Combination Therapy With Niraparib and Bevacizumab for Ovarian Cancer

Benedict Benigno, MD:Combining niraparib with bevacizumab, the rationale would be to try to give the patient the longest-possible progression-free interval. As we saw, the patient had a recurrence in 2 years and then a recurrence in 1½. It would be very nice if the second recurrence were to show up in 3½ years because, in my opinion, the longer the platinum-free interval, the more likely they are to respond to the reinvigoration of platinum.

There was a trial discussed at the recent meeting of the Society of Gynecologic Oncologists in Honolulu, Hawaii, looking at the combination of bevacizumab with a PARP inhibitor. And not only was it well tolerated, but the results were improved over using 1 of those alone in the maintenance setting.

I have been using this for several years. I used it before it went into the mainstream, including a board member of my Ovarian Cancer Institute who tolerated a PARP inhibitor with bevacizumab for over a year without difficulty.

With a PARP inhibitor, the GI [gastrointestinal] tract is the Achilles’ heel. So they should be treated proactively for dyspepsia, nausea, vomiting, and diarrhea. Fatigue is an overwhelming problem with a PARP inhibitor, so they must be counseled to please push themselves. It’s the cancer Olympics. I want you to go into training. I want you to win a gold medal. They sometimes have rashes; they sometimes have dysgeusia. There are a host of symptoms, but nausea, vomiting, diarrhea, the GI tract, and fatigue are the big problems along with hematologic adverse events, dropping the platelet counts, the white blood cell count, and the hemoglobin. With bevacizumab, you have a different group of symptoms. You have problems with proteinuria, problems with pseudo-encephalopathy syndrome, and problems with platelet count occasionally. But these do not cross over the PARP inhibitor with bevacizumab. So the combination is far better than most of us thought it was going to be.

I have had to stop 1 patient on a PARP inhibitor because of fatigue. Generally speaking, you lower the dose, you have them exercise, and I use Ritalin [methylphenidate] in these patients sometimes with very interesting and excellent results.

Well, I look at their profile—I mean their age, and exactly how they might be able to tolerate this regimen. The addition of bevacizumab does provide an added level of concern, especially in the elderly patient. I would want to see that her kidney function and liver function studies were within normal limits. I would look at how they tolerated the chemotherapy, and I might, if they were somewhat fragile, start with a PARP inhibitor and consider if that was well tolerated, to add bevacizumab at a later date.

Things are changing so rapidly. Immunotherapy is being used with a greater frequency in gynecologic cancers. Personally, I think chemotherapy is going to have a death knell associated with it in the very near future. It’s had a 70-year run since Sidney Farber’s legendary work with childhood leukemia in the 1940s. I think it’s going to be replaced by targeted therapy, PARP inhibition, immunotherapy, and perhaps other agents that could be added into this cocktail, which would provide a patient with far better statistics and a much better quality of life.

Unfortunately, it’s unusual for me to be able to find a patient with ovarian cancer on whom I can use immunotherapy, because you do need to have either a deficiency in the mismatch repair or a microsatellite insufficiency MSI high, and that occurs in only 5% of patients with ovarian cancer. Whereas it will be seen in about 16% of patients with endometrial cancer.

When PARP inhibitors were first approved, they were approved only for patients with a mutation on theBRCAgene. And 1 of the great contributions of the NOVA trial was that it showed that patients who wereBRCAwild type could benefit from a PARP inhibitor, albeit it not as well as those who wereBRCA-mutated. Maybe the addition of other things to a PARP inhibitor may overcome the need to have a deficient MMR [mismatch repair] or a high MSI. One of the very interesting papers that emerged from the recent SGO [Society of Gynecologic Oncology Annual] Meeting on Women’s Cancer had to do with recurrent cancer of the ovary and the use of pembrolizumab, what is an immunotherapy drug; bevacizumab; and metronomic oral Cytoxan, regardless of the MMR or MSI status. Perhaps adding something to the immunotherapy drug will make it effective regardless of MMR or MSI status.

It’s a very exciting time to be an oncologist. For decades—and I’m not talking about a few months but for decades—it’s been the debulking procedure, 6 rounds of carboplatin and Taxol, and then as so many of my patients have told me, waiting for the other shoe to drop, which is a metaphor for the advent of a recurrence. Now we have bevacizumab, we have PARP inhibition, and we have the extremely exciting arena of immunotherapy.

Transcript edited for clarity.

Case: A 58-Year-Old Female With Progressive Ovarian Cancer

H & P

• A 58-year-old female presents to the clinic for bloating, pelvic pain, early satiety, and urinary urgency. She reports intolerance to strenuous activity at the gym for the past four months but is still able to carry out daily activities such as work, and house chores.
• PE: controlled HTN, abdominal distension;
  • BP: 130/70 mmHg
  • ECOG: 1

Imaging

• CT with contrast of the pelvis, abdomen, and chest reveals bilateral serous cystadenocarcinomas

Biopsy and Labs

• Pathology: high-grade serous carcinoma, epithelial ovarian cancer
• BRCA1-/2wt
• HRD/+
• CA-125: 280 U/mL

Treatment

• Diagnosis: stage IV ovarian cancer
• Patient underwent hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and tumor debulking
• Received IV paclitaxel and carboplatin and bevacizumab, 6 cycles

Follow-up

• CA-125, 43 U/mL upon completion of 6 cycles chemotherapy
• Ten months later at routine follow up, patient presented with recurring symptoms; CA-125, 565 U/mL
• Started on carboplatin/paclitaxel for 6 cycles plus bevacizumab
• Patient achieved a partial response, started on niraparib maintenance therapy
• Four months later:
  • CBC: WNL, SCr: 0.8, AST: 10 u/L, ALT: 7 u/L, and ANC: 1.7 x 10⁹/L
  • BP, WNL
  • ECOG 1