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

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.