Considerations for Selecting PARP Inhibitor Maintenance Therapy

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

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

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

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EP: 6.Considerations for Selecting PARP Inhibitor Maintenance Therapy

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

Ramez Eskander, MD: With the evolution of PARP inhibitors as a treatment strategy in the ovarian cancer space, we’ve realized that we’ve made significant gains and have various treatment options in the setting, and it’s important to note that this patient in this clinical scenario was counseled and was treated with maintenance rucaparib in the platinum-sensitive response. Again, this patient had received maintenance bevacizumab monotherapy in the front line after initial completion of chemotherapy. It is a patient who is PARP inhibitor naïve specifically. And that’s important to remember. We know the data regarding rucaparib, the ARIEL3 clinical trial supporting the efficacy, the safety, and the tolerability of this drug, which was again given until disease progression or unacceptable adverse events. There was also an interesting abstract that was presented that compared real-world data among PARP inhibitors. There are other options for PARP maintenance in the platinum-sensitive setting in a patient who is PARP naïve. And what we saw was that rucaparib and olaparib appeared to be better tolerated than niraparib when it came to dose interruptions or dose reductions. We don’t have any head-to-head data the way that we want it, but they are data that help us contextualize potentially the treatment-related tolerability or adverse effects that may be experienced on therapy. The other important thing to note is that niraparib has an individualized starting dose, a dose that’s dependent on baseline weight and platelet count. If you have a patient who has struggled with thrombocytopenia, understanding that may guide you away potentially from one PARP inhibitor to consider another PARP inhibitor such as rucaparib for maintenance strategy. Analogously, a patient who has poorly controlled hypertension may not tolerate niraparib as well, and you might want to consider others.

There are nuances here when making this decision. We know that there are multiple agents that are approved in this setting, but the patient clinical case may help inform and guide treatment choices. And again, rucaparib is dosed at 600 mg twice a day. You have multiple opportunities for dose reduction to help keep a patient on treatment, which again is the most important component to drive efficacy in this setting. I have used all PARP inhibitors in clinical practice. I’ve used them in the front line as maintenance treatment strategies. I’ve used them in the platinum-sensitive recurrent setting. I’ve used them as treatment monotherapy in the later-line setting previously. It’s important to know, the take-home message here is all of these drugs can be given. They’re given orally. You want to be thoughtful about treatment-related adverse effects, but almost universally patients can stay on treatment as long as they’re benefitting from therapy. And it’s uncommon to have to discontinue treatment because of adverse effects. And I empower you when you’re using these medications to be proactive about adverse-event mitigation strategies, dose reductions and interruptions, with a goal for continuing treatment for as long as possible. And rucaparib can be used in a setting just like this. I have many patients who are treated with rucaparib in a platinum-sensitive maintenance strategy, some with many years of benefit. I have patients treated with rucaparib as a treatment strategy.

That pivots nicely into review of the ARIEL4 clinical trial. And ARIEL4 is a study that looked at rucaparib vs chemotherapy in patients with advanced stage epithelial ovarian cancer who were also found to have a deleterious BRCA mutation. This may not be as relevant in the future. Why? Because now we know that patients who have a BRCA mutation in the front line should be all receiving maintenance PARP in the frontline setting. When they recur, there are no data for PARP rechallenge after prior PARP yet. Those are emerging data and we’re learning more about it. But as it exists right now, it’s limited. But the ARIEL4 clinical trial looked specifically at BRCA-mutated patients, looking at rucaparib vs chemotherapy. And again, patients were randomized to rucaparib 2:1, 600 mg orally twice daily vs physician’s choice chemotherapy. And their progression-free intervals were defined. And what we saw was a benefit when you looked at rucaparib vs chemotherapy. Patients with relapsed BRCA-mutated ovarian cancer who received rucaparib based on the ARIEL4 clinical trial had a significant improvement in progression-free survival vs standard of care chemotherapy. Again, it’s hard to know what the relevance of this is going to be with earlier-line use of PARP inhibitors, but it does suggest that if you happen to have a patient who you run into in clinical practice who has not yet seen a PARP and has recurrent disease, rucaparib can be used as an effective treatment strategy for these patients vs chemotherapy. And gives us another bow in our quiver to use in these patients. It’s administered orally. It does not require them to come to an infusion center and receive an infusion. And that’s clinically relevant in patients who are dealing with recurrent ovarian cancer.

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