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

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

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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: PARP inhibitors have emerged as paradigm changing in the ovarian cancer space. We to some degree simplify the mechanism of action, although we believe it’s more complex. But essentially what you have is DNA damage is occurring constantly, particularly in malignant cells that are replicating carelessly. And when you acquire double-stranded DNA breaks, you need effective homologous recombination deficiency [HRD] dependent on BRCA, although there are other low fidelity, higher error mechanisms for DNA repair. But you need a functional BRCA for high fidelity repair of double-stranded breaks. Conversely, we also have single-stranded breaks in the DNA, and PARP and the PARP proteins are responsible for facilitating the repair of single-stranded DNA breaks. What we’ve identified is in patients who are BRCA mutated or homologous recombination deficient, they can't repair double-stranded breaks efficiently. If you have single-stranded breaks, at the replication fork those become double-stranded breaks. And if you have nonfunctional BRCA or homologous recombination deficiency, that drives cell death, synthetic lethality.

Conversely, if you give a patient a PARP inhibitor, then you’re going to be ineffective at repairing the single-stranded breaks, driving double-stranded breaks, DNA damage, cells unable to repair those who are homologous recombination deficient or BRCA mutated, and increase cell death. Beyond that, we also understand that there’s PARP trapping, when the PARP inhibitor binds to the PARP on the DNA complex, it’s unable to be dissociated. That leads ultimately to cell death as well. The mechanism of action of PARP inhibitors is to prevent effective DNA damage repair. When you have inefficient DNA damage repair, you have accumulation of DNA damage, and in cells that are HRD, homologous recombination deficient, there’s a propensity, a greater increase in cell death, but even in those that are biomarker negative, you could still see the impact via PARP trapping, for instance. And PARP inhibitors are used most frequently as mentioned in the ovarian cancer space, although there are now PARP approvals in other solid malignancies as you may be aware.

There are class effects for these drugs. There are potential treatment-related adverse events that we have to be thoughtful about. And we counsel patients about this proactively. If you’re proactive, and if you’re able to speak to your patient about treatment-related adverse events, you prepare them for what they may experience and you’re able to keep them on treatment. Rucaparib is dosed at 600 mg orally twice daily, and importantly you can have dose reductions. You can go from 600 to 500 mg twice a day to 400 mg twice a day. And what’s relevant here is that when you think about the treatment-related adverse effects, the most common is fatigue. You educate your patients that fatigue may be expected, but that with time it should improve. You educate them about GI [gastrointestinal] adverse effects, nausea, abdominal cramping, sometimes diarrhea. You prescribe antiemetic pain medications. You prescribe antidiarrheals if they’re having diarrhea, or you educate them about foods that may help with their symptoms. And there are hematologic adverse events. That’s why we check blood counts when patients are started on PARP inhibitors regularly because we know that one of the more common treatment-related adverse effects hematologically is anemia, less commonly neutropenia, and less commonly with rucaparib, thrombocytopenia. If we’re thoughtful about these treatment-related adverse effects, we can be proactive. We can dose interrupt or dose reduce if appropriate to keep patients on treatment because the goal is to keep patients on therapy in this recurrent setting until disease progression or unacceptable treatment-related adverse effects.

I do mention there are some more life-threatening but less common adverse effects that can be experienced. Myelodysplastic syndrome [MDS] or AML [acute myeloblastic leukemia] can be an adverse effect from treatment with PARP inhibitors in the maintenance setting in the recurrent phase. That’s why we don’t want to ignore hematologic abnormalities that were persistent for a period of time. You want to really be thoughtful about checking blood counts until you reliably know that your patient is tolerating treatment. You check intermittently. If you have hematologic toxicity or adverse events that persist for 4 weeks or longer, you want to refer those patients for consideration of a bone marrow biopsy because you want to exclude MDS or AML. Pneumonitis can occur exceedingly rarely with PARP inhibitors but can occur on treatment. All of these are things that we have to be thoughtful about in the treatment setting. But importantly, the tolerability on trial has been clearly established, meaning the percentage of patients who need to discontinue therapy for treatment-related adverse effects is very low, on the order of 10% or less. This speaks to the fact that if we are effective in counseling and in adverse event mitigations, patients can stay on therapy even if they require a dose interruption for a period of time or a dose reduction, which are both things that can easily be done.

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