Berzosertib Doublet Becomes First AFT inhibitor to Show Benefit in Platinum-Resistant High-Grade Serous Ovarian Cancer

The first randomized study of an ATR inhibitor in any malignancy demonstrated the benefit of berzosertib added to gemcitabine as treatment of patients with platinum-resistant high-grade serous ovarian cancer, according to a report published in the Lancet Oncology.

In the study, 70 patients were randomly assigned to receive either berzosertib plus gemcitabine (n = 34) or gemcitabine alone (n = 36).

All 70 patients in the study were all evaluated for the primary end point of progression-free survival (PFS) and the secondary end points, overall survival (OS), objective response rate (ORR), duration of response (DOR), number of patients with a reduction in CA-125 by greater than 50%, PFS at 6 months, and safety.

At a median follow-up of 43.0 weeks (interquartile [IQR], 23.2-69.1 weeks) for patients who received gemcitabine alone and 53.2 weeks (IQR, 25.6-81.8 weeks) for those who received berzosertib plus gemcitabine, PFS events were observed in 50% and 69% of patients, respectively. Among those treated with single-agent gemcitabine, the median PFS favored the combination at 22.9 weeks (90% CI, 17.9-72.0) compared with 14.7 weeks (90% CI, 9.7-36.7) in the monotherapy group (HR, 0.57; 90% CI, 0.33-0.98; one-sided log-rank test P =.044).

The overall population had an ORR of 11% with gemcitabine versus 3% with the combination therapy. The clinical benefit rate (CBR) was 35% (90% CI, 22-51) in the combination arm versus 25% (90% CI, 14-40) in the gemcitabine only group (P = .44).

In the subset of patients with a platinum-free interval of 3 months or less, the median PFS was 27.7 weeks (90% CI, 15.7-not reached [NR]) in the combination arm versus only 9.0 weeks (90% CI, 8.7 month-NR) in the gemcitabine alone arm. Out of 11 PFS events total for these patients, the hazard ratio was 0.29 (90% CI, 0.12-0.71; one-sided long-rank test P = .0087). The ORR was identical for both arm at 8%, and the CBR was 54% (90% CI, 29%-78%) for patients who received the combination and 23% (90% CI, 7%-49%) for those who received monotherapy (P =.23).

Patients with a platinum-free interval greater than 3 months showed a median PFA pf 18.6 weeks (90% CI, 9.4-NR) when given berzosertib plus gemcitabine compared with 15.3 weeks (90% CI, 14.7-NR) when given gemcitabine alone. Overall there were 14 PFS events in this subgroup (HR, 1.04, 90% CI, 0.51-2.12; one-sided log-rank P =.46). The ORR for this subgroup was 13% in the gemcitabine alone arm whereas, no patients in the combination arm achieved an objective response. This led to a CBR favoring the gemcitabine monotherapy group at 26% (90% CI, 12%-45%) compared with 24% (90% CI, 10%-44%) in the combination group.

“The PFS benefit of adding berzosertib to gemcitabine was notable in patients with a platinum-free interval of 3 months or less but not for those with a platinum-free interval greater than 3 months. These findings might reflect the fact that tumors of patients with a platinum-free interval of three months or less are enriched for biomarkers of replicative stress which are likely to be predisposed to respond to ATR inhibition; this hypothesis is being investigated in ongoing correlative work,” study authors, led by Panagiotis A Konstantinopoulos, MD, PhD, wrote.

The 6-month PFS rate for the overall population was 50% (90% CI, 35%-71%) in the berzosertib plus gemcitabine arm versus 36% (90% CI, 24%-55%) in the gemcitabine only arm. In the subgroup of patients with a platinum-free interval ≤ 3 months, the 6-month PFS rate was 53% (90% CI, 31%-91%) in the combination arm versus 39% (90% CI, 23%-65%) in the single-agent arm. Patients with a platinum-free interval of 3 to 6 months, had a 6-month PFS rate of 48% (90% CI, 30%-77%) if treated with berzosertib/gemcitabine compared with 39% (90% CI, 23%-65%) when treated with gemcitabine alone.

Crossover from single-agent gemcitabine to berzosertib plus gemcitabine was granted to patients who developed disease progression during the study. A total of 15 patients (67%) from the gemcitabine arm crossed over to receive the berzosertib doublet. A post-hoc analysis demonstrated a median PFS of 19 weeks (90% CI, 8.7-NR) in the crossover population.

Grade 3/4 treatment-related adverse events (AEs) were observed in the study. The most common for the gemcitabine group versus the berzosertib group were decreased neutrophil count (39% vs. 47%), decreased platelet count (6% vs. 24%). There was no clinically significant bleeding among patients who were treated with the combination, but 1 patient in the gemcitabine arm did experience significant bleeding. There was 1 treatment-related death in each study arm, which was caused by sepsis in the monotherapy arm and pneumonitis in the berzosertib combination arm.

A total of 36 patients (11%) from the gemcitabine only arm and 34 (185 ) from the berzosertib arm discontinued treatment.

Twenty-right percent of patients had serious AEs, of which the most common were fever or febrile neutropenia.

Patients in the study received intravenous gemcitabine at 1000 mg/m² and intravenous gemcitabine 1000 mg/m² at 210 mg/m². At baseline, patient characteristics were well-balanced between the study arms. The majority of patients were classified as white which was 94% in the gemcitabine monotherapy arm and 88% in the combination arm. Sixty-one percent of patients in the single-agent gemcitabine arm had an ECOG performance status of 0 and 39% had a performance status of 1 compared with 59% and 41% of patients in the combination arm. At diagnosis, in the monotherapy arm, 44% of patients were stage III, 39% were stage IV, and 17% were unknown. Of the patients in the berzosertib/gemcitabine arm, 6% were stage II, 53% were stage III, 36% were stage IV, and 15% were unknown.

The platinum-free interval for the study population was ≤ 3 months for 36% in the gemcitabine group and 38% of the berzosertib/gemcitabine group. The platinum-free interval was greater than 3 months and less than 6 months in 64% on the patients who received gemcitabine alone compared with 62% of those who received the combination.

Most patients in the study had at least 2 prior lines of therapy, which was 50% of the gemcitabine alone arm and 59% of the combination arm. In 31% of the monotherapy group and 41% of the combination group, at least 1 previous treatment was administered in the platinum-resistant setting. A large proportion of patients had prior PARP inhibition including 81% of the single-agent arm and 68% of the doublet arm, nor did they have antiangiogenic therapying 75% and 71%, respectively. Most patients also did not have a BRCA mutation, but 14% of patients belonging to the gemcitabine monotherapy arm and 18% of those in the combination arm did have BRCA mutations. Mutational status was unknown in 17% of the gemcitabine alone patients and 21% of the berzosertib/gemcitabine patients.

_Reference:

_{Konstantinopoulos PA, Cheng SC, Hendrickson AW, et al. Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2020; 21: 957–68. doi: 10.1016/ S1470-2045(20)30180-7}