Best results were seen with complete debulking during upfront surgery

Adding the PARP inhibitor olaparib to bevacizumab maintenance therapy for ovarian cancer among patients who have responded to platinum-taxane chemotherapy improves outcomes regardless of when surgery took place, according to an analysis of the seminal PAOLA-1 data. While sample sizes were too small to confirm benefits among patients with residual disease after surgery, numerical trends favored olaparib.

“It is important to note that the PAOLA-1 trial population was unselected for biomarker status or surgical outcome, meaning it is representative of most patients in clinical practice,” lead author Christoph Grimm, MD, Medical University of Vienna, Austria, said during a presentation of his data during a Society for Gynecologic Oncology (SGO) webinar on April 29, 2020. “In the present analysis, we evaluated the efficacy of olaparib plus bevacizumab in the PAOLA-1 trial by timing of surgery and the presence of residual tumor after surgery.”

The findings were initially to be presented at the SGO 2020 annual meeting, planned to take place in Toronto, Canada from March 28-31. The conference was cancelled due to the Covid-19 pandemic, but the study abstracts were subsequently released online.

“Compared with bevacizumab alone, maintenance olaparib plus bevacizumab improved progression-free survival [PFS] regardless of the timing of surgery or residual disease status after surgery,” said Grimm. “The magnitude of the PFS benefit was greatest when surgery achieved complete surgical debulking, particularly in the upfront setting… Expert gynecological oncologists are critical for high-grade ovarian cancer management in order to achieve complete surgical resection and optimize maintenance therapy with olaparib plus bevacizumab.”

As previously reported, in PAOLA-1 the addition of olaparib to bevacizumab maintenance therapy in patients with ovarian cancer was associated with a longer investigator assessed PFS (median 22.1 versus 16.6 months; HR 0.59; 95% CI 0.49-0.72).

Grimm reported on a new analysis of the data that investigated the efficacy of olaparib plus bevacizumab by timing of surgery (upfront or interval; a prespecified analysis) and the combination of the timing of surgery plus the presence of residual tumor after surgery, based on the presence of macroscopic residual disease (a post hoc analysis).

Overall, 271 of the 527 patients in the olaparib arm (50%) received upfront surgery, and among these patients, 111 had macroscopic residual disease. Another 228 (40%) had interval surgery, and 65 of these patients had macroscopic residual disease. The remaining 38 patients who received olaparib (7%) did not undergo surgery. In the placebo arm, 138 patients had upfront surgery (51%) and 53 of these patients had macroscopic residual disease. Another 110 (41%) had interval surgery, and 35 of these patients had macroscopic residual disease. The remaining 21 patients (8%) did not have surgery.

Among patients who had upfront surgery, median PFS was 29.6 months with olaparib and 18.2 months with placebo (HR 0.52; 95% CI 0.40-0.69). Among those who had interval surgery, results were similar, with a median PFS of 21.4 versus 16.7 months (HR 0.66; 95% CI 0.50-0.87).

In patients who had upfront surgery and no residual disease, median PFS was 39.3 months with olaparib and 22.1 months with placebo (HR 0.47; 95% CI 0.29-0.75). In patients who had interval surgery and no residual disease, median PFS was 22.1 versus 17.7 months (HR 0.61; 95% CI 0.41-091).

PFS was not significantly improved with the addition of olaparib among patients who had residual disease, regardless of whether they had upfront or interval surgery, but numerically still favored olaparib. (HR 0.74; 95% CI 0.48-1.15 and HR 0.70; 95% CI 0.41-1.20, respectively). Grimm noted that “these results should be interpreted with caution given the small number of patients in this subgroup.”

PAOLA-1 is a randomized, double-blind, international phase III trial of 806 patients with newly diagnosed, FIGO stage III to IV, high-grade serous or endometrioid ovarian cancer, fallopian tube or primary peritoneal cancer, and who were having a response to first-line platinum–taxane chemotherapy. They were randomized to oral olaparib 300 mg twice daily for up to 24 months plus bevacizumab15 mg/kg on day 1 every 3 weeks for 15 months, including when combined with platinum-based chemotherapy (n = 537), or placebo plus bevacizumab (n = 269). The primary outcome was investigator-assessed intent-to-treat PFS, stratified by first-line treatment outcome and tumor BRCA mutation status.

“Dr. Grimm added some very interesting data looking at the role of when surgery was performed as well as the role of whether there was any difference in terms of residual disease,” said Thomas J. Herzog, MD, of the University of Cincinnati Cancer Center in Cincinnati, OH in a comment on the study during the SGO webinar. “What I thought was most remarkable was the significant difference of 17 months in the group who received upfront surgery. … Upfront and no residual – you would expect that to be the group that does well, better than the others because of selection bias, but the fact that you saw such a significant difference in terms of months [of PFS] that were added is interesting, especially when you think about the historical use of bevacizumab in subgroups that we think benefits … [which] is high-volume disease, large residual. Here we see something different.”

  1. The addition of olaparib to bevacizumab for maintenance therapy for ovarian cancer after response to first-line platinum–taxane chemotherapy is associated with improved progression-free survival, regardless of timing of surgery.
  2. The greatest benefits were seen with successful surgical debulking in the upfront setting.

Alison Palkhivala, Contributing Writer, BreakingMED™

The PAOLA-1 trial was sponsored by Arcagy Research.

Grimm reports receiving consulting/speaker fees/ research funding from AstraZeneca, MSD, PharmaMar, Roche, GSK/Tesaro, Celgene, Vifor Pharma, Clovis, Amgen, Meda Pharma, and Roche Diagnostics.

Herzog reports being on advisory boards for and/or receiving honoraria/reimbursement from Genentech, Caris, Tesaro, Clovis, Johnson&Johnson, and AstraZeneca.

 

Cat ID: 445

Topic ID: 78,445,730,445,692,357,693,192,356