Background: PAL + ET showed significant progression-free survival (PFS) benefit vs ET alone in patients (pts) with HR+/HER2- advanced breast cancer (ABC) in PALOMA2 (PAL2) and PALOMA3 (PAL3). Exploratory analyses were conducted on pts who received neo/adjuvant therapy to evaluate the effect of initial disease-free interval (DFI) in PAL3 or treatment-free interval (TFI) in PAL2 on PFS outcomes. Other analyses assessed luminal (Lum) subtype on PAL efficacy. Methods: Pre/postmenopausal pts whose disease has progressed after prior ET (PAL3; N = 521) and postmenopausal pts previously untreated for ABC (PAL2; N = 666) were randomized 2:1 to receive ET (fulvestrant [F] 500 mg or letrozole [L] 2.5mg/d, respectively) + PAL (125 mg/d, 3 wk on/1 wk off) or placebo (PBO). Median follow up was 14 mos (PAL3; 23Oct2015) and 37 mos (PAL2; 31May2017). DFI in PAL3 was calculated as time between first diagnosis of BC and disease recurrence and TFI in PAL2 as time between end of any neo/adjuvant therapy and relapse. Subpopulation treatment effect pattern plot (STEPP) analysis evaluated the association between DFI/TFI and PFS outcomes of PAL+ET vs PBO+ET for each study. In PAL3 and PAL2, 226 and 364 pts respectively provided FFPE tissue from recurrent or de novo disease where Lum subtype was determined. Gene expression profiling used HTG Molecular’s EdgeSeq OBP to assess Lum A/B subtype. Results: In PAL3 and PAL2, 355 and 334 pts, respectively, received adjuvant therapy (232/347 PAL + F and 123/174 F + PBO; 219/444 PAL + L and 115/222 L + PBO). Median DFI in PAL3 was 49.2 mo in PAL + F and 52.0 mo in F + PBO; > 80% of pts had DFI > 2 y. Median TFI in PAL2 was 48.9 mo in PAL + L and 44.9 in L + PBO; ~70% of pts had TFI > 2 y. STEPP analyses suggest no impact on PFS outcomes from baseline DFI in PAL3 and TFI in PAL2. Both Lum A and B pts benefited more from PAL +ET than PBO+ET in PAL2 (Lum A HR [95% CI], 0.546 (0.385-0.773); Lum B: 0.508 [0.335-0.768]) and PAL3 (Lum A: 0.408 [0.253-0.659]; Lum B 0.642 [0.379-1.089]). Conclusions: Adding PAL to ET showed a significant increase in PFS regardless of the length of initial TFI/DFI and of Lum subtype. Sponsor: Pfizer Clinical trial information: NCT01740427, NCT01942135