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

July 15, 2020

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 recently published study.

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