Frontline Maintenance Therapy in Advanced Ovarian Cancer

EP: 1.Case Presentation: A 64-Year-Old Woman With Ovarian Cancer

EP: 2.Role of Molecular Testing in Advanced Ovarian Cancer

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EP: 3.Frontline Maintenance Therapy in Advanced Ovarian Cancer

EP: 4.Switch Maintenance Therapy In Advanced Ovarian Cancer: The ARIEL3 Trial

EP: 5.PARP Inhibitors in Advanced Ovarian Cancer: Mechanism of Action and Tolerability

EP: 6.Considerations for Selecting PARP Inhibitor Maintenance Therapy

EP: 7.Ovarian Cancer: Current Status and Future Directions

Ramez Eskander, MD: The treatment of frontline ovarian cancer has changed in the last several years. I would venture to say that we’ve entered a world of maintenance strategies for most patients in the frontline setting. The perspective to take, or what I would consider the important factors in making a decision vary based on the patient, their disease status, performance status, and in a shared-decision making capacity to determine what is best for that patient at that time. The way I like to think about maintenance treatment is based on the molecular testing for that patient. If a patient is found to have a germline or a somatic BRCA mutation, the data from SOLO-1, which was a maintenance study that explored olaparib as a monotherapy in patients with a germline or somatic BRCA alteration, showed a dramatic improvement in progression-free survival [PFS]. [Susana] Banerjee, [MBBS, MA, PhD, FRCP] recently presented the 5-year PFS data confirming the magnitude of benefit preserved well after the discontinuation of the 24 months of olaparib in comparison to the placebo arm. And that hazard ratio was approximately 0.3, so a 70% reduction in the risk of disease progression or death. Patients with a germline or somatic BRCA mutation should be on a maintenance PARP inhibitor in the frontline setting because of that advantage, that benefit with PARP therapy.

The next layer beyond that is identifying those patients who do not have a BRCA aberration, either germline or somatic, but who have evidence of homologous recombination deficiency, that HRD population. And in those patients, based on both the PRIMA frontline clinical trial as well as PAOLA-1 looking at the magnitude of benefit of PARP or PARP plus bev [bevacizumab] in the homologous recombination deficient patient population, again, a hazard ratio of approximately 0.3 to 0.4, we would advocate that patients with homologous recombination deficiency consider maintenance bevacizumab plus a PARP inhibitor or PARP inhibitor alone. And this question can be debated about whether you do a PARP inhibitor alone or a PARP inhibitor plus bevacizumab because as many are aware, the missing arm of the PAOLA-1 clinical trial was PARP monotherapy. Although with the data that are emerging that the bevacizumab plus PARP arm of the PAOLA-1 trial appeared to show benefit even in these “lower-risk” patients with primary ovarian cancer, if a patient is on bevacizumab with chemotherapy, you can continue the bevacizumab and add the PARP on if they’re homologous recombination deficient.

The more difficult population to have an answer for in this setting is what we call the biomarker negative cohort. For patients who don’t have evidence of a BRCA mutation or homologous recombination deficiency, we know that there’s an approval for PARP maintenance in the setting, but the magnitude of benefit with respect to progression-free survival with PARP vs placebo for those patients was less than 3 months on the PRIMA trial. And we know that we have an approval for maintenance bevacizumab in the frontline setting where the progression-free survival advantage was approximately 4 months. Here you have a benefit with these therapeutic interventions. It’s not nearly as significant as the benefit in those patients who are homologous recombination deficient or biomarker positive. And that’s more of a discussion you have with your patient to try to gauge what their expectations are for treatment and what they feel like they would like to pursue in terms of a maintenance strategy.

My personal clinical practice is to use bevacizumab frequently in these patients, with bevacizumab maintenance. That’s what was done in this clinical case scenario, where this patient was biomarker negative and was treated with chemotherapy followed by bevacizumab maintenance. And what’s relevant here is I’m thinking about what am I going to do at recurrence. The reason that’s relevant is we have data from [Sandro] Pignata, [MD, PhD,] and colleagues that rechallenging with bevacizumab after prior bev [bevacizumab] exposure preserves the approximate 3-month progression-free survival benefit. Giving bevacizumab post-bevacizumab appears to still be beneficial in these patients. We don't have data about PARP post-PARP inhibitor. If we use the PARP inhibitor as a maintenance strategy up front in the biomarker-negative patient, how does that effect my ability to use it again in the platinum-sensitive setting as a maintenance strategy, which was what was done for this patient who initially received bevacizumab?

This transcript has been edited for clarity.

Case:A 64-Year-Old Woman With Ovarian Cancer

Initial Presentation

• A 64-year-old woman presented with abdominal bloating, low back pain, early satiety and progressive fatigue
• PMH: hysterectomy 5 years ago for benign indication; hypothyroidism managed medically; generalized anxiety disorder managed medically
• PE: diffuse lumbosacral pain with movement; abdominal tenderness and significant abdominal distension with a fluid weight consistent with ascites; unintentional weight loss of 8 lbs
• ECOG PS 1

Clinical work-up

• Pelvic ultrasound showed a ~5-cm complex left ovarian mass
• Chest/abdomen/pelvis CT revealed a complex pelvic mass and was also notable for abdominal ascites, omental cake, and retroperitoneal and inguinal adenopathy
• Paracentesis (1200cc) cytology confirmed high-grade serous ovarian cancer
• Omental biopsy histology also confirmed high-grade serious ovarian cancer
• Germline molecular testing: BRCA1/2wt
• Somatic testing: BRCA1/2 negative; HRD proficient
• CA-125, 360 U/mL
• Diagnosis: Stage III, high-grade serous epithelial ovarian cancer

Treatment

• Patient underwent TAH/BSO, lymph node dissection, with optimal debulking; R0
  • Carboplatin/paclitaxel q3 weeks for 6 cycles; CA-125 normalized; CR
  • Bevacizumab maintenance
• At 1 year post treatment, CA-125 increased; imaging revealed progressive retroperitoneal adenopathy suggestive of recurrent disease; not deemed a candidate for secondary surgery
  • Rechallenged with carboplatin/paclitaxel q3 weeks for 6 cycles; PR; predominantly enlarged lymph nodes
  • Rucaparib monotherapy maintenance