Expert Details the Importance of PARP Inhibitors for BRCA-Mutant Ovarian Cancer in 2 Case Studies

Shannon Westin, MD, MPH

Shannon Westin, MD, MPH

Shannon Westin, MD, MPH, recently explained the treatment considerations and decisions she makes when treating patients with ovarian cancer. Westin, an associate professor in the Department of Gynecologic Oncology and Reproductive Medicine, and the director of early drug development at The University of Texas MD Anderson Cancer Center, explained her treatment decisions based on 2 case scenarios during aTargeted Oncologylive case-based peer perspectives presentation.

Case 1

January 2017

A 69-year-old Caucasian woman presented to the emergency department with shortness of breath. Her past medical history indicated mild hypertension and diabetes mellitus, medically managed, and morbid obesity. A physical exam showed large-volume ascites.

A CT angiography of the chest showed large bilateral pulmonary effusions, but no pulmonary thromboembolism. A CT of the abdomen and pelvis demonstrated peritoneal carcinomatosis and bilateral masses. Laboratory findings were remarkable for CA 125, 525 U/mL. A thoracentesis (1500 cc); cytology showed high-grade adenocarcinoma and a paracentesis (4500 cc); cytology showed high-grade adenocarcinoma. A core biopsy of omentum showed high-grade serous carcinoma. Markers for p53, PAX 8, WTI, and CK7 were all positive, andBRCA1/2wild type.

TARGETED ONCOLOGY:What are the treatment options for this patient?

My first thought is that this is a classic presentation for ovarian or peritoneal cancer. The number one question that we are always trying to determine with a patient like this is, should we first go for a cytoreductive surgery? Or, should we pursue neoadjuvant chemotherapy?

There are a number of ways that you can make that decision. Certainly, some of the things [to consider] for this patient is the presence of bilateral pulmonary effusions, which can make it quite difficult to debulk a patient. So neoadjuvant chemotherapy would be a reasonable option. Another option would be to perform a laparoscopy to utilize the validated score to determine the ability to optimally debulk a patient and then decide for neoadjuvant chemotherapy versus primary cytoreductive surgery based on the results of that surgery.

TARGETED ONCOLOGY:How would adjuvant chemotherapy be used in this setting?

If we decided to pursue neoadjuvant therapy, a combination of paclitaxel/carboplatin given intravenously would be reasonable. That could be given every 3 weeks, or in a dose-dense fashion. Ideally, the patient would go on to receive an optimal cytoreductive surgery and then be continued on adjuvant chemotherapy after surgery.

TARGETED ONCOLOGY:When do you typically test forBRCA1/2mutation status?

The recommendation for germline testing would be for a patient to be tested at the time of diagnosis. Once you know you have a high-grade ovarian cancer, that patient should be tested for germlineBRCA1/2mutations.

TARGETED ONCOLOGY:Do you test for somatic mutations in the tumor?

This testing is a little bit more controversial as far as when to do it. It is indicated now for ovarian cancer. We often won't test for somatic mutations in the tumor until the patient recurs. As newer drugs are getting moved up to the upfront setting, it may be prudent to test for somatic mutations upfront. We are eagerly anticipating results from PARP inhibitor maintenance trials. It may be that, in the future, we will want to do the testing early. At this point, with what we know, we don't use those data until the recurrence setting.

The patient underwent debulking surgery with incomplete cytoreduction. She was treated as part of a clinical trial with carboplatin/paclitaxel plus bevacizumab (Avastin) followed by continuous bevacizumab maintenance.

April 2018

Fifteen months later, the patient complained of severe abdominal bloating and fatigue. Imagining showed multifocal recurrence within the abdominal cavity. Her CA 125 was elevated to 322 U/mL and she had an ECOG performance status of 1.

She was started on carboplatin/docetaxel (Taxotere) and after 6 cycles of therapy she had a partial response to therapy with bulky residual disease. She was then initiated on rucaparib (Rubraca) maintenance therapy, 600 mg twice a day (BID). Her hemoglobin fell to 7.2 g/dL; managed with treatment interruption, and then dose reduction to rucaparib 500 mg.

TARGETED ONCOLOGY:What is your reaction to the patient's response to first-line therapy?

We are starting to move away from platinum-sensitive and platinum-resistant. But certainly, her platinum-free interval of 15 months is a positive prognostic sign and indicates that the tumor would be sensitive to platinum again.

TARGETED ONCOLOGY:What is the rationale for using maintenance therapy?

The rationale is to potentially improve progression-free survival (PFS) and prevent recurrence. Additionally, this would allow the patient to have time off from platinum therapy. I think that we know that PARP inhibitor maintenance can work regardless of if the patient's tumor isBRCAmutant. There is a potential differential of efficacy, based on if there is presence of aBRCAmutation versus a homologous or combination dysfunction versus a completely wild-type patient. But there still is benefit in all 3 of the trials that have been done with PARP inhibition in the maintenance setting.

TARGETED ONCOLOGY:Which trial supports the use of PARP inhibitor rucaparib in the maintenance setting?

The ARIEL III study was a randomized phase III trial that allowed any patient with either high-grade serous or high-grade endometrioid-type ovarian, peritoneal, or fallopian tube cancer that was sensitive to their most recent platinum and specifically had some form of response to therapy as well as normalization of their CA 125.¹

Patients were than randomized 2:1 to either rucaparib maintenance therapy at 600 mg BID or placebo. They did build in stratification based on mutations of eitherBRCA1/2or a non-BRCAhomologous or combination gene. They were also stratified by response to most recent platinum, as well as platinum-free interval.

Importantly, they did a step-down analysis. They started with just analyzing theBRCAmutated. Then they moved on to the so-called homologous recombination deficiency (HRD) cohort, which included germline or somaticBRCAmutation, as well as those tumors that were thought to be homologous or combination-deficient based on lose of heterozygosity score.

The primary endpoint was PFS. There was a significant difference in PFS across all of the groups and improvement in PFS in any group that got rucaparib. The PFS was most profoundly different in theBRCA-mutated group, with an 11-month PFS advantage versus the HRD-positive group, there was an 8-month advantage, and in the intention to treat group, there was about a 5-month advantage. Across all of the groups, that differential of efficacy in the most targeted groups were theBRCA-mutant groups, but [there was] still benefit across HRD and non-HRD tumors.

TARGETED ONCOLOGY:Are there any toxicity concerns to consider?

These are oral agents. So, you can see gastrointestinal toxicities, hematologic toxicities, such as anemia in the case of this patient, thrombocytopenia, and neutropenia. There are other and more specific toxicities to each PARP inhibitor. We can see some of the PARP inhibitors cause elevation and creatinine. Some cause elevated transaminitis. It is just a matter of knowing what to expect, and managing that appropriately.

Regarding the patient's anemia, right when a patient gets off of platinum you will sometimes see a drop in hemoglobin levels. That can sometimes be treated with a transfusion. You don't necessarily have to dose reduce for that first occurrence. You might consider just transfusing this patient, giving them a quick break, and then restarting them at the same dose and seeing if, now that they are farther away from their last systemic chemotherapy or platinum, can you maintain them at the highest dose level? But, it certainly wasn't unreasonable to stop and dose reduce at that point.

TARGETED ONCOLOGY:What are the choices for second-line therapy?

The most important thing is that the patient gets a platinum-based doublet. The different partners of the doublet that are appropriate include: paclitaxel, docetaxel, like this patient got, pegylated liposomal doxorubicin, or gemcitabine. What this patient received was a reasonable option.

Additionally, there are a number of clinical trials now, and there is an FDA approval of bevacizumab in this space. So, certainly, the utilization of bevacizumab in addition to chemotherapy is reasonable and has demonstrated improved PFS and even overall survival (OS) in 1 of the trials. It is something that you need to talk to the patient about to determine exactly what your goals are and what options you are going to give her for maintenance.

TARGETED ONCOLOGY:Is re-resection an option?

For this patient, she had multifocal disease, so re-resection would not be thought to be favorable. There are data to indicate that if there is single-site or even 2-site recurrence, secondary cytoreductive surgery can improve outcomes. However, results of the recent GOG 213 trial, indicated that even in recurrent disease it only had a few sights and was thought to be surgically resectable.²The use of secondary cytoreduction did not actually impart benefit.

This is an area where we are gathering ongoing information to make decisions, and it is still something that I talk to patients with about, but it may not be something that is clear cut.

TARGETED ONCOLOGY:How does the use of frontline bevacizumab affect second-line therapy options?

The use of frontline bevacizumab is going to increase because it just received an FDA approval in this space. It is too soon to tell how it will affect second-line therapy. There were data that were presented at the ASCO Annual Meeting this year, the MITO/MANGO study, that demonstrated that the use of bevacizumab in the recurrent setting after previous use of bevacizumab yielded better PFS.³So, it is preferable to reuse bevacizumab in a patient that had benefited in the past.

It may be that if you know the patient had great benefit from a bevacizumab-containing combination, you want to reuse that. That is another thing you would want to think about, but the data are still maturing as to whether this yields an OS benefit and toxicities, but it is still something that needs to be considered.

TARGETED ONCOLOGY:If this patent develops recurrent disease, what are her options for third-line therapy?

It depends on that platinum-free interval. How long does she go on the PARP inhibitor without having a recurrence? And, do you want to retreat with platinum if she's had enough time between that last platinum-based therapy? Of course, if it is a short period of time, you might consider other cytotoxic chemotherapies versus participation on clinical trials.

TARGETED ONCOLOGY:Is it possible to use another PARP inhibitor?

The use of another PARP inhibitor after progression on a PARP inhibitor is unclear. We don't know if there is going to be utility there. I think that there is a thought that they still might work, but it'll depend on the mechanisms of resistance and growing information about PARP after PARP therapy. It is a little too soon to tell.

Case 2

March 2013

A 49-year-old African-American woman presented to her primary care physician complaining of abdominal bloating. Her past medical history showed chronic hepatitis B infection and mild hypertension. Her family history revealed that her mother died of breast cancer at age 59 and that her cousin on her mother’s side died of ovarian cancer at age 65.

A CT showed ascites and bilateral 8-cm adnexal masses. She had a CA 125 of 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) was achieved and germline molecular testing showed aBRCA1alteration.

Her pathology confirmed high-grade epithelial ovarian cancer involving the omentum, both ovaries, and 3 micrometastatic lymph nodes.

TARGETED ONCOLOGY:What is this patient's risk of recurrence?

There are micrometastatic lymph nodes, but there is still involvement of the omentum for this patient. You get the sense that the omentum was bulky, although we don't have that detail. So, if she has bulky stage III ovarian cancer, she is looking at about a 60% to 70%, maybe even as high as an 80%, chance of recurrence.

If the omentum was only micrometastatic like the lymph nodes, then we might be more around a 50% to 60% risk of recurrence. But that is still quite high.

TARGETED ONCOLOGY:Would you order additional molecular testing for this patient?

Right now, we have the germlineBRCAmutation status. That is very reasonable [to perform]. As I mentioned before, there are options for somatic testing of the tumor. But generally, we don't pursue that until the recurrent setting. You are going to want to do this when you have something to act on. It may be that in the future we have more targeted therapy options towards the upfront setting, and we would want to get that testing earlier. Now, we would not order that until the patient recurs.

TARGETED ONCOLOGY:What are her therapeutic options?

You are going to look at standard care again, which is the combination of carboplatin and paclitaxel. You have the option of giving that intravenously every 3 weeks or dose dense. There is also an option to give it intraperitoneally. You would need to discuss that with the patient regarding what the potential benefits are for PFS and OS, as well as the toxicity differentials between those options.

Now, there is an opportunity to add bevacizumab in the upfront setting, both with chemotherapy as well as followed by bevacizumab maintenance. So, that is certainly something that could be offered to patients and you might discuss all of those details with her.

TARGETED ONCOLOGY:What would you recommend for this patient?

You have a buffet of options for this patient. The data would indicate that the majority of them are quite similar. You need to drill down as to what she is willing to do, the schedule that she's willing to take on, the toxicity risks that she's willing to take on, and if she wants to potentially get a maintenance therapy and is willing to continue that after the completion of therapy.

In general, at our institution for a patient that we can get to no gross residual disease, we discuss intraperitoneal chemotherapy in detail with them and that would be what I would discuss with her versus participation in a clinical trial.

TARGETED ONCOLOGY:Should she have been considered for neoadjuvant therapy?

As we discussed in case 1, there are a number of different ways to try to determine if you can optimally debulk a patient. This patient was able to get to no gross residual disease, so surgery seems like the right choice for her. Based on the information in the case, there is nothing to push me towards neoadjuvant therapy upfront, but I might have done a laparoscopy to evaluate and determine if I could truly get that patient to no gross residual disease.

She was treated withintravenous injection/intraperitoneal injection paclitaxel/cisplatin. After completion, her CA 125 lowered to 14.2 and she had no clinical evidence of disease.

September 2015

Eighteen months later, routine follow-up revealed that her CA 125 again rose to 203 U/mL. Lymph node disease and carcinomatosis were revealed upon imagining.

TARGETED ONCOLOGY:What are the options for therapy after progression?

As we discussed in case 1, generally surgery is considered if there are 1 or 2 lesions and you think that you can optimally debulk a patient. This patient is found to have carcinomatosis and multiple sites of disease, so I would not favor surgery in this setting.

Instead, I would favor a platinum-based therapy using 1 of the combinations that we mentioned. I would also consider the potential for bevacizumab. However, we know that she isBRCAmutant. Now, when we pick our therapy for so-called platinum sensitive recurrent disease, you have to think about what you are potentially going to offer the patient for maintenance. I would discuss PARP inhibitor maintenance with this patient from the beginning. If she was interested in pursuing that, I would treat her with a platinum-based doublet with the goal of transitioning her to PARP inhibitor maintenance.

She was treated with gemcitabine/carboplatin for 6 cycles. Her CA 125 was 11.3 with clinically no evidence of disease.

TARGETED ONCOLOGY:What are the treatment options for this patient at this point?

The patient was treated with gemcitabine/carboplatin. She received 6 cycles and got down to another clinical complete response, with a CA 125 of 11.3. Hopefully you have already discussed with the patient what her options are. She certainly could go on nothing—observation is an option. But, there are so many maintenance strategies that are available now, both FDA approved and indicated in this setting. It would be hard for us not to offer her something, unless she was very ill and did not want to take any other medications.

TARGETED ONCOLOGY:What are you likely to recommend in this setting?

I would offer her a PARP inhibitor maintenance based on the significant benefit of PFS, especially in thatBRCA-mutant population.

References:

1. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomized, double-blind, placebo-controlled, phase III trial.Lancet. 2017;390(10106):1949-196 doi: 10.1016/SO140-6736(17)32440-6.
2. Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction I recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicenter, open-label, randomized, phase III trial.Lancet Oncol. 2017;18(6):779-791. doi: 10.1016/S1470-20245(17)30276-6.
3. Sandro P, Domenica L, Florence J, et al. Chemotherapy plus or minus bevacizumab for platinum-sensitive ovarian cancer patients recurring after a bevacizumab containing first-line treatment: the randomized phase III trial MITO16B-MaNGO OV2B-ENGOT OV17.J Clin Oncol. 2018;36(suppl; abstr 5506).