First-Line Therapies in Ovarian Cancer

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

EP: 2.Molecular Testing: Ovarian Cancer

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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

EP: 6.Future Treatments in Ovarian Cancer

Lyndsay Willmott, MD: This patient was treated by her provider with carboplatin and paclitaxel, which has been established as the standard of care for frontline therapy of ovarian cancer. This is a very reasonable choice. When providers are deciding what they may choose to do in the adjuvant setting, part of what impacts that choice is based on the patient’s surgical outcome. If this patient undergoes up-front surgery and has resected to no gross residual disease, then we may consider them to be in lower-risk group. Though the truth is there are probably no real cases of lower-risk advanced-stage ovarian cancer. But lower-risk groups may include those women who were deemed candidates for surgical excision and then undergo surgery and have resection of all their visible or gross disease, and then subsequently placing them onto carboplatin and paclitaxel.

Interestingly, this patient was then placed onto bevacizumab in maintenance, having not been on bevacizumab as a component of her up-front adjuvant therapy. Personally, I don’t typically start bevacizumab in maintenance setting if I haven’t used it along with cytotoxic chemotherapy, because that isn’t how the initial trials were designed. The initial trials utilized bevacizumab along with the cytotoxic chemotherapy, and then after completion of the cytotoxic chemotherapy, transition to bevacizumab. I’m a rule follower in general, so I typically would utilize the bevacizumab along with the cytotoxic and then start the bevacizumab maintenance.

There have been a number of trials that have had secondary analyses to see who may benefit from the addition of bevacizumab. There’s some suggestion that perhaps these higher-risk patients—patients who required neoadjuvant chemotherapy because their disease burden was too much to undergo an up-front surgery, or patients who had evidence of residual disease at the completion of their surgery—they may benefit from the addition of bevacizumab to the cytotoxic backbone. There may be some consideration for utilizing that triplet therapy in those higher-risk patients.

As far as whether I may have made this with modifications, this patient had a lot of testing in the up-front setting, including HRD [homologous recombination deficiency] testing. Obviously, that’s a different group of patients, so there could be a consideration that if you wanted to use bevacizumab in that patient population, if you’ve used the bevacizumab along with the cytotoxic and the patient subsequently has a diagnosis of HRD, then they would be a candidate to have olaparib added in for maintenance along with their bevacizumab, based on the PAOLA-1 trial. Or if this patient hasn’t had bevacizumab along with her cytotoxic, you could consider adding niraparib after completion of her carboplatin and paclitaxel as maintenance. That’s single-agent niraparib maintenance. That’s based on the PRIMA trial. In that trial, the biomarker specificity wasn’t required to allow those patients to receive niraparib monotherapy based on their trial and break down of the subgroups that were evaluated, which included all comers regardless of BRCA status or homologous recombination deficiency. Those are some options for treatment for this particular patient that were a little different from what was discussed within the case.

Many providers have questioned whether all patients with ovarian cancer are candidates for some form of up-front maintenance therapy. Certainly, based on indications, all patients could be candidates for maintenance therapy. Does that mean all patients should get maintenance? These are 2 different questions and answers. The most important thing when we’re talking with our patients with cancer is to understand their goals of therapy and for them to understand the pros and cons of maintenance. Obviously, we have multiple maintenance opportunities, including bevacizumab maintenance, and combination maintenance strategies for patients who have BRCA mutations or homologous recombination deficiency with bevacizumab plus olaparib. Patients who have a BRCA mutation, either germline or somatic, could be candidates for olaparib monotherapy. For all comers, regardless of BRCA mutational status or homologous recombination deficiency status, they could be candidates for niraparib therapy as far as maintenance strategies are concerned.

As it turns out, it appears that all patients with ovarian cancer may be candidates for maintenance. But obviously, these medications have toxicities and pros and cons for use, so it’s very important to talk with your patient about their opportunities for maintenance. Discuss why they meet benefits based on their own particular tumor profiling or genetic status and talk to them about their feelings regarding these toxicities. That can help decide whether patients should go onto maintenance therapy.

The factors that help determine whether you’re going to use maintenance therapy, or which maintenance therapy you use, are determined by which cytotoxic combination you choose. If a patient is going to be going on to neoadjuvant chemotherapy, or someone with significant disease burden was unable to be successfully cyto-reduced to no growth residual disease, and you decide that patient is someone who you want to place onto cytotoxic [chemotherapy] plus bevacizumab, then that may help to direct what you’ll use for maintenance. For example, the majority of providers who start a patient on bevacizumab during their cytotoxic chemotherapy would then subsequently continue that bevacizumab in maintenance. And if you have done molecular testing during treatment, including assessment for presence of homologous recombination deficiency or BRCA mutation, then that patient, based on the PAOLA-1 trial, could subsequently start olaparib in maintenance along with their bevacizumab.

Another example of this would be a patient in whom you test during their treatments and you determine that they have evidence of a BRCA mutation. That certainly might allow you to decide that you want to transition them from their cytotoxic [chemotherapy] onto PARP inhibitor maintenance. One of the most important things when we look at these clinical trials is that patients have to have at least responded to their platinum-based cytotoxic chemotherapy with partial response at the completion of their up-front chemotherapy. Patients who aren’t responding to their platinum are thankfully very uncommon, but platinum-refractory primary patients probably wouldn’t be the best candidates to go on to a PARP inhibitor, based on their own response. These patient characteristics can help decide what you’re going to use for your initial treatment strategy. And then your initial treatment strategy can certainly influence if you choose to use maintenance, and if so, if you’re going to use some single-agent maintenance or if you’re going to use a combined modality maintenance therapy.

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.