Individualized Treatment Strategies Strengthen Gynecologic Oncology Armamentarium

Gynecologic cancer care, informed by genetic testing, is expanding to include PARP inhibitors sequenced with chemotherapy in ovarian cancer and checkpoint inhibitors in the upfront endometrial cancer setting, according to Marilyn Huang, MD.

“The landscape for the treatment of gynecologic cancers is changing rapidly,” Huang said in an interview with OncLive^® following an Institutional Perspectives in Cancer webinar on gynecologic cancers. “We’ve seen this over the past 5 years. It’s an exciting time.”

In the interview, Huang highlighted key points from the meeting, including the importance of considering individual patient needs when using PARP inhibitors in ovarian cancer, developments in the frontline treatment of patients with endometrial cancer, and how more inclusive and accessible clinical trials can broaden treatment opportunities across gynecologic cancers.

Findings from the interim analysis of the phase 3 RUBY trial (NCT03981796) demonstrated that treatment with dostarlimab-gxly (Jemperli) plus carboplatin and paclitaxel led to an estimated 24-month progression-free survival (PFS) rate of 61.4% (95% CI, 46.3%-73.4%) vs 15.7% (95% CI, 7.2%-27.0%) with placebo in patients with mismatch repair–deficient (dMMR), microsatellite instability–high endometrial cancer.¹ Additionally, the phase 3 NRG-GY018 trial (NCT03914612) showed that treatment with pembrolizumab (Keytruda) plus paclitaxel and carboplatin led to a 12-month PFS rate of 74% vs 38% with placebo plus chemotherapy in the cohort of patients with dMMR endometrial cancer (HR, 0.30; 95% CI, 0.19-0.48; P < .001). In the mismatch repair–proficient (pMMR) cohort of this trial, the median PFS was 13.1 months with pembrolizumab vs 8.7 months with placebo (HR, 0.54; 95% CI, 0.41-0.71; P < .001).² Huang contextualized these findings within the endometrial cancer treatment landscape and emphasized the unanswered questions regarding optimal therapies for patients with pMMR disease.

Huang is the Richard and Louise Crockett Endowed Professor, as well as professor and director in the Division of Gynecologic Oncology in the Department of Obstetrics and Gynecology at the University of Virginia Comprehensive Cancer Center in Charlottesville.

OncLive: What is the role of PARP inhibitors in ovarian cancer?

Huang: For any patient with newly diagnosed, high-grade serous ovarian cancer with a germline or somatic tumor mutation [in] BRCA or [that is] homologous recombination deficiency [HRD]–positive, a PARP inhibitor should be offered as maintenance therapy in the frontline setting.

Paola A. Gehrig, MD, of UVA, presented two case studies involving the use of PARP inhibitors. Please describe the first ovarian cancer case discussion.

The first case was a 52-year-old woman who had presented with a large pelvic mass and was subsequently diagnosed with stage IIIB ovarian cancer. She had a negative germline test, but her tumor tested positive for a somatic BRCA mutation. [We discussed] when [we would] obtain genetic testing and how those test results inform patient treatment.

In this case, the first test conducted was germline genetic testing. If that is positive, then usually subsequent tumor or somatic testing is not needed, and those patients are offered a PARP inhibitor following adjuvant chemotherapy. For patients who test negative for a germline mutation, [we typically] send for tumor or somatic molecular testing panels. If [those show] an HRD-positive result, those patients will generally receive PARP maintenance therapy.

Did you and your colleagues reach a consensus regarding when you would perform genetic testing and what treatments you would prescribe based on the results?

[Deciding] when to test is tricky and depends on individual provider practice patterns. This case had presented with a large pelvic mass, so, at the time of surgery, if we don’t know whether it’s ovarian cancer, many providers will still send frozen sections for a quick diagnosis. Or, if we’re in the operating room, and it is clearly ovarian cancer, sometimes we will postoperatively obtain genetic testing while the patient is still in the hospital.

There are different rules depending on where you practice, [that dictate] whether you can do genetic testing while patients are in inpatient care. However, [if you perform] genetic testing in that post-operative period as you consider starting chemotherapy, you [will] have the germline test results within 1 to 2 cycles of adjuvant chemotherapy. That hopefully gives you enough time to then send off for the somatic testing, so those results are available by the time [the patient] finishes frontline therapy.

How does the second ovarian cancer case discussion presented by Dr Gehrig highlight the nuances of treatment sequencing in ovarian cancer?

[This patient] had advanced-stage lung cancer and was treated with 3 prior lines of therapy for her lung cancer. Then, [while in] complete response with no evidence of disease, [she presented with] new-onset abdominal bloating and early satiety. This was thought to be advanced-stage lung cancer recurrence, but on workup, she was found to have advanced-stage ovarian cancer and was started on neoadjuvant chemotherapy by a community medical oncologist.

Unfortunately, as she was starting neoadjuvant chemotherapy, she presented to the hospital with a partial bowel obstruction requiring surgery, including a diverting ostomy and a feeding tube because she’d lost weight and had post-operative complications. She received 8 cycles of chemotherapy and, during that time, underwent genetic testing and was germline BRCA positive. She eventually received interval debulking surgery and was reversed.

The question in this case was: Would providers offer [this patient] additional chemotherapy, knowing that she already received 8 cycles up front and had optimal tumor reduction at the time of her interval debulking surgery, or say that she’s reached maximal effort with chemotherapy and start her on a PARP inhibitor? We don’t have much data to help guide [this answer]. We did not necessarily reach a consensus.

Some people felt they should probably give her 3 additional cycles [of chemotherapy] vs starting the PARP inhibitor. The choice of PARP inhibitor is also variable. [There is also not a consensus there, but] it’s nice to have options. While [the PARP inhibitors] are similar, their toxicity profiles [vary]. For patients who are not good pill takers or do not remember to take pills, the niraparib [Zejula] dosing is easier to set reminders and ensure compliance for than the olaparib [Lynparza] twice daily dosing with more pills. We discussed those considerations when talking to patients about which PARP inhibitor [they should potentially receive].

What would you have offered to the patient in that case study?

[Regarding] additional chemotherapy, [I would have said] there’s not much data in this setting to help inform us of our decision. It would depend on how she recovered from her surgery. She had been through a lot of treatment. For those reasons, I would have favored starting the PARP inhibitor, knowing data are available for PARP inhibitor maintenance therapy. Then again, she had treatment for other cancer, so she may be at higher risk for myelodysplastic syndrome or acute myeloid leukemia. I would probably watch her carefully.

What research could inform the decision to use PARP inhibitors vs chemotherapy?

The [phase 1] NOW study [(NCT03943173), findings from which were] presented at the 2023 SGO Annual Meeting from The University of Texas MD Anderson Cancer Center [in Houston], investigated neoadjuvant PARP inhibitors in germline BRCA mutation carriers. An interesting question is: Can we replace chemotherapy altogether? We’re not there yet. [The patients in NOW] who received neoadjuvant PARP inhibitors then had interval cytoreduction and chemotherapy. This is the patient population we would like to see those studies in. [We would like to be able to offer them] a pill. While there are toxicities associated with that, non-chemotherapy options are needed. 

Regarding the presentation given by Brian Slomovitz, MD, of Mount Sinai Medical Center in Miami Beach, Florida, what is the significance of the RUBY and NRG-GY018 trials?

These studies [included patients with] recurrent or advanced-stage endometrial cancer [who received] standard chemotherapy with dostarlimab in RUBY and pembrolizumab in NRG-GY018. Dr Slomovitz discussed the [unique] statistical designs [of these trials]. These trials will read out at different times, so we can’t say which [combination] is better, [but they] generate more questions.

We’re excited to see combination treatments for endometrial cancer. The most exciting cohort of patients reported in both studies was [those with] dMMR or tumor satellite instability–high disease. For the dMMR cohort, a single-agent checkpoint inhibitor has already been FDA approved in the recurrent setting. In the upfront setting, [with checkpoint inhibitors plus] chemotherapy, we saw remarkable hazard ratios [for PFS], 0.30 in NRG-GY018 and 0.28 in RUBY. We’re moving [checkpoint inhibitors] into frontline therapy, so hopefully when patients receive maintenance therapy and stop treatment, we [will] have effectively cured them of their disease. The overall survival data are not yet mature in either study. We’ll see whether the FDA approves [these combinations] for use up front.

We still don’t know what to do with the pMMR group. Single-agent checkpoint inhibitors have not been approved in that cohort. [We do not know] how to sequence these drugs. We have more questions than answers right now. However, it’s exciting, since we haven’t had new drugs approved in upfront endometrial cancer in a long time.

What is your overall message to colleagues regarding the research shared at this IPC?

Staying up to date with all the information can be challenging. Getting together with gynecologic cancer experts, whether gynecologic oncologists or medical oncologists who specialize in gynecologic cancers, to have multidisciplinary conferences [can] optimize best practices.

Enrollment in clinical trials is important, as is enrolling patients who are representative of the population so these trials [accurately] represent the patients we treat. Many patients on clinical trials are selected based on criteria that may not make sense. Working with our colleagues to design more inclusive studies that better represent our patient populations is something we’re working to do at UVA. Our goal is to have a trial for every patient who wants one.

What criteria would you like to see clinical trials expand upon, so they enroll more representative patient populations?

One challenge is that we select patients based on geographic location. Most clinical trials are open at academic cancer centers and are not necessarily partnered with smaller hospital systems, largely because of infrastructure and the amount of time and staff required to run trials. Thinking outside the box and challenging the medical community to design studies with a broader reach to patients who may not have access to large academic institutions [is important]. [We should] decentralize many [aspects of] clinical trials, such as [making] at-home blood draws [possible] and using telemedicine. [These options may] encourage patient participation and reduce some of the burden.

References

1. Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. Published online March 27, 2023. doi:10.1056/NEJMoa2216334
2. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. Published online March 27, 2023. doi:10.1056/NEJMoa2302312