The Billion Dollar Question in Ovarian Cancer: What Therapies to Use for Maintenance and Recurrence

Although PARP inhibitors have shown promise when treating patients with ovarian cancer, certain subgroups of patients have few effective options following disease progression, according to Ritu Salani, MD, who detailed notable agents and trials that are gaining traction in an interview with OncLive^®.

With impressive efficacy seen leading to its November 2022 accelerated approval in adult patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received 1 to 3 prior systemic treatment regimens, the antibody-drug conjugate (ADC) mirvetuximab soravtansine-gynx (Elahere) is currently one agent under evaluation in the platinum-sensitive setting.¹ The active phase 2 PICCOLO trial (NCT05041257) is investigating the agent in patients with recurrent platinum-sensitive disease and high FRα expression. The phase 3 GLORIOSA trial (NCT05445778) is enrolling the same patient population, but in this trial patients will be randomly assigned to receive mirvetuximab soravtansine plus bevacizumab (Avastin) or bevacizumab as maintenance therapy.²

When asked what maintenance options in ovarian cancer could look like, Salani answered “that is the billion-dollar question. We have PARP inhibitors for ovarian cancer and there are studies looking at a cellular therapy in ovarian cancer in the homologous recombination–proficient population, but the door is wide open. We have studies looking in the platinum-sensitive space looking at mirvetuximab for patients who have FRα-[positive disease]. We had a study looking at [targeting] NaPi2b, but unfortunately, that study was closed due to futility.”

“Additionally, there is a HER2-targeted ADC in the gynecologic cancer space [under evaluation as well–we are] looking at better options for our patients,” Salani, the director of Gynecologic Oncology and the Gynecologic Oncology Fellowship at UCLA Health in Los Angeles, California, added. “We also have TROP2-targeted agents in trials in different disease spaces for gynecologic malignancies. We’re always open to looking at new trial options.”

Most recently, the TROP2-directed ADC BNT325/DB-1305 received fast track designation from the FDA for patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer.³ Data from an ongoing phase 1/2 trial (NCT05438329) presented at the 2023 ESMO Congress supported the regulatory decision and demonstrated that patients with TROP-expressing advanced solid tumors (n = 23) who received a median of 3 prior lines of therapy achieved an objective response rate (ORR) of 30.4%. Further, the disease control rate (DCR) was 87.0%.⁴ 

PARP Inhibitors Show Promise, But Gaps Remain for HRD-Negative Disease

“For ovarian cancer PARP inhibitors have revolutionized the care for patients with BRCA mutations and [other] homologous recombination–deficient [HRD] mutations, but the HRD-negative group continues to be a [population] that we need better therapies for,” Salani said. “We know there’s a high rate of recurrence, so looking at better maintenance options for those patients is important. Once cancer recurs, it can be very challenging to treat, and continuing to look at options for both the platinum-resistant and the platinum-sensitive populations and figuring out how we can better control the disease [is key]. My personal area of interest is surveillance and if we have better targeted therapies, we can do a better job with monitoring these patients and intervening early.”

Data from the phase 3 PAOLA-1/ENGOT-ov25 trial (NCT02477644) examining maintenance olaparib (Lynparza) plus bevacizumab vs placebo plus bevacizumab after first-line platinum-based chemotherapy demonstrated this, revealing positive final overall survival (OS) results in the HRD-positive population of patients with ovarian cancer; patients who received the PARP inhibitor in combination with bevacizumab (n = 255) achieved a 5-year OS rate of 65.5% vs 48.4% with bevacizumab alone (n = 132; HR, 0.62; 95% CI, 0.45-0.85). However, in the HRD-negative population, 5-year OS rates for patients given the combination (n = 192) vs monotherapy (n = 85) were 25.7% vs 32.3%, respectively (HR, 1.19; 95% CI, 0.88-1.63).⁵

At the 2023 ASCO Annual Meeting results from an interim PFS analysis of the ongoing phase 3 DUO-O trial (NCT03737643) revealed that patients with HRD-negative disease receiving durvalumab (Imfinzi) with paclitaxel/carboplatin and bevacizumab followed by maintenance durvalumab, bevacizumab, and olaparib (n = 211) achieved a median progression-free survival of 20.9 months vs 17.4 months for those receiving chemotherapy plus bevacizumab followed by maintenance bevacizumab alone (n = 216; HR, 0.68; 95% CI, 0.54-0.86).⁶

Investigational Agents for Serous Ovarian Cancer Following Progression

“When we talk about these [gynecologic] cancers we talk about them as an overview, but we shouldn’t forget about some of the rare tumor types where we are still also looking at making progress,” Salani said. “In low-grade serous ovarian cancer we have a trial called RAMP 301 [NCT06072781] looking at a very provocative pathway. We’re now starting to understand these targets better and are able to better design or tailor our trials to these patients with rare diseases.”

Salani detailed that the notable upcoming phase 3 RAMP 301 trial of avutometinib (VS-6766) plus defactinib (VS-6063) vs investigator’s choice of therapy for patients with serious ovarian cancer can help aid in answering questions in this rare tumor type.⁷ In the phase 2 RAMP 201 trial (NCT04625270) patients with recurrent low-grade serous ovarian cancer who received the doublet (n = 29) achieved a confirmed ORR of 45% compared with 10% for those who solely received avutometinib (n = 31).⁸ The DCR with the doublet was 90%.

“In RAMP 301, the 2 drugs are targeting the RAF/MEK pathway and then the FAK pathway, so it’s an interesting target. The trial design allows for crossover [so] patients [who progress] will be able to get access to this option. Unlimited prior lines of therapy [are also allowed] so it’s a very broad inclusion group that highlights the need in this patient population. The phase 2 data were presented this past year and were very exciting with response rates much higher than what we’ve seen before. Understanding how to use these drugs and how to manage toxicities of newer drugs is always a learning curve that we have to experience, but if we can provide better outcomes for our patients, it’s well worth it.”

References

1. FDA grants accelerated approval to mirvetuximab soravtansine-gynx for FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or peritoneal cancer. FDA. November 14, 2022. Accessed March 5, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-mirvetuximab-soravtansine-gynx-fra-positive-platinum-resistant
2. Gonzalez-Ochoa E, Veneziani AC, Oza AM. Mirvetuximab soravtansine in platinum-resistant ovarian cancer. Clin Med Insights Oncol. 2023;17:11795549231187264. doi:10.1177/11795549231187264
3. 3. BioNTech and DualityBio receive FDA fast track designation for next-generation antibody-drug conjugate candidate BNT325/DB-1305. News release. BioNTech SE. January 31, 2024. Accessed March 5, 2024. https://investors.biontech.de/news-releases/news-release-details/biontech-and-dualitybio-receive-fda-fast-track-designation-next
4. Marathe O, Cheng Y, Spira AI, et al. DB-1305 (a Trop-2 targeted antibody-drug-conjugate [ADC]) in patients (pts) with advanced solid tumors: preliminary clinical results from the phase (Ph) I/IIa study. Ann Oncol. 2023;34(suppl 2):S480. doi:10.1016/j.annonc.2023.09.1875
5. Ray-Coquard IL, Leary A, Pignata S, et al. Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial. Ann Oncol. 2023;34(8):P681-P692. doi:10.1016/j.annonc.2023.05.005
6. Harter P, Trillsch F, Okamoto A, et al. Durvalumab with paclitaxel/carboplatin (PC) and bevacizumab (bev), followed by maintenance durvalumab, bev, and olaparib in patients (pts) with newly diagnosed advanced ovarian cancer (AOC) without a tumor BRCA1/2 mutation (non-tBRCAm): results from the randomized, placebo (pbo)-controlled phase III DUO-O trial. J Clin Oncol. 2023;41(suppl 17):LBA5506. doi:10.1200/JCO.2023.41.17_suppl.LBA5506
7. A study of avutometinib (VS-6766) + defactinib (VS-6063) in recurrent low-grade serous ovarian cancer (RAMP 301). ClinicalTrials.gov. Updated March 4, 2024. Accessed March 5, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06072781
8. Banerjee SN, Ring KL, Nieuwenhuysen EV, et al. Initial efficacy and safety results from ENGOT-ov60/GOG-3052/RAMP 201: a phase 2 study of avutometinib (VS-6766) ± defactinib in recurrent low-grade serous ovarian cancer (LGSOC). J Clin Oncol. 2023;41(suppl 16):5515. doi:10.1200/JCO.2023.41.16_suppl.5515