Ovarian Cancer: The Role of PARP Inhibitors and Beyond

Bradley J. Monk, MD, FACOG, FACS:One of the important considerations in treating platinum-sensitive relapse is not only bevacizumab, as we’ve discussed, but also PARP inhibitors. In early 2017, PARP inhibitors—first niraparib, then olaparib in August of 2017, and ultimately rucaparib, which is pending—were approved in platinum-sensitive relapsed ovarian cancer. So, in this particular patient, she would receive carboplatin/paclitaxel/bevacizumab, but she could have received carboplatin/paclitaxel and then if she responded, which was likely, PARP inhibition maintenance. And, again, we have 2 FDA-approved options, niraparib and olaparib, and soon a third likely, rucaparib. And the way that works is that patients who respond to platinum again have trouble repairing the platinum-induced double-stranded breaks, which is whatBRCAis. PARP works inBRCApatients, and PARP inhibition works in patients who respond to platinum. And that’s why it’s FDA approved in that setting.

Personally, this particular patient was treated with bevacizumab because she can be treated with PARP any time. Definitely, she could get it as maintenance, but she can also get it as treatment. There are now 2 PARP inhibitors that are also FDA approved in treatment. So, with PARP inhibitors, you’ve got 2 choices: maintenance in platinum-sensitive relapse or treatment. The treatment indication for olaparib is prior regimens and a germlineBRCAmutation, and for rucaparib, it’s 2 prior regimens, germline or somatic. So, I don’t know what the definition of a regimen is. Maybe bevacizumab counts as a regimen, but in any scenario, after she gets carboplatin/paclitaxel/bevacizumab, as she did, she will then have the option to get treatment with PARP inhibition. I get it that the sequence could have been reversed. We don’t have any randomized trials comparing what should be used first. I do know, though, that giving bevacizumab first probably does not reduce the activity of PARP inhibitor treatment.

So, that’s why this was done, because GOG 213 shows a 5-month improvement in overall survival when bevacizumab is added to carboplatin/paclitaxel in platinum-sensitive relapse. She got it, she had a long second progression-free survival, and now she can get a PARP inhibitor when she gets her second recurrence. Which PARP inhibitor? It’s tough. As I said, we got 2 that are labeled in treatment. They have some different side effects, but these PARP inhibitors are more similar than different, and the chance of responding to a PARP inhibitor in this setting after 2 lines of therapy in platinum-sensitive andBRCAgermline mutated is more than 50%. So, think about it. She was diagnosed in 2014. She has had 2 chemotherapy regimens, carboplatin and paclitaxel twice. She had almost a year of maintenance bevacizumab, and it has been 4 years. And now she’s going to embark upon PARP inhibition, and the chance of responding is greater than 50%. Then, after that, she has many other options. She’s still got pegylated liposomal doxorubicin, she’s still got topotecan, she’s still got weekly paclitaxel, she’s still got clinical trials. So, this will be a patient who easily lives 5, 6, 7 years, and she has already lived almost 4. And she has only had two 5-month periods of cytotoxic chemotherapy.

The era of targeted therapy in ovarian cancer is here, and I’ve reviewed bevacizumab. It’s approved in platinum-sensitive relapse. Soon, it will probably be approved in frontline therapy. I’ve told you about 2 PARP inhibitors that are labeled in maintenance platinum-sensitive relapse, olaparib and niraparib. And I’ve told you that you can have treatment with PARP inhibitors with the appropriate number of lines of prior therapy and a molecular signature, rucaparib and olaparib. So, that’s 4 FDA-approved targeted therapies that I’ve shared with you. We’re there. Immuno-oncology is next, antibody—drug conjugates are next, combinations are next, other biomarkers are next. The future is bright, and it is satisfying, finally, to take care of ovarian cancer patients because our options are so vast.

Transcript edited for clarity.

Platinum-Sensitive Recurrent Ovarian Cancer

September 2014

• A 40-year old Caucasian female presented to her gynecologist with abdominal pain and increased urinary urgency and frequency
  • PMH: unremarkable
  • FH: mother died of breast cancer at age 46
  • PE: tenderness in abdominal right lower quadrant; shifting dullness on abdominal palpation and percussion
  • Ultrasound: Abdominal and pelvic ultrasound showed a right-sided solid pelvic mass and ascites
• The patient was then referred to a gynecologic oncologist
  • Genetic testing was positive for BRCA1 mutation
  • Abdominal/pelvic CT findings showed a 5-cm x 2.5 cm x 3-cm right pelvic mass; ascites and omental cake was noted
  • CA125, 998 U/mL
• Biopsy findings showed stage 3C epithelial ovarian cancer
• Hysterectomy, bilateral salpingo-oophorectomy, and omentectomy was performed and optimal debulking was achieved (residual disease <1 cm)
• Treatment was initiated with IV/IP carboplatin/paclitaxel
  • After 6 cycles of therapy, CA-125 level declined to 9.3 U/ml.
  • Chemotherapy was tolerated well and without any unexpected toxicities

November 2016

• The patient reported feeling bloated and exhausted
• CT scan confirmed disease recurrence with ascites
• She was treated with carboplatin/paclitaxel/bevacizumab for 6 cycles and had a good response to therapy
• Following completion, she was continued on maintenance bevacizumab
• She continued to show improved response

January 2018

• The patient reported back with complaints of weight loss and abdominal distension
• CT scan revealed presence of small diffuse intraperitoneal masses