3 day 1) out of 54 expected. Analysis will be assessed with the exact binomial test. At least 11 patients must maintain PSA < 0.2 ng/mL by 12 months of therapy among 32 evaluable patients in the combination arm to justify further investigation of this strategy. A drop-out rate of 10% has been considered. Clinical trial information: NCT04332744.

Background: Cyclin-dependent kinases 4 and 6 inhibitors in combination with endocrine therapy frequently lead to a complete cell-cycle arrest (CCCA) in luminal EBC. However, the rates of pathological complete response (pCR) or Residual Cancer Burden (RCB) 0-I are modest. The effect of this treatment in terms of molecular downstaging as assessed by a genomic signature more refined than Ki67 remains undetermined. We aimed to assess the biological and clinical activity of letrozole plus palbociclib as neoadjuvant treatment in HR-positive/HER2-negative EBC pts with an Oncotype DX RS ≥18. Methods: DxCARTES was a multicenter, open-label, non-comparative, phase 2 trial across 16 hospitals in Spain. Participants were pre- and post-menopausal women aged ≥18 years with centrally confirmed HR-positive/HER2-negative, Ki67≥20%, stage II-IIIB EBC with a RS ≥18. Eligible pts with baseline RS 18-25 (cohort A) and RS 26-100 (cohort B) received six 28-days cycles of letrozole (2.5 mg QD), ± goserelin if premenopausal, plus palbociclib (125 mg QD, 3/1 schedule) before surgery. Tumor samples were prospectively collected at baseline and surgery for Ki67 and RS assessments. The coprimary endpoint was the proportion of pts in either cohort who achieved RS ≤25 or a pCR (ypT0/is ypN0) at surgery. Secondary endpoints included analysis of RCB, preoperative endocrine prognostic index (PEPI), CCCA (Ki67<2.7%), overall response rate (ORR) as per RECIST v.1.1, and safety as per CTCAE v.5.0. A Simon’s 2-stage design was planned to recruit 33 pts in each cohort. Interim futility analyses were planned with 12 and 18 pts included in cohort A and B, respectively. The analyses were designed to attain an 80% power, with a 10% drop out rate assumption, at a nominal 1-sided α level of 2.5%. The response probabilities for null (H0) and alternative hypotheses (H1) in cohort A were H0: ≤ 72% and H1: ≥ 93%, and in cohort B were H0: ≤ 13% and H1: ≥ 35%, respectively. Results: Between May 5, 2019 to Dec 30, 2019, 67 pts were enrolled and received the study treatment (33 pts allocated to cohort A and 34 pts to cohort B). Pts’ characteristics at diagnosis were well balanced between the two cohorts and of the 67 pts included, 32.8% were premenopausal, 49.3% had axillary node involvement, and median Ki67 was 27% (24-37.5%). A total of 32 pts from cohort A and 33 pts from cohort B were evaluable for the coprimary endpoint. Median duration of treatment was 5.6 months (IQR 5.5-5.8) and median time from the last dose of palbociclib and surgery was 10.5 days (IQR 5.5-14). At surgery, 22 of 32 (68.8%) pts in cohort A and 19 of 33 (57.6%) pts in cohort B had RS ≤25. No pts in cohort A and 2 of 33 (6.1%) pts in cohort B achieved a pCR, meeting the coprimary endpoint in cohort B, but not in cohort A. In cohort A, the proportion of pts with RCB 0-1 was 5.3%, PEPI 0 was 11.1%, and CCCA was 58.1%. In cohort B, the proportion of pts with RCB 0-1 was 23.1%, PEPI 0 was 33.3%, and CCCA was 59.4%. The ORR by breast MRI was 78.1% (25 of 32 pts) in cohort A and 63.6% (21 of 33 pts) in cohort B. The most common grade 3-4 adverse event in both cohorts was neutropenia (23 of 33 [69.7%] pts in cohort A vs 20 of 34 [58.8%] pts in cohort B). No deaths were observed during the study in either cohort. Conclusions: Our results suggest that the neoadjuvant palbociclib plus letrozole activity is independent of the molecular aggressiveness of the disease. Although the prognostic value of molecular downstaging is unknown, a significant proportion of HR-positive/HER2-negative EBC pts with high RS at baseline achieve a pathological or molecular downstaging with this regimen. Further investigation is needed to determine if this strategy could avoid the use of chemotherapy in this population. Citation Format: Antonio Llombart-Cussac, Ángel Guerrero-Zotano, Manuel Ruiz, Begoña Bermejo, Miguel Gil-Gil, Juan de la Haba, Emilio Alba, Vanesa Quiroga, Vicente Carañana, Ander Urruticoechea, Serafín Morales, Meritxell Bellet, Antonio Antón, José Manuel Pérez-García, María Fernández-Abad, Sonia Servitja, Pedro Sánchez-Rovira, Sofia Braga, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortes. Neoadjuvant letrozole plus palbociclib in patients (pts) with hormone receptor (HR)-positive/HER2-negative early breast cancer (EBC) with baseline Ki67 ≥20% and an Oncotype DX Breast Recurrence Score® result (RS) ≥18: DxCARTES [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 P5-16-12.

Background: Endocrine therapy (ET) is the preferred therapy option for patients (pts) with hormone receptor-positive (HR[+]) advanced breast cancer (ABC), except for pts with visceral crisis who often receive chemotherapy to achieve rapid symptom control. Cyclin-dependent kinases 4/6 inhibitors have improved the effectiveness of ET across all subgroups of pts with ABC by targeting potential mechanisms of resistance. An exploratory analysis revealed that the addition of abemaciclib to ET conferred the largest benefit in pts with poor prognostic characteristics (liver metastases, high grade tumors, or progesterone receptor-negative status) [Di Leo, NPJ Breast Cancer 2018; 4: 41]. ABIGAIL aims to provide consistent evidence that abemaciclib plus ET is superior or non-inferior to paclitaxel in terms of early overall response as first-line regimen in HR[+], HER2-negative ABC pts with poor prognosis. Trial Design: This is a multicenter, randomized, open-label, phase 2 trial. Eligible participants are men and women of any menopausal status aged ≥18 years with HR[+], HER2-negative ABC who had no prior systemic therapy in the advanced setting and at least one of the following aggressive disease criteria: (i) Visceral disease; (ii) High histological grade and/or progesterone receptor-negative status; (iii) Lactate dehydrogenase >1.5 × the upper limit of normal; (iv) Relapse while on or within 36 months of completing adjuvant ET. Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease as per RECIST 1.1, and adequate organ function are also required. A total of 160 pts will be randomly assigned (1:1) to receive abemaciclib (300 mg/day orally during each 28-day cycle) plus ET as per investigator’s criteria (either letrozole [2.5 mg/day orally] or fulvestrant [500 mg intramuscularly on days 1, 15 of cycle 1, and on day 1 thereafter], or paclitaxel (90 mg/m² intravenously on days 1, 8, 15). Men and pre-/peri-menopausal women will receive a gonadotropin-releasing hormone agonist if randomized to abemaciclib plus ET. At investigator’s discretion, pts in the paclitaxel arm could receive abemaciclib plus ET at any point after the first 12 weeks or extend chemotherapy for a total of 6 cycles. Randomization will be stratified according to the presence of visceral disease and endocrine therapy. The primary endpoint is 12-week overall response rate (ORR) as per RECIST 1.1. Key secondary endpoints include ORR, clinical benefit rate, 12-week progression-free survival, progression-free survival, time to response, duration of response, overall survival, time to first subsequent therapy, time to second subsequent therapy, and time to first chemotherapy for pts in abemaciclib plus ET arm, patient-reported outcomes, and safety as per NCI-CTCAE 5.0. The sample size assumes the comparison of two proportions in an asymptotical normal test. We expect that 12-week ORR will be higher in the abemaciclib plus ET arm than paclitaxel arm (30% vs. 15%), with the assumption of a 5% non-inferiority margin. Based on a 10% dropout rate, a sample size of 160 pts is necessary to attain 80% power at nominal level of two-sided alpha of 0.05. We will test the superiority of abemaciclib plus ET as compared with paclitaxel if the non-inferiority is achieved. Both analyses, will be conducted with the Newcombe hybrid score method for confidence intervals. This trial was opened to accrual in May 2021. Citation Format: Antonio Llombart-Cussac, Joseph Gligorov, Serena Di Cosimo, Cinta Albacar, Patricia Cortez, Eduardo Martinez-De Dueñas, Ana López, Vicente Carañana, Jacques Medioni, Luigi Cavanna, Marina Elena Cazzaniga, Sofia Braga, Passos Coelho, Miguel Sampayo-Cordero, Andrea Malfettone, José Manuel Pérez-García, Javier Cortes. Phase 2 study of abemaciclib in combination with endocrine therapy with or without paclitaxel induction in patients with hormone receptor-positive, HER2-negative advanced breast cancer and aggressive disease criteria: ABIGAIL [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 OT2-19-06.