Advanced Ovarian Cancer After Third-Line Therapy

Kathleen Moore, MD:Referencing back to our historical case, our patient has seen 3 lines of platinum-based chemotherapy and has now recurred again and is still considered appropriate for retreatment of platinum. The standard of care, probably until 3 weeks ago, would still be carboplatin-based therapy, and that would be appropriate. You could select single-agent carboplatin because she’s seen doublet therapy 3 times and she may be a little tired. So single-agent carboplatin may be appropriate. She has not yet seen carboplatin and pegylated liposomal doxorubicin. So if she’s of a constitution that you feel like doublet therapy could be useful, then that would be an option.

This is a patient who we know does not have a germlineBRCAmutation, so it would be important to test her tumor. We don’t have that piece of information yet, and that may also help us in this line of therapy. If we sent her tumor off for genomic testing and she was found to have either a germlineBRCAmutation or was positive for the homologous recombination deficiency [HRD] assay, then you might pick carboplatin or carboplatin/pegylated liposomal doxorubicin, try and get her into response again, and then use PARP [poly ADP ribose polymerase] maintenance. The PARP maintenance indication is not just for frontline therapy or for first recurrence. It can be any line of therapy. In fact, all of the studies that have looked at the use of PARP maintenance in the recurrent setting allowed for several lines of therapy. Safety data do exist there. So those are very reasonable therapies for her.

The shift in the standard of care, potentially, came with SOLO3. SOLO3 was presented at ASCO [the American Society of Clinical Oncology annual meeting] in 2019. We’re waiting for the manuscript. It has not resulted in a change in the label, but it was the first randomized study to evaluate a PARP inhibitor alone versus chemotherapy. So, instead of chemotherapy. Instead of doing induction carboplatin, or induction carboplatin/pegylated liposomal doxorubicin, and then trying to hope to get to a PARP, this goes straight to the PARP versus chemotherapy.

And this is only in a platinum-sensitive population. They all had to have aBRCAmutation, but the control arm did not contain platinum. So that is 1 thing to know. But when you look at the response rate here—there were patients who had to have been in the third line or beyond—the response rate was 80% for a PARP inhibitor in that late line of therapy. Again, in a biomarker-directed population, but that’s a pretty remarkable response rate in the fourth line and beyond with very durable responses. The progression-free survival difference also supported that overall response rate endpoint as a marker of benefit in that patient population.

Now we’ve had an indication. In fact, the first indication for olaparib was inBRCA-associated tumors that had received at least 3 lines of chemotherapy based on a basket trial that showed us a 33% response rate in that population. And so, this is the confirmatory study for that. That has been an accelerated approval for a long time, so it may not change the label so much but it does add to the dialogue about, do you need chemotherapy at all in this recurrent setting, or can you go straight to a PARP inhibitor? We have the paper I just referenced that led to an indication.

You have work with rucaparib from Study 10 and ARIEL2, which led to the accelerated approval of rucaparib in patients with 2 or more lines of therapy and a response rate that exceeded 50%. That was a single-arm study. So those indications have been there, but only for patients withBRCA-associated tumors, and in the case of rucaparib, it could be somatic as well. So I think there’s been some comfort with substituting in that biomarker-directed population. Whether we really completely are able to use PARP inhibitors beyond that particular biomarker population into HRD, into all-comers platinum-sensitive, those studies are coming.

For this patient without aBRCA-associated cancer, that would not be an indication right now. Her best line of therapy would probably be platinum-based therapy with hopes to get her to PARP maintenance, but very soon that story may change. If she did have a somaticBRCAmutation, a consideration could be to use either olaparib or rucaparib instead of chemotherapy, and that would be on-label as well. But you would need her molecular profiling to know that.

Transcript edited for clarity.

Case: A 58-Year-Old Female With Heavily Pretreated Recurrent Ovarian Cancer

H & P

• 58-year-old female diagnosed in 2014 with stage IV ovarian cancer
  • Pathology: high-grade serous carcinoma, epithelial ovarian cancer
  • CA-125: 460 U/mL
  • CT with contrast of the pelvis, abdomen, and chest revealed a 4-cm mass in the left ovary and peritoneal carcinomatosis
  • Patient underwent suboptimal debulking surgery; residual disease 1.5 cm
  • Received IV/IP carboplatin/paclitaxel (6 cycles); achieved complete remission
• 2 years later (2016) symptoms returned; CA 125, 255 U/mL; ECOG: 1
  • Received carboplatin/paclitaxel (6 cycles) and bevacizumab; achieved good partial remission; CA 125, 45 U/mL; continued on bevacizumab maintenance
• 1.5-years following second-line therapy (2017), again presented with symptoms; CA 125, 550 U/mL; ECOG: 0
  • Genetic testing;gBRCA1/2wild-type
  • Received carboplatin/gemcitabine (6 cycles); CA 125, 46 U/mL; achieved complete remission
• Currently:
  • CA 125, 620 U/mL
  • CT shows several small masses in the lung left lower lobe (largest is 3 cm)
  • ECOG: 0