A 68-Year-Old Woman With Stage IV Ovarian Cancer - Episode 5

Maintenance Therapy: NCCN Guidelines, PAOLA-1 Trial

Ramez Eskander, MD: Maintenance therapy is emerging as a very attractive paradigm in the treatment of patients with advanced-stage ovarian cancer. Part of this parallels our understanding of the molecular drivers of these malignancies, specifically with the data following SOLO-1 in the BRCA-mutated population, with a dramatic improvement in progression-free survival [PFS] with incorporation of olaparib, with a hazard ratio of 0.3. We have now brought olaparib into the front-line maintenance setting for patients who have a germline or a somatic BRCA mutation, and that is now part of clinical practice and ties to the importance of germline and somatic BRCA testing in these patient populations.

In parallel, we’ve had several studies recently that have also explored a maintenance frontline PARP inhibitor, niraparib specifically, or veliparib, in patients extending beyond the BRCA population. So rather than just focusing on the BRCA-mutated population, we’re asking about the relevance of maintenance PARP inhibition in patients who have a complete or partial response to frontline platinum combination therapy, in patients who are BRCA wild type, homologous recombination deficient HRD, or homologous recombination proficient. The data from these trials were published in The New England Journal of Medicine, showing a preserved benefit across platforms, across these trials, for a maintenance PARP inhibitor in the intention-to-treat all-comer population. The third study that followed in the same breath was the PAOLA-1 trial, which also looked at a maintenance veliparib plus bevacizumab combination regimen.

The NCCN [National Comprehensive Cancer Network] guidelines that were recently released and updated in 2020 speak to this incorporation of a maintenance strategy, stratifying patients as we make our clinical determination based on their germline and somatic BRCA status, in an effort to help us think about how we’re going to approach maintenance in these patients. What our maintenance therapy options are currently, and again those include the maintenance PARP inhibitor olaparib, our FDA approval at this time is in the germline and somatic BRCA-mutated population, and that may potentially expand to the non-BRCA-mutated population, although we don’t know that yet; maintenance bevacizumab, which is already approved in the frontline setting; and potentially the opportunity for a combination of maintenance olaparib plus bevacizumab based on PAOLA-1. Again that approval has not yet been determined, but could potentially be an opportunity for our patients in the future.

In the clinical trials that were performed to try to determine the benefit of a maintenance strategy, the goal was to expand maintenance again beyond patients who have a BRCA1/2 germline or somatic alteration. The PAOLA-1 study was an investigator-initiated trial, and it looked at the combination of olaparib plus bevacizumab versus bevacizumab plus placebo in frontline patients who had primary or interval cytoreductive surgery, and again had a complete or partial response to primary therapy. The randomization was performed, and the intent was to see whether there would be synergistic benefit in combining bevacizumab with the PARP inhibitor olaparib versus using olaparib alone. What we saw in the intention-to-treat population, in all-comers, there was a 6-month improvement in progression-free survival with the combination over single-agent olaparib, from 16 months to approximately 22 months median progression-free survival. What was very exciting was in the BRCA-mutated patient population, the hazard ratio was 0.3 once again, with what we would consider an active placebo arm. The patients in this study who were randomized, were randomized to either bevacizumab, which based on GOG-0218 and ICON7, we know is an effective strategy, versus bevacizumab plus olaparib, and the hazard ratio in the BRCA-mutated population remained at 0.3. So a 70% reduction in the risk of disease progression in the combination arm. Very exciting data, significant PFS numbers.

There is some dialogue about what the relevance would have been of an olaparib monotherapy arm on the PAOLA-1 trial, meaning olaparib plus bevacizumab, placebo plus bevacizumab, and adding a third arm that would have been placebo plus olaparib, so that we can really define the relative contribution of the addition of bevacizumab to olaparib in the BRCA-mutated and the HRD population. Now those are data that we do not have. Nonetheless, the data that we did extract from the trial results were incredibly exciting, again, with an intent to potentially open the maintenance landscape to patients beyond the BRCA1/2-mutated population.

Transcript edited for clarity.


Case Overview:

Initial Presentation

  • A 68-year-old postmenopausal woman presented with fatigue, urinary frequency, early satiety, abdominal bloating and distention
  • PMH: HTN, medically treated with lisinopril
  • SH: retired; grandmother of 3; never-smoker; social alcohol use
  • PE: abdominal distention, bloating, and a positive fluid wave test; otherwise unremarkable


Clinical work-up

  • Pelvic exam with transvaginal ultrasound showed a right ovarian mass
  • Chest/abdomen/pelvis CT with contrast revealed a right adnexal 5.3-cm complex mass, a suspicious intraparenchymal liver lesion, retroperitoneal lymph node enlargement and concurrent pleural effusion
  • Lymph node and adnexal mass biopsy confirmed high-grade, epithelial ovarian cancer; positive cytology of pleural effusion
    • T1N1M1
  • Germline molecular testing showed BRCA1/2 wild-type, HRD+
  • CA-125, 438 U/mL
  • ECOG: 1

Treatment

  • Patient underwent TAH/BSO, lymph node dissection, with suboptimal debulking; residual disease 1.3 cm
  • Paclitaxel/carboplatin/bevacizumab + maintenance bevacizumab
    • After 3 cycles, patient underwent second debulking surgery, R0
  • Continued on bevacizumab for 6 more cycles
    • Achieved partial response, post treatment CA-125, 40 U/mL
       

Follow-up

  • At 3 months
    • CA-125, 18 U/mL
    • Chest/abdomen/pelvis CT showed no gross pelvic masses or nodes
    • Pelvic exam was unremarkable