Evaluation of homologous recombination deficiency (HRD) status with pathological response to carboplatin +/- veliparib in BrighTNess, a randomized phase 3 study in early stage TNBC.

519 Background: HRD status is significantly associated with a higher rate of response to neoadjuvant platinum-based therapy and improved PFS following adjuvant doxorubicin and cyclophosphamide (AC) in TNBC. We assessed the prognostic and predictive role of the HRD assay for platinum and PARP inhibitor response in BrighTNess. Methods: 634 stage II-III TNBC pts were randomized 2:1:1 to: Arm A: Paclitaxel (T) q wk x 12 + carboplatin (P) (AUC 6) q3 wk x 4 + veliparib (TPV) - > AC q2-3 wk x 4; Arm B: T + P + placebo (TP) - > AC; or Arm C: T + dual placebo (T) - > AC. HRD status was defined as HRD+ (HRD score ≥ 42 or a tumor BRCA1/2 mutation) or HRD- (HRD score < 42 and no tumor BRCA1/2 mutation). An exploratory HRD threshold of ≥ 33 vs < 33 was also assessed. Results: HRD status was available for 438 pts. HRD data by arm for pCR for the 42 and 33 cut-offs are shown. Within each arm using the 42 and 33 cut-offs, respectively, ORs for pCR by HRD status (HRD+/HRD-) were 2.85 (p = 0.0005) and 3.10 (p = 0.004) for Arm A, 1.55 (p = 0.30) and 2.28 (p = 0.10) for Arm B and 2.13 (p = 0.13) and 1.52 (0.48) for Arm C. Comparing between arms using the 42 threshold, ORs for pCR (Arm A/Arm B, Arm A/Arm C, Arm B/Arm C) in the HRD+ group were 1.04, 3.02 and 2.90 and were not statistically significantly different than in the HRD- group (0.57 [p = 0.23], 2.26 [p = 0.60] and 4.0 [p = 0.61]). Similar results were observed with the 33 cut-off. Conclusions: In BrighTNess, higher rates of pCR were observed in HRD+ pts across all treatment arms. However, pts treated with P had higher rates of pCR in both HRD+ and HRD- subsets. The exploratory HRD threshold of 33 appeared to provide greater sensitivity to identify responders with the addition of P + V. Receipt of AC in all pts may have contributed to the lack of interaction observed between HRD status and P +/- V treatment. Clinical trial information: NCT02032277.Arm pCR HRD+ ≥ 42 pCR HRD- < 42 pCR HRD+ ≥ 33 pCR HRD- < 33 TPV-AC (A) n = 213 87/141 (61.7%) 26/72 (36.1%) 93/153 (60.8%) 20/60 (33.3%) TP-AC (B) n = 116 51/84 (60.7%); p = 0.88# 16/32 (50%); p = 0.18# 57/92 (62%); p = 0.89# 10/24 (41.4%); p = 0.61# T-AC (C) n = 109 24/69 (34.8%); p = 0.0003‡ 8/40 (20%); p = 0.08‡ 25/79 (31.6%); p = < 0.0001‡ 7/30 (23.3%); p = 0.46‡ # = for TPV-AC vs TP-AC; ‡ = for TPV-AC vs T-AC