Abstract GS1-02: Phase III study of palbociclib combined with endocrine therapy (ET) in patients with hormone-receptor-positive (HR+), HER2-negative primary breast cancerand with high relapse risk after neoadjuvant chemotherapy (NACT): First results from PENELOPE-B
Authors: Loibl Sibylle , Marmé Frederik , Martin Miguel , Untch Michael , Bonnefoi Hervé , Kim Sung-Bae , Bear Harry , Carthy Nicole Mc , Olivé Mireia Melé , Gelmon Karen , Sáenz José García , Kelly Catherine M , Reimer Toralf , Toi Masakazu , Rugo Hope S , Seiler Sabine , Nekljudova Valentina , Denkert Carsten , Gnant Michael , Makris Andreas , Burchardi Nicole , von Minckwitz Gunter 
Published: February 2021

Background: About one third of patients with hormone-receptor-positive (HR+), HER2- primary breast cancer with residual invasive disease after neoadjuvant chemotherapy will relapse despite adjuvant endocrine therapy. The risk of relapse can be assessed more accurately using the CPS-EG scoring system (Mittendorf et al. JCO 2011). Therapeutic inhibition of cyclin-dependent kinase 4 and 6 (CDK 4/6) by palbociclib combined with endocrine therapy demonstrated highly relevant efficacy in metastatic breast cancer. Thus, we hypothesize that palbociclib may also be active in these high-risk patients with primary breast cancer. Methods: PENELOPE-B (NCT01864746) is a double-blind, placebo-controlled, phase III study in women with centrally confirmed HR+, HER2- primary breast cancer without a pathological complete response after taxane-containing neoadjuvant chemotherapy and at high-risk of relapse (CPS-EG score ≥3 or 2 and ypN+). After completion of neoadjuvant chemotherapy and locoregional therapy, patients were randomized (1:1) to receive 13 cycles of palbociclib 125mg daily or placebo on days 1-21 in a 28d cycle in addition to standard endocrine therapy. Randomization was stratified by lymph node status (at surgery), age, Ki-67, global region, and CPS-EG score. Primary endpoint is invasive disease-free survival (iDFS). Final analysis was planned after 290 iDFS events with efficacy boundary p&lt;0.0463 due to 2 interim analyses. Main secondary endpoints include iDFS excluding second primary invasive non-breast cancers, overall survival, and safety. Results: A total of 1250 patients were randomized between 2/2014 and 12/2017. Median age was 49.7 years [range 19-79]; 96.8% had residual disease in the breast, 94.6% were ypN+; G3 was reported in 47.4%, Ki-67 &gt;15% in 27.7 %; 54.7% of patients had risk status CPS-EG score ≥3. 1118 patients (89%) completed at least 7 cycles of therapy. 50.1% of patients received aromatase inhibitor (AI), 49.8% tamoxifen, 6.6% AI + gonadotropin-releasing hormone (GnRH) and 9.7% tamoxifen + GnRH. Most common related serious adverse events (SAEs) were infections and vascular disorders. 8 fatal SAEs were reported. Conclusions: PENELOPE-B evaluates the effect of palbociclib for 1 year compared to placebo in addition to endocrine therapy in high-risk primary breast cancer patients. The database was locked with 308 events on September 25th 2020. After breaking the blind for analysis, top line results will be available as of mid October 2020. Results of the final iDFS analysis will be presented at the meeting.

Citation Format: Sibylle Loibl, Frederik Marmé, Miguel Martin, Michael Untch, Hervé Bonnefoi, Sung-Bae Kim, Harry Bear, Nicole Mc Carthy, Mireia Melé Olivé, Karen Gelmon, José García Sáenz, Catherine M Kelly, Toralf Reimer, Masakazu Toi, Hope S Rugo, Sabine Seiler, Valentina Nekljudova, Carsten Denkert, Michael Gnant, Andreas Makris, Nicole Burchardi, Gunter von Minckwitz. Phase III study of palbociclib combined with endocrine therapy (ET) in patients with hormone-receptor-positive (HR+), HER2-negative primary breast cancerand with high relapse risk after neoadjuvant chemotherapy (NACT): First results from PENELOPE-B [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 GS1-02.