Defining Rucaparib's Value in Recurrent Ovarian Cancer

Shannon Westin, MD:This patient had an excellent response to chemotherapy. She was able to get to no evidence of disease again based on her CA 125 level and imaging. Certainly, this is what we would hope for and expect, especially in a germline-mutant population. Those patients tend to respond, or their tumors tend to respond, very well to chemotherapy. We’re often able to get them to a complete response again. So, she was right in line with what we would hope for. The problem, as we mentioned even in the upfront setting—and this is the same in the recurrent setting—is that these patients will often recur, and that’s really been the rationale for adding maintenance therapy.

Specifically in a patient population that has germlineBRCAmutations, the strategy of utilizing PARP inhibition has been very favorable over the last few years. This particular patient was offered rucaparib on a clinical trial. This clinical trial has been reported: ARIEL3. Her response was about 2 years of disease-free survival. That’s about average. I think that the actual trial was more like 17 to 18 months, but that’s certainly within the range of what we would expect. She had quite a bit of benefit from the use of PARP inhibition in this setting.

This particular patient had a very common adverse event that we see with the treatment of rucaparib, which is a transient elevation in her transaminases. She had an elevation of both ALT as well as AST. Initially when we were managing these patients, we would stop the drug, let things resolve, and then restart it. But what we learned, both in the ARIEL2 and ARIEL3 studies, is that this will often be a transient elevation that’ll go away on its on without interrupting a drug. So, you want to be safe and make sure there’s no evidence of hepatitis or inflammation or damage to the liver.

Watch that total bilirubin. You can use something called Hy’s Law, not to get too technical. Make sure the patient doesn’t qualify based on that law, and you can treat through. You just want to check on them maybe every couple of weeks and make sure you’re not seeing continued elevation. But the majority of these patients can stay on the same dose level, and they don’t even need to be dose reduced. Sometimes, if you do see some elevation—that transient elevation is continuing—you can do a dose reduction to just try to get that trend to go in the opposite direction.

Rucaparib has generally been extremely well-tolerated for the majority of patients who have utilized it for treatment. We talked about elevation and transaminitis or transaminases. We can also see a transient elevation in creatinine. But generally, this is not associated with renal failure or renal disease. Again, you can calculate a GFR, make sure that the kidneys are functioning well, and treat right through. This is not something that requires a dose interruption or even a dose reduction.

In addition, there are cross-PARP adverse events that we see; there are certain class effects. Things like nausea or GI distress can be seen early on. But with early management, aggressive management, and making sure the patient knows that these things can happen, you can get those to go away quite quickly. Something you can use is prophylactic antiemetics. Start giving them nausea medicine, an antiemetic, 30 minutes to an hour before the drug. Maybe even put a little food in their stomach to allow for them not to take it on a completely empty stomach. Those types of things can really mitigate the nausea, some of the reflux, and those types of things that can be very disturbing to patients.

Other things, like diarrhea or constipation, have not been as common. Generally, what we see in the first few months on therapy are the majority of the adverse events. Once you can mitigate those and manage those, patients can remain on these drugs for an extended period of time—like our patient here, for 2 years—with very few continued adverse events.

When you have a patient with platinum-sensitive recurrence, especially one who has a known germline or somaticBRCAmutation, it really makes sense to use these types of precision medicine strategies. We now have a number of PARP inhibitors available at our fingertips that have been clearly demonstrated to improve progression-free survival by some 15, 16, 17, or 18 months. That is a really impressive number that we haven’t previously seen in the setting of platinum-sensitive recurrence.

Now, we all worry when we start using new agents, and targeted therapies like PARP inhibitors can have different side effects than what we’re used to or what we’ve seen in the past with chemotherapy. But all you have to do is read the label and learn what to expect. Help educate your patients. Make sure they know that just because it’s a pill, that doesn’t mean there are no side effects. Make sure you mitigate those side effects early, and these patients can stay on therapy with a really long potential clinical benefit.

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