New Approaches Reshape Treatment Across Ovarian Cancer Settings

For patients with low-grade serous ovarian cancer (LGSOC) and platinum-resistant disease, long-elusive treatment advances are finally emerging. The 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and the European Society for Medical Oncology (ESMO) Gynaecological Cancers Congress 2025 unveiled pivotal data, from targeted combinations to glucocorticoid modulation and immunotherapy, that are rewriting current paradigms. Here is what community oncologists need to know to translate these advances into practice.

Approval

The combination of avutometinib (VS-6766) and defactinib (VS-6063; Avmapki Fakzynja co-pack) gained an accelerated approval from the FDA on May 8, 2025.¹ The agent is indicated for patients with recurrent LGSOC whose tumor harbors a KRAS mutation and who have been treated with at least 1 prior systemic therapy.

The approval was based on findings from RAMP 201 (NCT04625270),² an open-label, multicenter trial that included 57 adult patients with measurable KRAS-mutated recurrent LGSOC. Overall, the KRAS mutation is found in one-third of patients with LGSOC.

KRAS mutation status was determined by local testing of tumor tissue. Patients received 3.2 mg of avutometinib twice weekly and 200 mg defactinib twice daily, both taken for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity.²

The primary efficacy outcome measure was overall response rate (ORR) assessed by blinded independent review committee according to RECIST 1.1 criteria. An additional efficacy outcome measure was duration of response (DOR). The confirmed ORR was 44% (95% CI, 31%-58%) and the median DOR was 31.1 months (95% CI, 14.8-31.1).²

“It’s notable that the duration of response was more than 31 months for those patients who responded,” Rachel N. Grisham, MD, associate attending physician, section head of ovarian cancer, and director of gynecologic medical oncology at Memorial Sloan Kettering Cancer Center in New York, New York, said during an interview with Targeted Therapies in Oncology.

“The mutation is also a prognostic indicator, so patients with a KRAS mutation have a higher response rate to standard-of-care treatment such as chemotherapy and MEK inhibitors,” Grisham continued.

The most common adverse events (≥25%), including laboratory abnormalities, were increased creatine phosphokinase levels, nausea, fatigue, increased aspartate aminotransferase levels, and rash.²

Grisham noted that a randomized phase 3 study of the combination vs investigator’s choice of therapy for women with recurrent LGSOC is currently enrolling. The RAMP 301 (NCT06072781) trial is open to all patients, both the KRAS wild type and KRAS-mutant disease.

“Both RAMP 201 and RAMP 301 accrued above the expected rate, showing that rare tumor studies can be conducted, and that’s encouraging,” Grisham said. It also demonstrates the importance of tumor testing. Grisham believes that germline and somatic testing in all patients with ovarian cancer should be carried out in the community setting and covered by insurance because the guidelines issued by ASCO, the National Comprehensive Cancer Network, and the Society of Gynecologic Oncology recommend it.

“There has been a large uptake of blood-based somatic testing on several diagnostic platforms using circulating tumor DNA,” Grisham said. “However, that is not necessarily as reliable in these rare tumors, which tend to be low shedders. I think it’s important that somatic tumor testing be conducted on the tumor itself and not through a blood-based assay, especially for these rare tumors,” she continued.³

Clinicians are hopeful the approval will result in further drug development for patients with LGSOC, particularly with more agents being moved to the frontline setting. Specifically, the CHAMELEON study (NCT06394804) is evaluating whether the combination of avutometinib, defactinib, and letrozole in patients with newly diagnosed LGSOC who have not received prior systemic treatment for their disease.

While targeted therapies gain ground in LGSOC, platinum-resistant disease—a perennial challenge—is experiencing its own paradigm shift.

Platinum-Resistant Ovarian Cancer

The selective glucocorticoid receptor modulator, relacorilant, blocks the effects of cortisol by binding to the glucocorticoid receptor. Findings from the phase 3 ROSELLA trial (GOG-3073/ENGOT OV72/APGOT-Ov10/LACOG 0223/ANZGOG2221/2023; NCT05257408) showed that when combined with nab-paclitaxel, progression-free survival (PFS) and overall survival (OS) were improved vs a higher dose of nab-paclitaxel alone in patients with platinum-resistant ovarian cancer (PROC). These findings were presented during the 2025 ASCO Annual Meeting and simultaneously published in the Lancet.^4,5

Investigators reported that the median PFS was 6.54 months (95% CI, 5.55-7.43) with relacorilant and nab-paclitaxel (n = 188) compared with 5.52 months (95% CI, 3.94-5.88) with nab-paclitaxel alone (n = 193), leading to a 30% reduction in the risk of disease progression or death (HR, 0.70; 95% CI, 0.54-0.91; P =.0076). The 6-month PFS rates were 52% and 42%, respectively, with relacorilant and nab-paclitaxel alone; the 1-year PFS rates were 25% and 13%, respectively.

Interim data for OS, which was at 50% maturity, showed that the median OS was 15.97 months (95% CI, 13.47-not reached) with relacorilant vs 11.50 months (95% CI, 10.02-13.57) with nab-paclitaxel alone, which was reported as clinically meaningful (HR, 0.69; 95% CI, 0.52-0.92; P =.0121). The 1-year OS rates were 60% and 49%, respectively.

“These findings are important because it potentially provides more treatment options for our patients with platinum-resistant disease,” Grisham said. “The vast majority of our patients with ovarian cancer are living with a chronic disease, and all our patients with recurrent disease will eventually become platinum resistant, so we need more options to prolong life,” Grisham continued.

Traditionally, approaches with non–antibody-drug conjugates in PROC relied heavily on combinations that used bevacizumab (Avastin) to try to increase the response rate of single-agent chemotherapy. However, not all patients are candidates for bevacizumab, especially those further along in their disease course. “Combining relacorilant with nab-paclitaxel allows clinicians to continue using a taxane, which is one of our most effective chemotherapies in PROC,” Grisham said.

The other welcome news with these results is that this combination does not require the identification of a biomarker, so it is open for use by any patient. Although many novel approaches require biomarker identification, this approach does not, making this drug available to any patient.

Grisham noted that relacorilant is a glucocorticoid-receptor antagonist, and the findings suggest that inhibition of glucocorticoids could lead to enhanced tumor response. “Nab-paclitaxel does not require steroid premedication, but we do routinely administer steroids to patients treated with paclitaxel because of the risk of hypersensitivity,” Grisham said. “And steroids are powerful agents that can cause hyperglycemia and other adverse events and may even decrease the efficacy of cancer directed therapy in some cases,” she continued. “It suggests that we should be judicious with our use of routine steroids.”

Immunotherapy may soon enter the ovarian cancer arsenal, with KEYNOTE-B96 data hinting at a potential role for PD-L1 testing.

Grisham discussed the findings from KEYNOTE-B96 (NCT05116189), a randomized double-blind phase 3 trial investigating pembrolizumab (Keytruda) in combination with chemotherapy with or without bevacizumab vs placebo plus chemotherapy with or without bevacizumab for the treatment of platinum-resistant recurrent ovarian cancer. The primary end point is PFS, and OS is a key secondary end point.

Data from a prespecified interim analysis showed that patients in the pembrolizumab arm demonstrated a statistically significant and clinically meaningful improvement in PFS regardless of PD-L1 status compared with placebo plus chemotherapy with or without bevacizumab. The study findings also showed a statistically significant and clinically meaningful improvement in OS in patients whose tumors express PD-L1 with a combined positive score of 1 or greater compared with placebo plus chemotherapy with or without bevacizumab.

“The study [data have] not been presented yet, but it’s really interesting, because generally, we do not think of PD-L1 as a very good predictive marker for ovarian cancer,” Grisham said. “We don’t routinely recommend choosing pembrolizumab for patients based on that marker in ovarian cancer, unlike cervical cancer or in other cancers where it’s a marker.” The findings could potentially change the mindset of using immunotherapy in ovarian cancer.

Currently, pembrolizumab is approved in ovarian cancer in a small number of patients who qualify for a tissue-agnostic indication based on having microsatellite instability-high disease or a high tumor mutation burden.⁶

Epithelial Ovarian Cancer

For newly diagnosed advanced disease, adding intraperitoneal IL-12 gene therapy (IMNN-001) to chemotherapy boosted resection rates and survival, representing a potential frontline option if phase 3 data confirm the benefit.

Data from the phase 1/2 OVATION-2 trial (NCT03393884) demonstrated that the addition of IMNN-011 to neoadjuvant and adjuvant chemotherapy led to trends toward improved PFS and OS vs perioperative chemotherapy alone for the treatment of newly diagnosed epithelial ovarian cancer. The results were presented at the 2025 ASCO Annual Meeting.⁷

Investigators reported that at a median follow-up of 24 months, patients in the intention-to-treat population who received IMNN-001 plus chemotherapy (n = 59) achieved a median PFS of 14.9 months (95% CI, 12.55-21.19) compared with 11.9 months (95% CI, 10.09-14.92) in patients treated with chemotherapy alone (n = 54; HR, 0.79; 95% CI, 0.51-1.23).

At 24 months of follow-up, the median OS was 40.5 months (95% CI, 28.09-not evaluable [NE]) in the IMNN-001 arm and 29.4 months (95% CI, 24.94-45.60) in the chemotherapy arm (HR, 0.74; 95% CI, 0.42-1.30; P =.2963). With follow-up extended to 31 months, the median OS was 46.0 months (95% CI, 39.20-NE) and 33.0 months (95% CI, 27.14-NE), respectively (HR, 0.69; 95% CI, 0.40-1.19; P = .1865).

IMNN-001 is a novel, IL-12 gene therapy; it features a lipopolymer nanoparticle delivery system that encases an IL-12 DNA-based plasmid. “This is an interesting study that compared patients who received neoadjuvant chemotherapy for ovarian cancer and then underwent interval debulking followed by adjuvant therapy,” Grisham said. “The study [data] did show an improvement in PFS and OS, as well as improvement in the complete resection rate for those patients who received the nanoparticle,” Grisham said.

OVATION-2 was a randomized, open-label, multicenter trial that enrolled patients at least 18 years of age with a suspected histologic diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal carcinoma that was International Federation of Gynecology and Obstetrics (FIGO) stage III or IV. Prior to recruitment for the randomized phase 2 portion, 15 patients received IMNN-001 in combination with chemotherapy as a safety lead-in.

In phase 2, patients were randomly assigned 1:1. In the experimental arm, patients received IMNN-001 at 100 mg/m² on days 8 and 15 of the first 21-day neoadjuvant cycle; days 1, 8, and 15 of the following 2 neoadjuvant cycles; and days 1, 8, and 15 of three adjuvant cycles. They also received carboplatin at an area under the curve of 6 on day 1 of each neoadjuvant and adjuvant cycle, and paclitaxel at 175 mg/m² on day 1 of each neoadjuvant and adjuvant cycle. In the control arm, patients received the same perioperative chemotherapy regimen without IMNN-001.

Safety and PFS served as the trial’s primary end point. Secondary end points included OS, ORR, surgical response, chemotherapy response score, and serologic response rates.

The manufacturer of IMNN-001 announced in a news release the dosing of the first patient for the phase 3 OVATION-3 (NCT06915025) study. The trial will evaluate IMNN-001 in combination with neoadjuvant chemotherapy for patients with newly diagnosed advanced ovarian cancer.⁸

TRUST study

The TRUST (NCT02828618) study⁹ is an international, multicenter trial evaluating primary cytoreductive surgery vs neoadjuvant chemotherapy followed by interval cytoreductive surgery in patients with ovarian, tubal, and peritoneal ovarian cancer.

Patients were eligible if they had suspected or histologically confirmed, newly diagnosed invasive epithelial ovarian cancer FIGO stage IIIB to IVB, and ECOG performance status 0 or 1. The primary end point was OS. Secondary end points were PFS, time until second progression or death, time to first and second subsequent anti-cancer therapy or death. The study focused on centers with ovarian cancer surgical expertise, and required specific quality assurance criteria for participating centers to ensure a high standard of surgical care, including a high rate of complete resection in upfront surgery.

“This study did not show an improvement in OS with primary debulking,” Grisham said. “But it did show an improvement in PFS and a benefit in patients with stage 3 disease. I think the real take-home message from the TRUST study highlighted the importance of surgical expertise; 72% of patients had a complete resection at the time of interval surgery, which is higher than we have seen in many prior trials of primary vs interval debulking.”

Grisham also noted that the findings suggest that regardless of whether a primary or interval debulking approach is used, the best outcomes are observed if patients are treated at a center of excellence and undergo surgery with a specialized gynecologic oncologist who performs this surgery routinely.

Takeaway Message

With recent approvals, the ovarian cancer setting is a rapidly evolving field. Approaches in LGSOC are gearing up, and the importance of germline and tumor somatic testing cannot be emphasized enough. Testing is no longer optional. From KRAS to HER2, biomarkers are the roadmap to survival in this new era.

“Every patient with ovarian cancer who has recurrent disease should be have somatic tumor tissue testing performed as well as immunohistochemistry testing done for HER2 and FRα so that they can have access to these newly approved treatments,” Grisham said. “They should know if they have these biomarkers.”

REFERENCES

1. FDA grants accelerated approval to the combination of avutometinib and defactinib for KRAS-mutated recurrent low-grade serous ovarian cancer. FDA. May 8, 2025. Accessed August 4, 2025. https://tinyurl.com/46vz3s75

2. Banerjee SN, Van Nieuwenhuysen E, Aghajanian C, et al. Efficacy and safety of avutometinib ± defactinib in recurrent low-grade serous ovarian cancer: primary analysis of ENGOT-OV60/GOG-3052/RAMP 201. J Clin Oncol. Published online July 11, 2025. doi:10.1200/JCO-25-00112

3. Su H, Fan R, Tian M, et al. Concordance of circulating tumor DNA and tissue genomic profiling in ovarian cancer: influencing factors and clinical significance.
J Clin Oncol. 2025;43(suppl 16):5548. doi:10.1200/JCO.2025.43.16_suppl.5548

4. Olawaiye A, Gladieff L, Gilbert L, et al. ROSELLA: a phase 3 study of relacorilant in combination with nab-paclitaxel versus nab-paclitaxel monotherapy in patients with platinum-resistant ovarian cancer (GOG-3073, ENGOT-ov72). J Clin Oncol. 2025;43(suppl 17):LBA5507. doi:10.1200/JCO.2025.43.17_suppl.LBA5507

5. Olawaiye AB, Gladieff L, O’Malley DM, et al. Relacorilant and nab-paclitaxel in patients with platinum-resistant ovarian cancer (ROSELLA): an open-label, randomised, controlled, phase 3 trial. Lancet. 2025;405(10496):2205-2216. doi:10.1016/S0140-6736(25)01040-2

6. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. FDA. Updated May 30, 2017. Accessed August 5, 2025. https://tinyurl.com/5uups9r3

7. Thaker P, Richardson DL, Hagemann AR, et al. A phase I/II study of the safety and efficacy of intraperitoneal IMNN-001 in combination with neoadjuvant chemotherapy (NACT) of paclitaxel and carboplatin in patients newly diagnosed with advanced epithelial ovarian cancer (EOC): updated survival analysis from OVATION-2 trial. J Clin Oncol. 2025;43(suppl 16):5516. doi:10.1200/JCO.2025.43.16_suppl.5516

8. IMUNON announces first site initiated for pivotal phase 3 OVATION 3 study of IMNN-001 in newly diagnosed advanced ovarian cancer. News release. Imunon, Inc. May 8, 2025. Accessed August 4, 2025. https://tinyurl.com/pa3jvch5

9. Reuss A, du Bois A, Harter P, et al. TRUST: trial of radical upfront surgical therapy in advanced ovarian cancer (ENGOT ov33/AGO-OVAR OP7). Int J Gynecol Cancer. 2019;29(8):1327-1331. doi:10.1136/ijgc-2019-000682