Future Treatments in Ovarian Cancer

EP: 1.Case Presentation: A 57-Year-Old Woman With Ovarian Cancer

EP: 2.Molecular Testing: Ovarian Cancer

EP: 3.First-Line Therapies in Ovarian Cancer

EP: 4.Rucaparib Maintenance Therapy in Ovarian Cancer: The ARIEL3 Trial

EP: 5.Toxicities With PARP Inhibitors for Ovarian Cancer

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EP: 6.Future Treatments in Ovarian Cancer

Lyndsay Willmott, MD: The ARIEL4 trial was a clinical trial designed to look at randomization of patients who have a BRCA mutation, either germline or somatic, in the setting of a recurrence to receive either cytotoxic chemotherapy or rucaparib. The comparison is between chemotherapy and oral PARP inhibition. The chemotherapies that the patients received in this clinical trial were based on their platinum sensitivity. If these patients were platinum-resistant, then they went on to paclitaxel. If they were platinum sensitive, then they went on to a platinum-based regimen. They were randomized to receive either of those chemotherapeutic agents or rucaparib.

When we look at the outcomes, the patients who were randomized to rucaparib had improvements in their progression-free survival vs patients who were randomized to the cytotoxic chemotherapy. That makes sense mechanistically. We were looking specifically at a patient population of those women who had a BRCA mutation. Based on the mechanism of action of rucaparib, the fact that these patients responded perhaps a little more robustly to the PARP inhibition vs the cytotoxic chemotherapy makes sense from a mechanistic standpoint.

The clinical trial did include a small subgroup of patients who had evidence of BRCA-reversion mutations. Those were patients who had a BRCA mutation and then subsequently had a reversion mutation. In other words, they’re acting like patients with BRCA wild-type disease. Those patients showed they had the reverse. It‘s a small group of patients, but in that patient population, they performed worse if they were randomized to rucaparib. It makes sense mechanistically. If they‘re very effectively able to repair their DNA double-stranded breaks because their BRCA is functioning more appropriately, then perhaps they’re less likely to respond to rucaparib monotherapy in this setting.

This allows us to consider whether you want to place a patient onto chemotherapy at time of recurrence. The truth is the majority of our patients are likely going to be exposed to PARP inhibition in earlier lines of therapy given the fact that PARP inhibitors are approved for use in the up-front setting and have been widely available for use in the platinum-sensitive recurrent setting for maintenance. The patient pool we’re talking about in this setting, who likely have never seen PARP inhibitors previously and who may be candidates for PARP inhibition at time of recurrence, is small. But there are certainly some patients who have a BRCA-associated ovarian cancer who haven’t received PARP inhibitors, and you should keep this in the back of your mind as an opportunity to consider monotherapy with PARP inhibitor as opposed to cytotoxic chemotherapy.

When we’re talking about ovarian cancer, we’re always trying to push the bar forward with our goal to cure more patients. That’s obviously the goal for all of us. We recognize that the opportunity for cure is likely most profound at the time of diagnosis. When you‘re looking at clinical trials, we’re starting to utilize a number of therapeutic modalities in the upfront setting in combination. There are number of clinical trials undergoing evaluation or that have completed accrual and are awaiting completion of their events, including the use of checkpoint inhibitors along with PARP inhibition. Unfortunately, thus far in ovarian cancer trials, checkpoint inhibitors haven’t been successful. We haven’t seen significant improvement in progression-free survival in prior clinical trials that have used checkpoint inhibition.

There have been some subset analyses from these trials trying to better understand, of the patients who are enrolled, are there a group of patients—perhaps biomarker driven with PD-L1 testing, for example—who may be more likely to respond to checkpoint inhibition? Or perhaps we need to utilize multiple drugs together to make these drugs more likely to be successful, combining drugs and hoping to see more robust response. There are a number of clinical trials that are pending their outcome evaluations that include checkpoint inhibition. I’m curious to see if some of those combination strategies may allow checkpoint inhibitors to be utilized in ovarian cancer.

We all understand that the viewpoint of ovarian cancers is drastically different from how it was 5 years ago. Five years from now, the landscape will have continued to shift and grow. We recognize that surgery and chemotherapy remain mainstays of treatment of patients with ovarian cancer in the up-front setting. But we also recognize that maintenance therapies can hopefully help us improve progression-free survival. In patients who have BRCA mutations, it’s truly standard of care to utilize PARP inhibition as part of their maintenance strategy. We certainly recognize that the presence of homologous recombination deficiency is also very prevalent, and these patients are also likely to benefit.

There’s the availability for patients, even those who are homologous recombination proficient, to go onto PARP inhibitor maintenance or course bevacizumab maintenance. But it’s that homologous recombination proficient group that remains our most challenging treatment population and the group of patients for whom we need to continue to try to push the bar forward. Because when we look at the outcomes from studies evaluating PARP inhibition in patients who are homologous recombination proficient, unfortunately that improvement in progression-free survival isn’t as profound as in patients who have a BRCA mutation or a homologous recombination deficiency. Those patients represent a more challenging group, and I’m very interested to see if we can make some progress in that group, especially to help them have improvements in their platinum-free intervals. Hopefully 1 day we can see improvements in overall survival in all our patients with ovarian cancer and improve our chances of curing patients.

Case Overview: A 57-Year-Old Woman With Ovarian Cancer

Initial Presentation

A 57-year-old woman presented with progressive abdominal discomfort and bloating, early satiety, new-onset constipation, and unintentional weight loss

PMH: postmenopausal; hypertension—medially controlled; osteoarthritis

PE: right lower quadrant tenderness on palpation

ECOG PS 1

Clinical work-up

Pelvic exam with ultrasound showed a ~4.5-cm right ovarian mass

Chest/abdomen/pelvis CT with contrast revealed a right adnexal mass with lymph node involvement and ascites

Paracentesis (1200cc) cytology confirmed high-grade serous epithelial ovarian cancer

Germline molecular testing: BRCA1/2wt

Somatic testing: BRCA1/2 negative; HRD positive

CA-125, 360 U/mL

Diagnosis: Stage III, high-grade serous epithelial ovarian cancer

Treatment

Patient underwent TAH/BSO, lymph node dissection, with optimal debulking; R0

Carboplatin/docetaxel q3 weeks for 6 cycles; CA-125 normalized; CR

Bevacizumab maintenance

At 2 years post chemotherapy, patient experienced abdominal bloating and pain, nausea and vomiting and progressive fatigue; CA-125 increased; imaging revealed progressive retroperitoneal adenopathy suggestive of recurrent disease; not deemed a candidate for secondary surgery

Rechallenged with carboplatin/docetaxel q3 weeks for 6 cycles; PR; predominantly enlarged lymph nodes

Rucaparib single-agent maintenance 600 mg bid

Patient developed clinically significant thrombocytopenia; dose reduced to 500 mg and patient remained on treatment until disease progression

Transcript edited for clarity.