Recurrent Ovarian Cancer: Third-Line Therapy and Beyond

Shannon Westin, MD:Unfortunately, this patient had about 2 years on rucaparib therapy, but ultimately began having some increase in symptoms again. She had some abdominal bloating and fatigue. We were concerned, so we checked her CA 125 and it was elevated up to 1000 U/mL. Subsequent imaging did prove that she had a recurrence of disease in her peritoneal cavity.

Once you have a patient who has been on PARP inhibitor maintenance and has had a recurrence, of course you’re going to look at the old standby, a platinum-free interval. This particular patient was off platinum for several years, so retreatment with a platinum-based combination therapy makes a lot of sense. The options are the same as what we discussed before. You can combine carboplatin with a number of different chemotherapies: paclitaxel, pegylated liposomal doxorubicin, docetaxel, or gemcitabine. These things would be discussed with the patient. You can manage the toxicities, determine the logistics, and go forward with one of these platinum-based doublets.

If you can get that patient to another response, which a lot of these patients with germlineBRCAmutations will have—their tumor will have another beautiful response to platinum-based therapy—then comes the question of, what do you do? Can you reinstitute maintenance? This is a question we really don’t have an answer to yet. Certainly, it’s tempting to retry a PARP inhibitor in a patient who has a target. But you’ve got to wonder, why did that tumor grow to begin with? We do know that there is a development of resistance to PARP inhibitors.

What we don’t know is if a particular tumor develops resistance to 1 PARP inhibitor. Or, is that resistance mechanism translated across all PARP inhibitors? Or, would a different PARP inhibitor perhaps work better? That question has not been answered yet, although there are studies that are either ongoing or in development that are hopefully going to tease that out.

I certainly think a PARP inhibitor alone may not be enough, and we have a number of different PARP inhibitor combinations that are in development across a number of different targets, such as with antiangiogenics or PI3 kinase pathway abnormalities. And then, there are combinations of PARP inhibitors with immune therapies, which are certainly very exciting. We don’t know where they’re going to fit, whether that be earlier on in the process or in a setting like this where you have progression on PARP inhibitor maintenance. But we’ve got a lot of different opportunities that are in development.

I’ve been doing this for a long time, and to have so many FDA-approved agents in the same setting after having basically the desert before, where we had nothing to offer these patients except for chemotherapy, is really exciting. I think it’s up to us to start teasing out who gets what and when, and really perfect our ability to use precision medicine in these patients.

Transcript edited for clarity.

A 49-Year-Old Woman with Platinum-Sensitive Epithelial Ovarian Cancer and GermlineBRCA1Mutation

March 2013

• A 49-year-old African American woman presented to her primary care physician complaining of abdominal bloating
• PMH: chronic HBV infection, mild HTN
• FH: mother died of breast cancer at age 59, cousin on mother’s side died of ovarian cancer at age 65
• CT, ascites and bilateral 8-cm adnexal masses
• CA 125, 285 U/mL
• She underwent exploratory laparotomy followed by omentectomy, bilateral salpingo-oophorectomy, pelvic lymph node dissection, appendectomy, and resection of pelvic nodules
  • No gross residual disease (R0)
  • Germline molecular testing showed aBRCA1alteration
• Pathology: high grade epithelial ovarian cancer involving omentum, both ovaries, and 3 micro-metastatic lymph nodes
• She was treated with IV/IP paclitaxel/cisplatin; after completion, CA 125, 14.2, clinically NED

September 2015

• 18 months later, on routine follow up, CA 125, 203 U/mL
• Lymph node disease and carcinomatosis on imaging  
• She was treated with gemcitabine/carboplatin for 6 cycles
  • CA 125, 11.3; clinically NED
• The patient was started on rucaparib maintenance therapy while enrolled on a clinical trial
• After 2 cycles of therapy, the patient’s live enzymes rose transiently and then returned to normal
  • AST, 127 U/L
  • ALT, 142 U/L
  • Creatinine, 1.5 mg/d            

November 2017

• The patient complained of worsening fatigue and bloating
• CA 125, 1004 U/mL