Mayer, Erica L.

525 Background: Homologous recombination deficiency (HRD) status can be used to identify patients who are eligible for treatment with DNA damaging agents. Using a 3-biomarker Genomic Instability Score (GIS) threshold of ≥42, studies have previously examined the association between HRD status and outcomes in patients with triple negative breast cancer (TNBC). However, evidence suggests that a GIS threshold of ≥33 may be more appropriate. Here, we conducted an exploratory analysis evaluating the ability of ≥33 and ≥42 GIS thresholds to predict response to platinum-based treatment in patients with TNBC. Methods: Patients across 5 cohorts (TBCRC0301, TBCRC0082, NCT013725793, PrECOG 01054, combined cisplatin cohort4) were included in this analysis if they had a primary TNBC diagnosis, received neoadjuvant platinum-based treatment, had a valid GIS, and had known pathologic complete response (pCR) status. GIS was determined by a combination of loss of heterozygosity, telomeric-allelic imbalance, and large-scale state transitions.4,5 BRCA mutation status was defined by loss of function resulting from a pathogenic variant in BRCA1 or BRCA2. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), were calculated by comparing binary threshold status and binary pCR status. Results: A total of 204 tumors (158 BRCAwt; 33 BRCAm; 13 unknown) were included; pCR to platinum-based treatment occurred in 55 cases (39 BRCAwt; 14 BRCAm; 2 unknown). Sensitivity, specificity, PPV, and NPV were comparable between the ≥33 and ≥42 GIS thresholds, with the ≥33 threshold producing higher sensitivity values. This was true when thresholds were applied to all samples and to BRCAwt samples only (Table). Among patients who achieved pCR in response to platinum-based treatment, 5.5% of patients in the full cohort and 7.7% of those in the BRCAwt cohort had a GIS between 33-41. Conclusions: To ensure that the majority of patients likely to benefit from treatment are identified, a GIS of ≥33 may be the most appropriate threshold to predict response to platinum-based treatment in patients with TNBC; however, a prospective trial will be needed to confirm these findings. Additional studies will be important to determine whether this threshold may be appropriate to determine eligibility for other DNA-damaging agents such as PARP inhibitors. 1. Ann Oncol. 2020;31(11):1518-25 2. J Nucl Med. 2015;56(1):31-7. 3. Breast Cancer Res Treat. 2015;151(3):629-38. 4. Clin Cancer Res. 2016;22(15):3764-73. 5. Breast Cancer Res Treat. 2014;16(6):1-9. [Table: see text]

518 Background: Body Mass Index (BMI) impacts breast cancer risk and prognosis. Conflicting results have been published regarding BMI as a predictive factor for endocrine therapy benefit. CDK4/6 inhibitors (CDK4/6i) in combination with endocrine treatment (ET) are standard-of-care treatments for metastatic hormone receptor-positive breast cancer. In contrast to cytotoxic chemotherapy, CDK4/6i are given at a fixed dose irrespective of BMI or weight. The PALLAS trial compared the combination of the CDK4/6i palbociclib and adjuvant ET to ET alone in the early breast cancer setting. This analysis investigates the impact of BMI on the efficacy and the side effect profile of palbociclib (P) in the PALLAS trial. Methods: In this pre-planned analysis, patients (pts) enrolled in PALLAS were categorized according to BMI as underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5-24.9 kg/m2), overweight (BMI 25-29.9 kg/m2) and obese (³30 kg/m2), respectively. Adverse event differences were assessed with Chi-squared tests. Time to early discontinuation of P was analyzed with Fine and Gray competing risk models. Cox models were used to investigate the association between BMI category and time to invasive disease-free survival (iDFS). Results: Of a total of 5698 pts included in this analysis, 68 (1.2%) were underweight, 2082 (36.5%) normal weight, 1818 (31.9%) overweight and 1730 (30.4%) obese at baseline. Significantly different rates of all grade neutropenia were observed in normal weight, overweight and obese pts with regard to total (88.5%, 85.7% and 74.7%), as well as grade 3 (64.1%, 62.0% and 43.9%) and grade 4 neutropenia (7.0%, 3.6% and 2.0%), respectively. The lower frequency and severity of neutropenia observed in overweight and obese pts was associated with a significant lower treatment discontinuation rate over time when compared to normal weight patients (overweight vs normal weight: HR 0.73 CI 0.63-0.84, p<0.0001, and obese vs normal weight: HR 0.65 CI 0.56-0.75, p<0.0001). In pts treated with P, neutropenia was the primary toxicity leading to treatment discontinuation in 21.1% of normal weight pts, 14.0% of overweight pts and 5.9% obese pts, respectively. Despite these observations, there was no statistically significant improvement in iDFS with the addition of P to ET in any weight category (normal weight HR 0.84 CI 0.63-1.12, overweight HR 1.10 CI 0.82-1.49 and obese HR 0.95 CI 0.69-1.30). Conclusions: This pre-planned analysis of outcomes by BMI in the PALLAS trial demonstrates significantly less frequent and less severe neutropenia in overweight and obese pts compared to those with normal weight, leading to significant lower treatment discontinuation rates. However, no difference in iDFS outcomes by BMI was observed. Additional long-term follow-up will further evaluate whether BMI ultimately impacts outcome. Clinical trial information: NCT02513394.

Abstract Background: As the development and use of oral anticancer agents increases, it is critical to understand patient adherence to both standard and investigational agents. The open label, phase 3 multicenter PALLAS trial investigates whether adding 2 years of the CDK4/6 inhibitor palbociclib (P) to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) over adjuvant ET alone in patients (pts) with HR- positive, HR2-negative, stage II-III breast cancer. Pts were randomly assigned to either Palbociclib (125 mg/day, 3 weeks on, 1 week off, in a 28-day cycle) plus ongoing provider/patient-choice adjuvant ET (P+ET) versus ET alone. We examined patient-reported adherence to ET +/- P during the first two years of study treatment. Methods: Adherence outcomes were measured in English-speaking pts in the U.S., UK, Ireland and Australia, Spanish-speaking pts in Spain and Mexico, and German-speaking pts in Germany and Austria. Adherence measures included drug diaries completed at each cycle, pill counts (for P only) collected at each study visit, and the Morisky Medication Adherence Scale-4 item and the McHorney Adherence Estimator questionnaires completed at cycles 2, 3, 6, 12, 18, and 24 (22 months). Mean adherence for each cycle was defined as the average proportion of prescribed pills taken (via drug diary) across all patients who initiated that cycle. Persistence was defined as the duration of drug initiation to treatment cessation (via drug diary). Generalized estimating equations were used to model the “most adherent” pts on the Morisky (score = 5 vs score &lt;5) and “low risk” for adherence problems on the McHorney (score=0 vs score &gt;0) to compare the average difference between arms over time for ET, adjusting for baseline demographic and clinical variables. Results: 81% (N=4688) of PALLAS pts were included in this analysis. Median persistence to ET was 23.6 months in P + ET (n=2169), 23.7 months in ET alone (2136) and 20.4 months for P (n=2194). The number of pts who initiated each cycle for ET declined over time and was similar between arms; the decline was more marked for P (Table 1). Mean adherence range as measured by drug diary was 98.2-99.3% for ET in P+ET and 98.0 - 99.4% in ET alone; and for P, ranged from 93.4 - 98.8%. The adherence and persistence results were nearly identical whether measured by drug diary or pill count for P. The observed percent “most adherent” for P measured by the Morisky scale ranged from 71.9% - 79.6% and the percent “low risk” for adherence problems measured by the McHorney scale, 64.0% - 73.4%. The percent of pts “most adherent” and “low risk” for adherence problems to ET was higher, on average over time, in the P+ET group compared to ET alone (75% vs 68%, p&lt;0.01; 75% vs 72%, p=.05, respectively). Conclusions: Self-reported mean adherence for both P + ET and ET alone was strikingly high for pts who remained on therapy; persistence was also high with ET during the 2-year treatment period. Current analyses suggest that nonadherence to either P or ET was likely not a major contributor to the iDFS results seen in the overall PALLAS trial. These results illustrate the importance of measuring and monitoring patient adherence to oral study agents. Support: AFT, Pfizer; ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). https://acknowledgments.alliancefound.org Table 1.Adherence and persistence in PALLAS over the 24 month treatment periodPalbocicilb + ETETPalbociclibETETTreatment cycleMean Adherence (SD)N*Mean Adherence (SD)NMean Adherence (SD)N193.4 (13.8)229098.7 (6.1)230999.0 (5.2)2343294.7 (13.3)218198.8 (6.4)220398.4 (7.1)2206397.4 (10.1)211298.7 (7.3)214298.8 (6.3)2168497.6 (10.2)203598.6 (7.8)211099.0 (5.7)2154597.6 (11.1)197598.3 (7.9)209398.1 (8.3)2148698.1 (8.7)189998.7 (6.6)203798.5 (8.2)2116798.1 (9.3)185599.0 (6.3)201298.6 (7.3)2102898.0 (9.1)181098.2 (8.2)199798.1 (8.2)2092998.4 (7.4)173399.0 (6.4)196298.8 (6.8)20511098.3 (8.6)171499.2 (4.9)194699.0 (5.5)20381198.3 (8.0)169198.5 (7.3)193798.2 (8.2)20311298.7 (6.2)161299.1 (5.3)191098.7 (7.5)19861398.5 (7.7)159698.9 (6.4)189398.8 (7.1)19691497.9 (9.3)157698.4 (7.3)188298.0 (9.1)19611598.5 (6.9)151499.2 (4.6)185499.0 (6.0)19281698.2 (8.7)148699.1 (4.6)183599.1 (5.7)19131798.1 (9.8)147998.3 (7.8)182698.5 (6.4)19031898.7 (6.8)141699.3 (4.1)176899.2 (5.3)18601998.7 (7.3)140899.3 (3.8)175699.4 (3.1)18482098.4 (8.9)139798.9 (5.3)174298.7 (5.8)18382198.5 (7.5)130199.0 (6.1)167698.8 (7.1)17842297.8 (9.7)124698.8 (6.2)164799.2 (5.7)17692398.1 (8.8)118098.2 (8.5)161998.4 (8.0)17552498.8 (7.2)108699.0 (6.3)146898.9 (7.1)16192598.8 (6.7)99699.2 (5.2)143298.8 (7.1)15892697.9 (11.2)84599.1 (5.7)140998.6 (8.8)1578ET=Endocrine therapy * Number of pts who initiated the treatment cycle. Citation Format: Eileen Shinn, David Zahrieh, Angela DeMichele, Nick Zdenkowski, Julie Lemieux, Jun Mao, Vesna Bjelic-Radisic, Michelle Naughton, Georg Pfeiler, Karen Gelmon, Ingrid Mayer, Daniel Egle, Gabriele Zoppoli, Tiffany Traina, Miguel Martin Jiménez, Silvia Antolin Novoa, Tufia Haddad, Arlene Chan, Alistair Edward Ring, Antonio Wolff, Jose JuanPonce Lorenzo, Dhanusha Sabanathan, Hal Burstein, Zbigniew Ireneusz Nowecki, Gunda Pristauz-Telsnigg, Adam Brufsky, Meritxell Bellet-Ezquerra, Theodoros Foukakis, Yelena Novik, Gabor Rubovszky, Karoline Muehlbacher, Otto Metzger, Theodora Goulioti, Ernest Law, Ann Partridge, Lisa Carey, Alex Zoroufy, Dominik Hlauschek, Christian Fesl, Erica Mayer, Michael Gnant. Adherence with adjuvant endocrine therapy with or without Palbociclib in the PALLAS trial [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 P4-12-01.

Abstract Background: Quality of life (QOL) in breast cancer patients (pts) can be greatly impacted by initial treatment and ongoing therapy, particularly if side effects and symptoms are not well tolerated. The PALLAS trial investigated whether the addition of 2 years of palbociclib (palbo) to adjuvant endocrine therapy (ET) improved invasive disease-free survival (iDFS) over adjuvant ET alone. We report on the main patient-reported outcome (PRO) quality of life (QOL) and symptom severity results of this trial by treatment arm. Methods: PALLAS is an ongoing multicenter, open label phase 3 trial that enrolled hormone receptor positive, HER2-negative, stage II-III breast cancer patients at 406 cancer centers across 21 countries. Patients were randomly assigned (1:1) to either 2 years of palbo (125mg/day, 3 weeks on 1 week off) plus ongoing provider or patient-choice adjuvant ET (palbo+ET) versus ongoing ET alone. The primary study endpoint was iDFS. Treatment with palbo in all pts stopped at the time of the second interim analysis (5/2020) due to futility; all pts then moved to follow up. The PRO analyses were triggered for completion after awareness of the pre-specified 469 iDFS cases in November 2020. Eight PRO endpoints were measured serially (i.e., day 1 of each monthly cycle for the first 3 months, then every 3 months for the first 2 years, and once at year 3). The endpoints were the EORTC QLQ-C30 global health status/QOL score, the Brief Fatigue Inventory score, the modified Brief Pain Inventory severity and pain interference scores, the EORTC QLQ-BR23 alopecia score, and the Breast Cancer Prevention Trial hot flash symptoms, vaginal problems, and musculoskeletal pain scores. Linear mixed models compared the average difference between arms across time points during the initial 2-year treatment period adjusting for cycle 1 day 1 (C1D1) PRO scores, demographic and clinical variables. The average differences between arms (palbo+ET vs ET alone) and the two-sided (1-[0.05/8]) x 100% confidence intervals, adjusted for multiple comparisons, were calculated. Analysis of covariance compared the average between-arm differences by endpoint at 3 years. Results: The PRO intention to collect population included 4688 (81%) of the overall trial pts, and was clinically and demographically representative of the remaining 1073 pts. Each analysis population, with measures at C1D1 and at least 1 post-C1D1 assessment for each PRO endpoint, comprised ≥ 89% of the 4688 pts and the proportions were similar between arms. After adjustment for baseline covariates, on average, no clinically important differences between arms were observed for any of the eight endpoints over the 2 year treatment period (Table 1). All effect sizes were below the pre-specified 0.2 threshold. These PRO results were similar at the 3 year time point. Conclusions: No clinically significant differences in either patient-reported QOL or symptom severity were found, on average, between participants in the two PALLAS treatment arms while either taking palbo+ET or ET alone, or after study-wide termination of palbo. In general, the addition of palbociclib in the adjuvant breast cancer setting did not contribute to increased symptom burden within this survivorship population. Further analyses will examine the relationship between PROs and treatment discontinuation by arm and study time point. Support: AFT, Pfizer, https://acknowledgments.alliancefound.org Table 1.Results of the Patient-Reported QOL and Symptom Severity Analyses Between the Two Treatment Arms During the First 2 Years of PALLASPRO Endpoint *Palbo + ET Adjusted average score (95% CI)ET alone Adjusted average score (95% CI)Average Difference + (Palbo + ET vs ET alone)[99.38% CI] Clinically ++ Important DifferenceEORTC QLQ-C30 Global Health Status/QOL71.7 (71.2, 72.2)74.0 (73.5, 74.5)-2.3 (-3.3, -1.4)**NoBrief Fatigue Inventory Score2.3 (2.2, 2.3)2.1 (2.0, 2.1)0.2 (0.1, 0.3)NoModified Brief Pain Inventory - Severity Score2.3 (2.2, 2.3)2.4 (2.4, 2.5)-0.2 (-0.3, -0.1)NoModified Brief Pain Inventory - Interference Score1.7 (1.6, 1.7)1.7 (1.6, 1.7)0.0 (-0.1, 0.1)NoEORTC QLQ-BR23 Alopecia1.4 (1.4, 1.4)1.3 (1.3, 1.3)0.1 (0.1, 0.1)NoBreast Cancer Prevention Trial - Hot Flash Symptoms1.2 (1.2, 1.3)1.2 (1.2, 1.3)0.0 (-0.1, 0.1)NoBreast Cancer Prevention Trial - Vaginal Problems0.8 (0.8, 0.8)0.8 (0.7, 0.8)0.0 (0.0, 0.1)NoBreast Cancer Prevention Trial - Musculoskeletal Pain1.2 (1.2, 1.2)1.3 (1.3, 1.3)-0.1 (-0.2, 0.0)No* For the EORTC QLQ-C30 Global Health Status/QOL subscale, higher scores indicate better QOL. For all other PRO endpoints, higher scores indicate worse symptom levels. ** The lower bound of the one-sided CI (adjusted for multiple comparisons) was -3.3. Because the lower limit is greater than the pre-specified non-inferiority margin of -3.44, non-inferiority of palbo+ET relative to ET-alone was concluded. The non-inferiority margin corresponds to a 0.2 SD in the EORTC QLQ-C30 global health/QOL score. +The average difference was adjusted for the following baseline covariates: Cycle 1 day 1 score, region (if applicable), age category, first adjuvant ET, race, ethnicity, N-stage, T-stage, histological grade, PgR, prior chemotherapy, ECOG Performance Status. ++Based on each instrument’s published clinically relevant cut-offs, if available. After calculating Cohen’s d treatment effect sizes, (i.e. by dividing the average difference by the ET-alone arm standard deviation from cycle 1 day 1), all effect sizes were below the pre-specified 0.2 threshold, and would not be considered clinically important. Citation Format: Michelle Joy Naughton, David Zahrieh, Michael Gnant, Nicholas Zdenkowski, Julie Lemieux, Jun J Mao, Vesna Bjelic-Radisic, Eileen Shinn, Marija Balic, Christoph Thomssen, Jane Neisel, Manuel Ruiz-Echarri, Sibylle Loibl, Claudine Isaacs, David Cameron, Fernando Manuel Henao Carrasco, Matthew Goetz, Viktor Wette, Gustavo Werutsky, Hope Rugo, Marcus Vetter, Ling-Ming Tseng, Kathy Miller, Florian Fitzal, Juan Miguel Gil Gil, Haeseong Park, Barbro Linderholm, Emilio Bajetta, Zoneddy Dayao, Aleix Prat, Karin Ehrhardt, Otto Metzger, Amal Arahmani, Ernest Law, Ann Partridge, Lisa Carey, Alex Zoroufy, Amylou Dueck, Dominik Hlauschek, Angela DeMichele, Erica Mayer. Quality of life and symptom severity in the PALLAS randomized trial of palbociclib with adjuvant endocrine therapy in early breast cancer (AFT-05) [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 P4-10-01.

Abstract Background Advances in the multidisciplinary care of hormone-receptor positive (HR+) early breast cancer (eBC) have markedly improved clinical outcomes: however, disease recurrence may still occur, particularly in patients (pts) with moderate or high-risk cancers at the time of diagnosis. The use of CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) is a standard of care for advanced breast cancer, supporting the rationale to study CDK4/6i in the eBC setting. Here we present the final protocol-planned analyses of the global phase III PALLAS trial investigating whether the addition of the CDK4/6i palbociclib (P) to adjuvant ET improves outcomes over ET alone for HR+/HER2- eBC. Methods PALLAS (PALbociclib CoLlaborative Adjuvant Study, NCT02513394) is a randomized phase III open-label trial in which pts with stage II-III HR+/HER2- eBC were randomized to receive either 2 years of P with adjuvant ET (P+ET) or ET alone. The primary endpoint is invasive disease-free survival (iDFS); secondary endpoints include distant recurrence-free survival (DRFS), locoregional recurrence-free survival (LRRFS), overall survival (OS), and safety. Mandatory biospecimen collection has supported the creation of an expansive translational science program, and long-term follow-up is planned. Revised sample size calculations required recruitment of 5600 pts in order to detect a 25% iDFS improvement in patients receiving P+ET with 85% power; this final protocol-planned analysis was planned after 469 iDFS events. Results From September 1, 2015 to November 30, 2018, 5,761 pts (median age 52 years, range 22-90) were randomized in 406 centers in 21 countries worldwide. 1,014 (17.6%) had stage IIA disease (capped) and 4,728 (82.1%) stages IIB/III. 4,754 (82.5%) had received prior (neo)adjuvant chemotherapy. After a protocol-planned 2nd interim analysis in May 2020 crossed the futility threshold, 349 P+ET pts still on active treatment stopped P and were transferred to follow-up. At the time of final analysis cutoff date (November 20, 2020), after a median follow-up of 31 months and 516 events recorded, iDFS was similar between the two arms, with 3-year iDFS of 89.3% (95% CI: 87.8-90.6%) for Palbo+ET, and 89.4% (88.0-90.7%) for ET alone (hazard ratio 0.96, 95% CI: 0.81-1.14). There was no statistically significant difference in secondary outcome endpoints. Subgroup analyses revealed no significant interactions between treatment effect and other factors (including risk category). The safety profile of P was as expected, with grade 3 or 4 neutropenia the most common side effect (safety population: 1759/2841 [61.9%] vs 11/2902 [0.4%]). Overall 42% of pts. discontinued P prior to the planned 2-year duration, 28.2% of Palbo+ET pts discontinued therapy due to adverse events, without an observed impact on survival outcomes. Conclusions Now with the full number of events, this analysis of the PALLAS trial shows that the addition of 2 years of P to ongoing adjuvant ET did not improve survival endpoints for pts with stage II-III HR+/HER2- eBC. Whether P is beneficial in the adjuvant setting for certain sub-groups of pts will be further evaluated with longer-term follow-up and by the ongoing translational science program. Support: ABCSG; AFT; Pfizer; ClinicalTrials.gov Identifier: NCT02513394; https://www.abcsg.org; https://acknowledgments.alliancefound.org Citation Format: Michael Gnant, Amylou C Dueck, Sophie Frantal, Miguel Martin, Hal Burstein, Richard Greil, Peter Fox, Antonio C Wolff, Arlene Chan, Eric Winer, Christian Singer, Kathy Miller, Marco Colleoni, Michelle Naughton, Gabor Rubovszky, Judith Bliss, Ingrid A Mayer, Guenther G Steger, Zbigniew Nowecki, Olwen Hahn, Norman Wolmark, Hope Rugo, Georg Pfeiler, Hannes Fohler, Otto Metzger, Céline Schurmans, Kathy P Theall, Dongrui R Lu, Kathleen Tenner, Christian Fesl, Angela DeMichele*, Erica L Mayer, *shared last authorship. Adjuvant palbociclib in HR+/HER2- early breast cancer: Final results from 5,760 patients in the randomized phase III PALLAS trial [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 GS1-07.

PURPOSE The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS. METHODS Patients with stage II-III HR+, HER2– disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS. RESULTS Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non–protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11). CONCLUSION Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.

PURPOSE Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor approved for advanced breast cancer. In the adjuvant setting, the potential value of adding palbociclib to endocrine therapy for hormone receptor–positive breast cancer has not been confirmed. PATIENTS AND METHODS In the prospective, randomized, phase III PALLAS trial, patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative early breast cancer were randomly assigned to receive 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with adjuvant endocrine therapy or adjuvant endocrine therapy alone (for at least 5 years). The primary end point of the study was invasive disease-free survival (iDFS); secondary end points were invasive breast cancer–free survival, distant recurrence-free survival, locoregional cancer-free survival, and overall survival. RESULTS Among 5,796 patients enrolled at 406 centers in 21 countries worldwide over 3 years, 5,761 were included in the intention-to-treat population. At the final protocol-defined analysis, at a median follow-up of 31 months, iDFS events occurred in 253 of 2,884 (8.8%) patients who received palbociclib plus endocrine therapy and in 263 of 2,877 (9.1%) patients who received endocrine therapy alone, with similar results between the two treatment groups (iDFS at 4 years: 84.2% v 84.5%; hazard ratio, 0.96; CI, 0.81 to 1.14; P = .65). No significant differences were observed for secondary time-to-event end points, and subgroup analyses did not show any differences by subgroup. There were no new safety signals for palbociclib in this trial. CONCLUSION At this final analysis of the PALLAS trial, the addition of adjuvant palbociclib to standard endocrine therapy did not improve outcomes over endocrine therapy alone in patients with early hormone receptor–positive breast cancer.

Abstract Background: In ER+ breast cancer (BC) models, Aurora A kinase (AURKA) activation is associated with expansion of CD44+/CD24low/- tumor initiating cells, down-regulation of ERα, and endocrine therapy resistance. Alisertib, a selective AURKA inhibitor, can restore ERα expression and endocrine sensitivity. Early phase studies evaluating alisertib alone or with fulvestrant for ER+ metastatic BC (MBC) demonstrated a favorable safety profile and promising antitumor activity [Haddad, Breast Cancer Res Treat. 2018]. A phase II trial was conducted to determine if the addition of fulvestrant to alisertib improved objective response rate (ORR) and to assess clinical activity of alisertib alone or with fulvestrant in patients (pts) with prior fulvestrant and CDK 4/6 inhibitor (CDK 4/6i). Methods: Pts were randomized 1:1 to Arm A, alisertib (50 mg PO BID Days 1-3, 8-10, 15-17 q 28 days) or Arm B, alisertib with fulvestrant (500 mg IM Day 1, 15 for Cycle 1 and q 28 days thereafter). Eligibility included postmenopausal women, history of ER+ BC, prior fulvestrant, ≤ 2 prior chemotherapy lines, and measurable disease. Stratification factors included prior CDK4/6i, ER level (&lt;10%, ≥10%), and primary/secondary endocrine resistance. Pts on Arm A could cross over to Arm B at progression. With 45 pts per arm, a one sided alpha=0.15 sequential binomial test would have an 85% chance of detecting an increase of ≥ 20% in the ORR of ArmB when the true ORR for Arm A is ≤ 20%. ORR was defined as a partial response (PR) + complete response (CR) by RECIST v.1.1 criteria. Secondary endpoints include progression free survival (PFS), 24-week clinical benefit rate (CBR = CR + PR + absence of progression for&gt; 6 cycles), overall survival, duration of response (DoR), and safety. Blood and tumor specimens were collected at baseline, end of Cycle 1, and progression. Results: Pts enrolled July 2017 - November 2019 with 118 pre-registered, 96 registered, and 90 evaluable for the primary endpoint (Arm A: 45, Arm B: 45). Median age was 60 (range 33, 85). Nearly all received prior fulvestrant (n=89, 98.9%), aromatase inhibitor (n=83, 92.2%), and CDK4/6i (n=88, 97.8%). Most had secondary endocrine resistance (n=71, 78.9%). Pre-registration biopsy for ER was positive in 84 pts (86.7%) and negative in 6 pts (13.3%). More pts on Arm B had prior everolimus (A: 35.6%, B: 57.8%) and prior chemotherapy (A: 44.4%, B: 55.6%) for MBC. The ORR for alisertib and fulvestrant was 20.0% (90% CI: 10.9-32.3%), not significantly greater than alisertib alone 17.8% (90% CI: 9.2-29.8%). The 24-week CBR for Arm A was 42.2% (90% CI: 29.7-55.6%; n=19, including 7 PR) and Arm B was 31.1% (90% CI: 19.9-44.3%; n=14, including 8 PR). As of July 1, 2020, the median DoR was not reached in either arm. The median PFS time was 5.6 months (95% CI: 3.9 - 9.3) for Arm A and 5.1 months (95%CI: 3.8 - 7.6) for Arm B. Seventeen pts (18.9%) remain on treatment (A: 12, B: 5) having received at least 11 cycles (range up to 32+ cycles). At least one dose reduction was required for pts (A: 19, B: 18), most commonly due to neutropenia. The most common severe (grade ≥3) adverse events included neutropenia (n=19, 42.2% in each arm), anemia (A: 15.6%, B: 8.8%), and fatigue (n=5, 11.1% Arm B only). Pts discontinued therapy due to disease progression equally in each arm (n=28, 62.2%), however more pts on Arm B (n=12) than Arm A (n=5) discontinued therapy due to toxicity, refusal or other reasons. Conclusion: While the addition of fulvestrant to alisertib did not improve ORR, promising clinical activity with alisertib monotherapy was observed overall and notably for pts with endocrine and CDK 4/6i-resistant MBC. More severe toxicities and treatment discontinuation were observed in pts receiving combination therapy. Correlative blood (CTC/cfDNA) and tissue (AURKA, ERα, and stemness biomarkers) studies are underway. Citation Format: Tufia Haddad, Antonino D'Assoro, Vera Suman, Jodi Carter, Brendan McMenomy, Erica Mayer, Meghan Karuturi, Aki Morikawa, Paul Marcom, Claudine Isaacs, Sun Young Oh, Amy Clark, Ingrid Mayer, Khandan Keyomarsi, Roberto Leon-Ferre, Karthik Giridhar, Ciara O'Sullivan, Prema Peethambaram, Timothy Hobday, Minetta Liu, James Ingle, Matthew Goetz. Randomized phaseII trial to evaluate alisertib alone or combined with fulvestrant for advanced, endocrine-resistant breast cancer (TBCRC 041) [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 PD2-05.

Abstract Background:Adherence to and tolerability of oral agents for the treatment of hormone receptor positive (HR+) breast cancer in the adjuvant setting may be challenging and can limit drug exposure. Palbociclib (P) is an oral CDK4/6 inhibitor; P in combination with endocrine therapy (ET) has demonstrated efficacy in HR+/HER-2 negative (HER2-) metastatic breast cancer (MBC). The global PALLAS study (NCT02513394) was designed to determine if the addition of P to adjuvant ET improves outcomes over ET alone in early breast cancer. The goal of this analysis is to describe P exposure and discontinuation in PALLAS, and explore any impact on study endpoints. Methods:Pts with stage II-III HR+/HER2- disease were randomized to receive 2 years of P (starting dose 125 mg daily, 3 weeks on, 1 week off) in combination with adjuvant ET (Arm A) or ET alone (Arm B). The primary objective was to compare invasive disease-free survival (iDFS) between arms; secondary endpoints included safety, quality of life, adherence, and translational science. Dose adjustments were defined per protocol in the setting of emergent toxicity. Continuous monitoring of toxicity, dose modifications, and early discontinuations was performed throughout the trial. Statistical analysis included tabulation of dose levels/reductions and reasons for treatment discontinuation, as well as landmark analysis comparing iDFS between those receiving &gt; 12 months (mo) vs &lt; 12 mo of P. Ongoing analyses include exploration of relative dose intensity and modeling of P dose intensity/duration and impact on iDFS. Results:A total of 5760 pts were randomized; 83% had received prior chemotherapy; 68% initiated aromatase inhibitor and 33% tamoxifen, with or without ovarian suppression. Grade 3/4 neutropenia was more common in Arm A vs B (62% vs 0.4%); febrile neutropenia was uncommon (1%). Other all-grade adverse events (AEs) more common in Arm A included other hematologic toxicity, fatigue, upper respiratory infection, nausea, diarrhea, and alopecia. A total of 55% of pts required P dose reduction to 100mg, and 34% to 75 mg, at some point during treatment. At a median follow-up of 23.7 mo at the second interim analysis, no significant difference in iDFS was observed between the arms (3-year iDFS of 87.9% vs 88.4%, HR 0.93, 95% CI 0.76, 1.15); consequently, pts in Arm A stopped P, and all pts moved to long-term follow-up. At time of data cut-off, 32% had completed the planned 2 years of P, 26% were still receiving P, and 42% had discontinued P prematurely. P discontinuation was 18% at 6 mo, 30% at 12 mo, 38% at 18 mo, and 45% projected at 24 mo. A total of 27% of Arm A pts (770 of 2840) discontinued therapy due to AEs, primarily neutropenia (460, 16%) and fatigue (71, 3%). Other reasons for P discontinuation included non-compliance (128, 5%), recurrent disease or second malignancy (104, 4%), or withdrawal of consent (100, 3%). Last observed dose level was 125mg, 100mg, and 75mg for 45%, 22%, and 33% pts, respectively. Among those discontinuing due to AEs, dose level at time of discontinuation was 75mg for 62%, suggesting some discontinuations occurred without maximum dose reduction. Pts who received &gt; 12 mo of P had a 2-year iDFS of 96.6%; those receiving &lt;12 mo had 2-year iDFS of 95.7% (HR 0.86, 95% CI 0.55-1.34). Conclusions:An early analysis of PALLAS has demonstrated that 2 years of adjuvant P in combination with adjuvant ET did not improve iDFS when compared with ET alone in pts with HR+/HER2- breast cancer. While 2 years of adjuvant P was feasible for the majority of pts, 42% discontinued P early, primarily for AEs. Further data examining drug discontinuations and relationships between drug exposure and clinical outcomes will be presented, expanding upon initial point estimates suggestive of a possible explanation of trial results. Citation Format: Erica L. Mayer, Christian Fesl, Amylou Dueck, Michael Gnant, Angela DeMichele, on behalf of the PALLAS study team. Treatment exposure and discontinuation in the PALLAS trial: PALbociclib CoLlaborative Adjuvant Study of palbociclib with adjuvant endocrine therapy for HR+/HER2- early breast cancer [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 PD2-03.

CRA1002 The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Monday, June 4, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.