Minimally Invasive Surgery, PARP Inhibitors, ADCs Propel Treatment Advances Across Gynecologic Oncology

Targeted PARP inhibitor combinations, immunotherapies, and evolving surgical techniques are shifting practice standards toward more effective and individualized patient approaches in ovarian cancer, cervical cancer, and endometrial cancer, according to Jubilee Brown, MD.

“Looking forward in a prospective trial is the next area where we will look to make progress [with minimally invasive surgery (MIS) in ovarian cancer],” Brown said in an interview with OncLive^® following an OncLive^® State of the Science Summit on ovarian cancer.

In the interview, Brown discussed future considerations for using MIS and PARP inhibitors in ovarian cancer, how immunotherapies have fulfilled an unmet need in cervical cancer, and the importance of leveraging molecular profiling to determine personalized therapeutic strategies in endometrial cancer.

Brown contextualized the significance of the ongoing phase 3 LANCE trial (NCT04575935), which is comparing MIS with laparotomy after neoadjuvant chemotherapy in patients with stage IIIC-IV ovarian, fallopian tube, or primary peritoneal cancer.¹ Additionally, she highlighted the importance of the phase 3 PAOLA-1 trial (NCT02477644), in which patients with newly diagnosed ovarian cancer who received maintenance olaparib (Lynparza), a PARP inhibitor, plus bevacizumab (Avastin) achieved a median progression-free survival of 22.1 months vs 16.6 months in those who received bevacizumab plus placebo.² The findings from this trial led to the May 2020 FDA approval of olaparib plus bevacizumab as maintenance therapy following complete or partial response to frontline platinum-based chemotherapy in patients with homologous recombination deficiency (HRD)–positive advanced ovarian cancer.

Brown is a professor and director of gynecologic oncology at Levine Cancer Institute, Atrium Health, in Charlotte, North Carolina.

OncLive^®: Regarding your presentation on minimally invasive surgery in ovarian cancer, what benefits have been seen so far with this surgical approach as opposed to open surgery?

Brown: MIS offers several advantages in the perioperative setting compared with open surgery, which is more traditionally performed. We see a shorter hospital stay, less blood loss, and fewer complications. Importantly, for patients with ovarian cancer, we see a lower risk of serious post-operative morbidity and a much lower risk of colostomy.

What unmet needs in this area might further investigation address?

Substantial research needs to be done in this area. Whenever we talk about a new surgical technique, especially in the cancer world, [we need] to ensure that the oncologic outcomes are the same [as standard techniques] or better with the new technique. As we adopt MIS in this area that was previously limited to open surgery, we see the benefits in terms of the surgical outcome, but we need to make sure the cancer outcomes are also the same or better. Upcoming trials, specifically the LANCE trial, should help answer this.

Right now, we have a fair amount of retrospective data. [At Levine Cancer Institute], we have shared our own institutional information. We’ve also partnered with other institutions in the area to provide our historical perspective. That’s all supportive and exciting because it shows improved surgical outcomes and equivalent oncology outcomes.

R. Wendel Naumann, MD, of Levine Cancer Institute, spoke about updates in cervical cancer. How are immunotherapies changing the treatment landscape for patients with recurrent or metastatic cervical cancer?

The advent of immunotherapy for patients with cervical cancer has totally changed the landscape. Before these new options for therapy, patients with cervical cancer had a dismal prospect. Their outcomes were limited, and their survival was short. Now, we have more than tripled the life expectancy of patients who have advanced and recurrent cervical cancer with modern immunotherapy.

Regarding Brittany Lees’ case-based discussion on PARP inhibitors in ovarian cancer, what patient characteristics might lead you to choose PARP inhibitor maintenance therapy with bevacizumab?

We have a lot of data now with the PAOLA-1 trial and [other] upfront and recurrent trials becoming mature. For all patients with BRCA mutations or BRCA-related mutations, either in the germline or somatic setting, PARP inhibitors absolutely play a role. In addition, [regardless of] whether patients have HRD, [they experience] a benefit with PARP inhibitors. Without question, PARP inhibitors play a role in those patients.

The PAOLA-1 trial showed that the combination of a PARP inhibitor and bevacizumab was effective. There are some limitations to those data, because we don’t know if the combination is better than a PARP inhibitor alone. However, it’s exciting information. It provides a real benefit to our patients with those characteristics. In the upfront setting, that’s important for us to discuss with our patients and offer to them.

In the recurrent setting, the newer data have caused us to pull back in certain areas. Future trials may inform how we use those combinations with PARP inhibitors.

With regard to the presentation by Erin K. Crane, MD, MPH, of Levine Cancer Institute, which also focused on PARP inhibitors in ovarian cancer, what future developments with these agents are you looking forward to?

There have been many trials in this area. As these trials reach maturity, this will serve to further underscore their importance for patients with both upfront and recurrent ovarian cancer. Combination therapy is where the future is directed. We will have much more information with PARP inhibitors and bevacizumab, PARP inhibitors and immunotherapy, and PARP inhibitors and checkpoint inhibitors, so we [can learn] how to better treat our patients and see if those combinations provide any advantage for them.

Yovanni Casablanca, MD, of Levine Cancer Institute, presented about managing platinum-resistant ovarian cancer. How has the November 2022 FDA approval of mirvetuximab soravtansine-gynx (Elahere) in folate receptor α (Frα)–positive, platinum-resistant ovarian cancer shifted practice in this area?

This is an exciting new opportunity for our patients. We are now testing most of our patients with platinum-resistant ovarian cancer forFrα. That’s a total paradigm shift because it’s an entirely new [drug] class. This antibody-drug conjugate [ADC] offers a completely different pathway to target in our patients. It’s been an exciting time to discuss that with all our patients with ovarian cancer.

Allison Puechl, MD, of Levine Cancer Institute, discussed updates in endometrial and cervical cancer. Please summarize the evolution of molecular profiling in endometrial cancer and the biomarkers that are currently guiding treatment decisions.

Molecular profiling has changed the landscape for patients with uterine cancer. Stage, histology, and grade [used to drive our] management decisions. Now, molecular profiling offers us the opportunity to personalize that treatment.

We look at POLE mutations, because we can potentially de-escalate therapy for a subset of patients with uterine cancer and thereby not overtreat them. In addition, medications such as trastuzumab [Herceptin] target HER2, so now we incorporate HER2 testing in patients with serous carcinomas of the uterus and other subtypes. [Additionally, we now incorporate] mismatch repair testing as a standard process because that also drives management and identifies patients who may have Lynch syndrome and be at risk for other types of cancers. We also know that estrogen and progesterone receptor testing should be done because this can provide another opportunity for patients [with] recurrent disease, because many of these patients are candidates for hormonal therapy.

[Treatment options are no longer limited to] radiation and chemotherapy based on primitive characteristics. Now, we can perform molecular profiling and pursue an algorithm-based treatment paradigm to treat patients who need to be treated with higher-risk disease and minimize the overtreatment of patients who are unlikely to recur or progress.

What ongoing gynecologic cancer research at Levine Cancer Institute are you excited about?

We have multiple trials that cover the panorama of patients with gynecologic cancers at Levine Cancer Institute. [The phase 1 STRO-002-GM1 trial (NCT03748186)] is [investigating] an ADC called STRO-002. This [trial] looks to provide an ADC with an effective payload for our patients with recurrent ovarian cancer. We were involved in some of the early phase 1 trial accrual with this drug, so it’s exciting to bring this to the next level with the next 2 cohorts of patients who are eligible for this drug.

The second exciting ovarian cancer trial that we have is the [phase 2] BOUQUET trial [NCT04931342], a rare tumor platform study for any patient with recurrent epithelial rare ovarian cancer. [This trial has arms for] mucinous carcinoma, low-grade serous carcinoma, malignant Brenner tumor, and any other rare epithelial recurrent ovarian cancers. Interestingly, this trial, rather than treating based on histology alone, molecularly profiles patients with rare tumors and gives them options for treatment arms based on their molecular profiling. It’s a novel way to find effective therapies for patients with rare tumors, and we’re excited to be a part of this trial.

Editor’s Note: Dr Brown reports former Speakers’ Bureau involvement with Clovis and Eisai; advisory board positions with Caris, Biodesix, Janssen, Tempus, AstraZeneca, Tesaro/GSK, and Clovis; consulting/speaking positions with Olympus, Clovis, Invitae, and Caris; and research positions with Tesaro/GSK and Genentech.

References

1. Minimally invasive surgery after neoadjuvant chemotherapy for the treatment of stage IIIC-IV ovarian, primary peritoneal, or fallopian tube cancer, LANCE trial. ClinicalTrials.gov. Updated July 13, 2022. Accessed March 6, 2023. https://clinicaltrials.gov/ct2/show/NCT04575935
2. Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381(25):2416-2428. doi:10.1056/NEJMoa1911361