Recent Developments in Ovarian and Endometrial Cancers Stir Excitement Among Clinicians

Matthew A. Powell, MD

Despite advanced ovarian and endometrial cancer still being accompanied by a poor prognosis and remaining largely difficult-to-treat diseases, optimism among clinicians has steadily ramped up in recent years with the development of multiple new promising agents and treatment regimens.

“We can be excited that our patients are living longer, but we’re really not curing that many more patients,” Matthew A. Powell, MD, said during a recent OncLive Peer Exchange. “The more we can do up front to get patients to that cure word—which we’re hesitant to use in oncology—is vital as we look at new agents being added to up-front therapy.”

“The biggest unmet need [in ovarian cancer] is improving outcomes in the homologous recombination–proficient [HRP] patient population,” Bhavana Pothuri, MD, said. “In addition to that, we need more therapeutic opportunities in platinum-resistant ovarian cancer.”

Ovarian cancer is the deadliest cancer that occurs in women and is the fourth-deadliest disease for women overall; patients with epithelial ovarian cancer have a 5-year overall survival (OS) rate of just 45.6%. Treatment strategies in ovarian cancer are largely dependent on the type and pathological stage of the disease, but chemotherapy remains the most important component. Other treatment approaches include surgery and radiation therapy, as well as targeted therapeutics and immunotherapy for patients with advanced disease.¹

Endometrial cancer is the most common gynecologic cancer in the United States. In 2018, it was the fourth most common cancer in women and the fifth most common cause of cancer death in the country; there were an estimated 63,230 new cases and 11,350 deaths attributed to uterine cancer during that year alone. The disease is often treated with surgery; other options include radiation therapy, chemotherapy, immunotherapy, and targeted therapies.²

In the OncLive Peer Exchange, expert clinicians provided data updates from clinical trials evaluating agents for the treatment of patients with endometrial and ovarian cancer, with a focus on developments in studies and trial analyses evaluating PARP inhibitors in ovarian cancer and immune checkpoint inhibitors in endometrial cancer. Investigators also highlighted ongoing studies examining novel agents and combinations in both disease settings.

The findings referenced were presented during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.

PARP Inhibitors in Ovarian Cancer

Ursula A. Matulonis, MD, started the conversation by giving an overview on the standard-of-care first-line maintenance options for patients with ovarian cancer. She noted that there have been 3 critical phase 3 clinical trials in recent years that have led to FDA approvals in this setting: SOLO-1 (NCT01844986), PRIMA (NCT02655016), and PAOLA-1 (NCT02477644).

Findings from SOLO-1 supported the December 2018 FDA approval of the PARP inhibitor olaparib (Lynparza) for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete response (CR) or partial response (PR) following frontline platinum-based chemotherapy. Treatment with the PARP inhibitor led to a significant improvement in investigator assessed median progression-free survival (PFS) compared with placebo (HR, 0.30; 95% CI, 0.23-0.41; P < .0001).³

In April 2020, the FDA granted approval to another PARP inhibitor, niraparib (Zejula), for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a CR or PR after first-line platinum-based chemotherapy. Findings from PRIMA showed that niraparib provided a PFS benefit compared with placebo in both the overall population (HR, 0.62; 95% CI, 0.50-0.76; P < .0001) and in patients with homologous recombination deficient (HRD) disease (HR, 0.43; 95% CI, 0.31-0.59; P < .0001).⁴

Shortly after the approval of niraparib, in May 2020, the FDA expanded the indication of bevacizumab (Avastin) for first-line maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a CR or PR to first-line platinum-based chemotherapy and whose disease is positive for HRD. Results from PAOLA-1 supported the regulatory decision, showing a pronounced benefit with the combination over bevacizumab monotherapy among patients with HRD-positive tumors (HR, 0.33; 95%

CI, 0.25-0.45).⁵

“One of the first decisions is whether you’re using bevacizumab,” Shannon N. Westin, MD, MPH, FACOG, said regarding how she selects an FDA-approved first-line maintenance treatment. “If you’re using bevacizumab, then the place that we have that FDA approval is with olaparib. For a patient population that has not started bevacizumab, you’re going to talk through [factors such as] once-a-day treatment, how long you’re going to do treatment, and toxicities, understanding that certain PARP inhibitors are going to have more gastrointestinal adverse effects and others are going to have more of an effect on platelets.”

The panelists then transitioned into highlighting exciting new data from clinical trials evaluating PARP inhibitors presented during ASCO 2023. “All these up-front phase 3 trials take so much work, effort, and time. We need to see a succession of results. The other issue is that when trials are developed, standard-of-care [treatment] changes when that trial is being executed, launched, and run,” Matulonis said.

The phase 3 DUO-O trial (NCT03737643) evaluated the safety and efficacy of first-line chemotherapy plus durvalumab (Imfinzi) and bevacizumab followed by maintenance therapy with durvalumab and bevacizumab with (arm 3; n = 378) or without olaparib (arm 2; n = 374). The comparator arm received frontline chemotherapy plus bevacizumab with maintenance bevacizumab (arm 1; n = 378). The trial enrolled patients with newly diagnosed stage III or IV high-grade epithelial ovarian cancer who were PARP inhibitor naïve.⁶

Findings from the study showed that the median PFS in arms 1, 2, and 3 was 19.3 months, 20.6 months, and 24.2 months, respectively. Patients in both experimental arms achieved a benefit in terms of PFS vs the comparator arm, with the benefit being more pronounced with the addition of olaparib (HR, 0.63; 95% CI, 0.52-0.76; P < .0001) compared with that of arm 2 (HR, 0.87; 95% CI, 0.73-1.04; P = .1312). Additionally, arm 3 offered a pronounced PFS benefit over arm 1 in patients who were HRD positive (HR, 0.51; 95% CI, 0.36-0.72) and HRD negative (HR, 0.68; 95% CI, 0.54-0.86).

“Olaparib plus bevacizumab is now a standard of care for patients who receive bevacizumab in the HRD setting and in the BRCA-mutated
setting,” Matulonis said of DUO-O. “That arm does not exist in this trial. It’s not an omission, but it’s an important deficiency of this study. There [are] also no [OS] data, which are critical for PARP inhibitor trials now.”

In a post hoc exploratory analysis of PAOLA-1, study authors aimed to define the efficacy of subsequent chemotherapy among patients who experienced disease progression after maintenance therapy with olaparib plus bevacizumab. In the olaparib arm, 192 patients experienced
disease progression during olaparib treatment and 145 did so after receiving the agent. In the bevacizumab monotherapy arm, 206 patients
experienced disease progression.⁷

Findings from the analysis showed that patients treated with subsequent chemotherapy who progressed during olaparib treatment experienced a median time from first subsequent therapy to second subsequent therapy of 6.1 months (95% CI, 4.9-7.3). Comparatively, patients who progressed after olaparib treatment and those who progressed in the control arm experienced median times from first subsequent
therapy to second subsequent therapy of 11.4 months (95% CI, 10.2-13.2) and 11.9 months (95% CI, 10.8-12.9).

“This kind of confirmed what we’ve all had a sense of, which is that patients [who] have progression on a PARP inhibitor are very different
from patients [who] have progression after they complete PARP inhibitor treatment,” Westin said. “That makes biologic sense. Those patients [who] had progression on a PARP inhibitor had lower response to subsequent chemotherapy. That gets at the idea that there are overlapping resistance mechanisms. We know platinum sensitivity predicts PARP response. Conversely, PARP sensitivity [potentially] should predict platinum response.”

Finally, the panelists reviewed findings from an analysis of PRIMA that identified predictors of long-term PFS (defined as 2 years or more) in patients who received niraparib. Study authors identified BRCA mutation and HRD status, International Federation of Gynecology and Obstetrics stage at diagnosis, primary tumor location, and absence of baseline nontarget lesions as being associated with extended PFS. Patients with BRCA2-mutant/HRD disease were much more likely to remain progression free for at least 2 years compared with those who were
BRCA wild-type plus HRP or had undetermined homologous recombination status (odds ratio [OR], 10.75; 95% CI, 5.16-22.41; P < .0001), as were those with 0 baseline nontarget lesions vs those with 2 or more (OR, 4.67; 95% CI, 2.08-10.49; P = .0002).⁸

The panelists finished up their discussion on ovarian cancer by mentioning an upcoming European phase 2 clinical trial (NCT04742075)
enrolling patients with relapsed ovarian cancer who are in a CR or PR following completion of their last chemotherapy course. Notably, the study will enroll only patients with BRCA wild-type. Patients will be stratified by HRD status (positive vs negative/unknown) and previous PARP inhibitor exposure (yes vs no).⁹

The study is evaluating the safety and efficacy of the addition of the cancer vaccine UV1 to olaparib plus durvalumab as maintenance therapy
compared with olaparib plus durvalumab as well as olaparib monotherapy. The primary end point is PFS, and secondary end points
include OS, overall response rate (ORR), and disease control rate.

Immune Checkpoint Inhibitors in Endometrial Cancer

Shifting focus to the treatment of patients with endometrial cancer, the panel moderator underscored the continued difficulties in
treating patients with the disease. “Just like ovarian cancer, we’ve seen some really exciting developments in endometrial cancer,” Ritu Salani, MD, said. “[However], one of the frustrating things about endometrial cancer is that it’s one of the few cancers where we’ve seen a rising incidence and a rising mortality. [We have seen] some exciting updates [although] we were kind of complacent with [endometrial
cancer]. And I don’t mean we weren’t studying it; we just hadn’t made any progress on it.”

A major breakthrough in the endometrial cancer treatment paradigm came in the form of results from the phase 3 RUBY trial (NCT03981796), which evaluated the PD-1 inhibitor dostarlimab-gxly (Jemperli) for the treatment of patients with primary advanced stage III or IV or first recurrent endometrial cancer, including those with mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H) disease.10
dMMR/MSI tumors represent 25% to 30% of all endometrial cancers. These types of endometrial cancers display increased expression of PD-L1/2, making them a potentially good target for anti–PD-1 therapy.

Findings from RUBY, which were published in the New England Journal of Medicine, demonstrated that treatment with dostarlimab led to a benefit in terms of 24-month PFS rate in the overall population compared with placebo (HR, 0.64; 95% CI, 0.51-0.80; P < .001); there was also a numerical OS benefit observed with dostarlimab (HR, 0.64; 95% CI, 0.46-0.87; P = .0021). Notably, among patients with dMMR/MSI-H disease, the 24-month PFS benefit with dostarlimab vs placebo was even more pronounced (HR, 0.28; 95% CI, 0.16-0.50; P < .001).

“Patient-reported outcomes [presented at ASCO 2023] showed that the addition of dostarlimab was not a detriment to patients’ quality of life,” Powell said. “Some of those data are still maturing, but we are quite excited to see that the safety profile held up for the study and quality of life was maintained.”

Findings from RUBY led to the July 2023 FDA approval of dostarlimab with carboplatin and paclitaxel followed by dostarlimab monotherapy for the treatment of patients with dMMR/MSI-H primary advanced or
recurrent endometrial cancer.¹¹

In another phase 3 study (NCT03914612) published in the New
England Journal of Medicine, the PD-1 inhibitor pembrolizumab (Keytruda) in combination with chemotherapy displayed efficacy in patients with stage III or IVA or stage IVB or recurrent endometrial cancer. In the cohort of patients who were dMMR, a 12-month PFS benefit was reported with the combination compared with chemotherapy alone (HR, 0.30; 95% CI, 0.19-0.48; P < .001). Moreover, a benefit in terms of 12-month PFS rate was also observed among patients who were mismatch repair proficient and received the PD-1 inhibitor vs those treated with chemotherapy alone (HR, 0.54; 95% CI, 0.41-0.71; P < .001).¹²

“Much like RUBY, [this study] found an astounding benefit in the dMMR [subgroup],” Pothuri said. “This trial was designed to have 2 separate analytics groups that were powered to detect a difference in each group. The preliminary data were presented [at ASCO 2023] and showed a benefit in both subgroups. This is really practice changing and there was benefit irrespective of biomarker status.”

Looking Ahead in Endometrial Cancer

Outside of the updated findings from phase 3 clinical trials, investigators also presented designs for several upcoming studies in endometrial cancer during ASCO 2023. “It’s a big year for endometrial cancer,” Powell said. “We’ll [likely] see 4 more trials reporting in the next year.
There’s a lot of information we’ll be discussing, and hopefully profound benefits for our patients.”

The phase 3 DOMENICA study (NCT05201547) will examine the benefits of substituting anti–PD-1 maintenance immunotherapy for standard chemotherapy in patients with endometrial cancer. Anti–PD-1 agents have displayed promising results as monotherapy and in combination with chemotherapy in patients with dMMR/MSI-H endometrial cancer. DOMENICA aims to answer whether anti–PD-1 therapy alone possesses superior efficacy vs chemotherapy, in which case firstline patients with advanced/relapsed dMMR/ MSI-H disease could be deescalated to prevent chemotherapy-related toxicities.¹³

The study will enroll patients with advanced/metastatic stage IIIA to IIIC2, stage IV, or relapsed dMMR endometrial cancer. Patients will be randomly assigned 1:1 to receive either dostarlimab monotherapy or chemotherapy. Crossover between the 2 arms is allowed at progression. The primary end point is PFS, with OS representing a key secondary objective.

In the phase 2 GY012 trial (NCT03660826), investigators are attempting to evaluate multiple novel drug combinations. GY012 is the first platform
study in endometrial cancer. Investigators presented the design of the second set of arms during ASCO 2023. Findings from the first set
established improved PFS for the combination of olaparib plus cediranib over cediranib monotherapy; however, they did not meet prespecified
statistical significance.¹⁴

Patients will be randomly assigned 1:1:1:1 to receive cediranib monotherapy, olaparib plus capivasertib, olaparib plus durvalumab, or an
alternative dosing schedule of cediranib plus durvalumab. Eligible patients must have recurrent, metastatic, or persistent endometrial cancer and have received at least 1 prior line of chemotherapy. The primary end point is PFS, and secondary end points include OS, ORR, and safety.

Finally, another phase 2 trial (NCT03617679) is aiming to replicate the successes observed with PARP inhibitors in BRCA-mutant/HRD ovarian
cancer. BRCA mutations are not common in endometrial cancer, but loss of function of the tumor-suppressor gene PTEN has been reported
in more than 80% of patients with endometrial cancer. Preclinical data have shown that endometrial cancer cell lines with PTEN loss
of function are sensitive to PARP inhibition. Moreover, this sensitivity to PARP inhibition in PTEN loss of function is independent of microsatellite
instability status.¹⁵

Patients with metastatic/recurrent endometrial cancer with a CR or PR following their most recent therapy will be randomly assigned 1:1 to receive the PARP inhibitor rucaparib (Rubraca) or placebo. The primary end point is PFS, with OS, ORR, and safety and tolerability representing
secondary end points. As of June 2023, 79 patients were enrolled in the study.

“All the upcoming ideas and landscape changes are going to be really instrumental,” Salani said. “Even though we started off [this discussion]
talking about the increasing incidence and mortality [of endometrial cancer], we are going to hopefully start seeing a real impact from the therapies and treatments that we’ve discussed today. And we’re not being complacent, we’re continuing to push forward to identify new needs and gaps and address those as quickly and as thoroughly
as possible.”