Berzosertib Plus Gemcitabine Proposed For Platinum-Resistant High-Grade Serous Ovarian Cancer

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Early findings indicate that combining the ATR inhibitor berzosertib with gemcitabine might extend progression-free survival (PFS) for patients with high-grade serous ovarian cancer resistant to platinum therapy. 

“High-grade serous ovarian cancers show increased replication stress, rendering cells vulnerable to ATR inhibition because of near universal loss of the G1/S checkpoint (through deleterious TP53 mutations), premature S phase entry (due to CCNE1 amplification, RB1 loss, or CDKN2A mRNA downregulation), alterations of homologous recombination repair genes, and expression of oncogenic drivers (through MYC amplification and other mechanisms)”, the investigators explain in The Lancet Oncology.

Panagiotis Konstantinopoulos, from the Dana-Farber Cancer Institute in Boston, Massachusetts, USA, and co-workers hypothesised that berzosertib and gemcitabine could work synergistically, with gemcitabine exacerbating replication stress in high-grade serous ovarian cancer and increasing tumour dependency on ATR, leading to “maximal susceptibility to ATR inhibition.”

Seventy patients with recurrent platinum-resistant disease were randomly assigned to receive gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-day cycle alongside intravenous berzosertib 210 mg/m2 on days 2 and 9 or gemcitabine alone.

The primary endpoint of the phase II trial was PFS, which was a median of 22.9 weeks for patients given gemcitabine plus berzosertib after a median 53.2 weeks of follow-up, versus 14.7 weeks for patients given only gemcitabine and followed up for a median of 43.0 weeks.

This gave a significant hazard ratio (HR) for progression or death of 0.57 in favour of gemcitabine plus berzosertib, the team reports.

For patients with a platinum-free interval of 3 months or less, the median PFS was 27.7 weeks with the combination treatment versus 9.0 weeks for gemcitabine alone, giving a significant HR of 0.29, whereas for patients with a platinum-free interval of more than 3 but less than 6 months, median PFS was a comparable 18.6 and 15.3 weeks, respectively.

Median overall survival (OS) differed significantly between the treatment groups for patients with a platinum-free interval of up to 3 months, at 84.4 weeks with the combination regimen versus 40.4 weeks with gemcitabine alone (HR for death=0.42). But OS did not differ significantly between the treatment arms for the full study group or those with a platinum-free interval of more than 3 but less than 6 months.

The most common grade 3 or 4 treatment-related adverse events (TRAEs) in the combination and gemcitabine-only arms were decreased neutrophils (47 vs 39%) and platelets (24 vs 6%). Serious AEs were reported for 26% of the combination arm – mainly thrombocytopenia (12%) – and for 28% of the gemcitabine-only arm, most commonly fever or febrile neutropenia (6%).

Overall, 18% of the combination arm discontinued treatment because of fatigue, abdominal pain, small bowel obstruction or pneumonitis, as did 11% of those given only gemcitabine, citing neutropenia, capillary leak syndrome, oedema or acute renal failure as the reason for discontinuation.

There was one treatment-related death due to pneumonitis with the combination regimen and one treatment-related death from sepsis with gemcitabine alone.

While acknowledging that the study was small with an open-label design, the authors say “it is reassuring that the standard gemcitabine alone group showed a median progression-free survival that was consistent with that previously reported for platinum-resistant ovarian cancer.”

They conclude: “These limitations notwithstanding, our findings warrant further investigation of gemcitabine plus berzosertib in a phase 3 trial in platinum-resistant ovarian cancer and support stratification based on platinum-free interval, number of previous lines of therapies, and previous antiangiogenic therapy. 

“Finally, our results support future assessment of ATR inhibitor therapy in combination with gemcitabine in additional tumour types, especially in tumours that are predicted to have high replication stress.” 

Reference 

Konstantinopoulos PA, Cheng S-C, Wahner Hendrickson AE, 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; Advance online publication 15 June 2020. https://doi.org/10.1016/S1470-2045(20)30180-7