Durvalumab plus carboplatin/paclitaxel followed by durvalumab with or without olaparib as first-line treatment for endometrial cancer: Longitudinal changes in circulating tumor DNA.

5512 Background: DUO-E (NCT04269200) showed statistically significant and clinically meaningful progression-free survival (PFS) with carboplatin/paclitaxel (CP) plus durvalumab (D) followed by D (CP+D) ± maintenance olaparib (O) vs CP in endometrial cancer (intent-to-treat [ITT] population; primary endpoints). The greatest benefit for CP+D was in mismatch repair deficient (dMMR) patients (pts); addition of O (CP+D+O) further enhanced PFS in MMR proficient (pMMR) pts (prespecified exploratory analyses). We present exploratory longitudinal circulating tumor (ct)DNA analyses. Methods: Pts were randomized 1:1:1 to CP (CP alone), CP+D, or CP+D+O arms. ctDNA was analyzed in plasma at baseline (BL; Cycle 1 Day 1 [C1D1]), during the chemotherapy phase (C3D1), prior to maintenance initiation (C7D1), and during the maintenance phase (C9D1) using the methylation-based Guardant Infinity assay (Guardant Health, Palo Alto, CA). Results: Of 718 pts randomized, the biomarker-evaluable population (BEP) comprised 347, 349, 350, and 349 pts at BL, C3D1, C7D1, and C9D1, respectively. Pt characteristics were similar to the ITT population but fewer pts had Eastern Cooperative Oncology Group status 1. ctDNA was detectable in 80% (278/347) of C1D1 samples, and presence of BL ctDNA was associated with shorter PFS across treatment arms. In both dMMR and pMMR pts, CP+D treatment during the chemotherapy phase led to numerically greater reductions in detectable ctDNA vs CP at C3D1; continued treatment with D led to lower ctDNA detection at C9D1 (Table) due to a lower proportion of pts switching from no detectable ctDNA to detectable (re-emergence) ctDNA between C7D1 and C9D1. The addition of maintenance O to CP+D had limited effect on ctDNA levels in dMMR pts; however, in pMMR pts, the ctDNA detection rate was lower at C9D1 vs CP or CP+D due to increased ctDNA clearance from C7D1 to C9D1 (CP+D+O vs CP+D: 48% vs 17%). Conclusions: In this post hoc exploratory analysis, BL ctDNA was associated with shorter PFS. The addition of D was associated with rapid reductions in ctDNA detection during chemotherapy and less re-emergence of ctDNA during maintenance. The addition of maintenance O was associated with further reduction of detectable ctDNA and increased ctDNA clearance in pMMR pts, reflecting an additional activity of the combination. Clinical trial information: NCT04269200 . ctDNA detection rates (% [n/N]). Population Treatment arm C1D1 C3D1 C7D1 C9D1 BEP CP 80 (94/118) 44 (51/117) 35 (41/117) 50 (58/117) CP+D 86 (96/112) 26 (29/112) 27 (30/112) 33 (37/112) CP+D+O 75 (88/117) 31 (37/120) 21 (26/121) 25 (30/120) dMMR CP 79 (11/14) 57 (8/14) 21 (3/14) 43 (6/14) CP+D 91 (21/23) 23 (5/22) 32 (7/22) 22 (5/23) CP+D+O 85 (22/26) 41 (11/27) 18 (5/28) 22 (6/27) pMMR CP 80 (83/104) 42 (43/103) 37 (38/103) 50 (52/103) CP+D 84 (75/89) 27 (24/90) 26 (23/90) 36 (32/89) CP+D+O 73 (66/91) 28 (26/93) 23 (21/93) 26 (24/93)