Palbociclib combined with endocrine treatment in breast cancer patients with high relapse risk after neoadjuvant chemotherapy: Subgroup analyses of premenopausal patients in PENELOPE-B.
Authors: Marmé Frederik , Martin Miguel , Untch Michael , Bonnefoi Herve R. , Kim Sung-Bae , Bear Harry Douglas , Mc Carthy Nicole , Gelmon Karen A. , García-Sáenz José A. , Kelly Catherine Margaret , Reimer Toralf , Toi Masakazu , Rugo Hope S. , Gnant Michael , Makris Andreas , Lechuga Mariajose , Seiler Sabine , Seither Fenja , Loibl Sibylle 
Published: June 2021

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Background: PENELOPE-B assessed efficacy of the CDK4/6 inhibitor 1-year palbociclib versus placebo added to endocrine therapy (ET) as post-neoadjuvant treatment in a high-risk breast cancer population. Palbociclib did not improve invasive disease-free survival (iDFS) compared to placebo (3-year iDFS 81.3% vs 77.7%) (Loibl et al. J Clin Oncol 2021). Here we report results from the subpopulation of premenopausal women. Methods: Patients with hormone receptor positive, HER2-negative breast cancer without pathological complete response after taxane‐containing neoadjuvant chemotherapy and at high risk of relapse (CPS‐EG score ≥3 or 2 and ypN+) 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 treatment including tamoxifen (TAM) +/- gonadotropin-releasing hormone analogue (GnRH) and aromatase inhibitor (AI) +/- GnRH. Randomization was stratified by nodal status at surgery, age ( < 50 vs ≥50 years), Ki-67, region, and CPS-EG score. Results: 616/1250 patients were premenopausal at the time of enrollment, 185 of these patients (30.0%) were younger than 40 years of age. 95.2% had ypN+ after surgery; 42.8% had ypT2 and 46.8% a CPS-EG score of 3. 23.1% of the premenopausal women had a Ki67 of > 15% in residual disease. 66.1% started with TAM alone; 19.3% with TAM and ovarian function suppression (OFS); and 13.6% received an AI+OFS. There was no difference in iDFS between palbociclib and placebo in the premenopausal women HR 0.948 (0.693-1.30). The 3-year iDFS was 80.6% and 78.3%, respectively. Palbociclib vs placebo in subgroups by endocrine treatment: TAM alone HR 1.05 (0.715-1.53) p = 0.817; TAM+GnRH HR 0.52 (0.267-1.02) p = 0.057 and AI+GnRH HR 1.58 (0.548-4.56) p = 0.397; pinteraction0.124. Hematologic toxicity was significantly more common with palbociclib. Non-hematological toxicity any grade palbociclib vs placebo were: fatigue 67.4% vs 51.3%; hot flushes 52.2% vs 54.8%; bone pain 15.6% vs 16.6%; and vaginal dryness 11.0% vs 11.5%. When receiving palbociclib fewer patients in the AI+GnRH group vs the TAM +/- GnRH cohort experienced anemia (54.1% vs 80.5%) and thrombocytopenia (37.8% vs 65.1%). Fatigue (75.7% vs 66.3%) and nausea (40.5% vs 24.9%) were more common with AI+GnRH than TAM +/-GnRH when palbociclib was added. Thromboembolic events were low with overall 9 events (4 vs 5; AI+GnRH 2.4% vs 1.3% TAM+/-GnRH). Conclusions: The addition of palbociclib to endocrine therapy did not improve iDFS in premenopausal women. These are the first safety results from a phase III study for the combination tamoxifen +/-GnRH and palbociclib. The addition of palbociclib to tamoxifen +/-GnRH in premenopausal women did not increase side effects compared to AI+GnRH and seems to be an alternative to AI+GnRH. Clinical trial information: NCT01864746.