ADC Development in Ovarian Cancer: What's Next for FRa and Beyond?

The development of antibody-drug conjugates (ADCs) remains a central theme in ongoing research within the realm of ovarian cancer, and work examining different targets and sequencing considerations will be paramount to advancing this class of agents, according to Kathleen Moore, MD, MD, FASCO.

“ADCs are a hot topic for a reason across solid and hematologic tumors: they’re working,” Moore said in a presentation at the 2025 SGO Winter Meeting.1 “There’s a lot of them in clinical development [in ovarian cancer and other solid tumors]...We are going to have to work on those for a bit to figure out how to use them [in ovarian cancer], but then we’re also going to need to be innovative in terms of what we do next in this space.”

During her presentation, Moore highlighted the first ADC to enter ovarian cancer space following the 2024 full FDA approval of mirvetuximab soravtansine-gynx (Elahere) for the treatment of adult patients with folate receptor α (FRα)–positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have previously received 1 to 3 systemic treatment regimens.2

The decision was supported by data from the phase 3 MIRASOL trial (NCT04209855), which showed that patients treated with the ADC (n = 227) experienced a median progression-free survival (PFS) of 5.62 months (95% CI, 4.34-5.95) vs 3.98 months (95% CI, 2.86-4.47) in those given chemotherapy (n = 226; HR, 0.65; 95% CI, 0.52-0.81; P < .0001).3 The median overall survival (OS) was 16.46 months (95% CI, 14.46-24.57) for the ADC compared with 12.75 months (95% CI, 10.91-14.36) for chemotherapy (HR, 0.67; 95% CI, 0.50-0.89; P = .005).

ADCs Emerge for Platinum-Sensitive Disease in a Post-PARP World

Moore explained that the incorporation of PARP inhibitors into the first-line maintenance setting has transformed care but this has also led to an increasing number of patients who ultimately experience disease progression on these agents and platinum-sensitive recurrence.

She added that for these patients, a refined definition of platinum-sensitive disease may be required. “Tumors that are platinum sensitive and progressed on [a] PARP [inhibitor] do appear to have different mechanisms of resistance and expectations of response to platinum,” Moore noted.

Moore highlighted studies that evaluated ADCs and found these agents to be efficacious in patients with platinum-sensitive ovarian cancer. In the phase 2 PICCOLO trial (NCT05041257), patients treated with mirvetuximab soravtansine (n = 79) experienced an overall response rate (ORR) of 51.9% (95% CI, 40.4%-63.3%).4 The median duration of response was 8.25 months (95% CI, 5.55-10.78), and the median PFS was 6.93 months (95% CI, 5.85-9.59).

In the phase 1 TroFuse-008 trial (NCT06049212), sacituzumab tirumotecan (n = 5) generated an ORR of 60% when given once every 2 weeks at a dose of 5 mg/kg.1 In the phase 2 TROPION-PanTumor03 trial (NCT05489211), patients with platinum-sensitive ovarian cancer treated with datopotamab deruxtecan-dlnk (Datroway; n = 9) achieved an ORR of 66.7%.

FRα and Other Targets

Ongoing research looking at novel ADCs involves other agents targeting FRα beyond mirvetuximab soravtansine, along with other agents directed against different targets.

“FRα is commonly expressed [in ovarian cancer]. In almost 80% [of patients] you’ll find some expression,” Moore said.

In the FRα space, data from the phase 1 STRO-002 study (NCT03748186) showed that luveltamab tazevibulin produced an ORR of 43.8% in patients with a FRα expression of more than 25% per tumor proportion score when given at a dose of 5.2 mg/kg.5 Patients treated with a dose of 4.3 mg/kg experienced an ORR of 31.3%. The median PFS among patients with a FRα expression of more than 25% was 6.1 months (95% CI, 4.1-7.2).

Similarly, findings from a phase 1 trial (NCT05378737) demonstrated that BAT-8006 induced an ORR of 37.0% across all levels of FRα expression (n = 54), an ORR of 39.4% in patients with a FRα expression of 50% or higher (n = 33), and an ORR of 46.7% in those with a FRα expression of 75% or higher (n = 15).6 The median PFS was 7.47 months (95% CI, 4.27-not reached). Moreover, in a phase 1/2 trial (NCT05579366), patients treated with rinatabart sesutecan at a dose of 120 mg/m2 (n = 18) achieved an ORR of 50.0% (95% CI, 26.0%-74.0%).7

Beyond FRα, other ADCs under development are designed to target CDH6, TROP2, HER2, and others.

Sequencing Considerations

As ADCs continue to be developed and agents make their way into the both the platinum-resistant and -sensitive settings, Moore cautioned that sequencing considerations will need to be made for this class of drugs, even in the frontline setting. She painted an example of how treatment decisions might be complicated by the availability of 2 ADCs directed at the same target, such as FRα.

“If you had a FRα-high tumor, what are you going to use first? Are you going to use both [ADCs]? I think so, but I don’t know,” Moore said. “If you are going to use both, in what order? Does the order matter in terms of how long you cobble together those periods of time to improve overall survival [OS]? Do you need a re-biopsy in between to make sure that you still have FRα? I don’t know the answer to any of these questions, but I’m very interested to figure it out so we can use the right drug and the right sequence of drugs for patients to improve OS once we’re in the recurrent setting.”

References

1. Moore KN. ADCs in gynecologic cancers: selection, sequencing, & strategy. Presented at: 2025 Society of Gynecologic Oncology Winter Meeting; January 30 -February 1, 2025; Whistler, British Columbia, Canada.
2. FDA approves mirvetuximab soravtansine-gynx for FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. FDA. Accessed March 22, 2024. Accessed January 31, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-mirvetuximab-soravtansine-gynx-fra-positive-platinum-resistant-epithelial-ovarian
3. Moore KN, Angelergues A, Konecny GE, et al. Mirvetuximab soravtansine in FRα-positive, platinum-resistant ovarian cancer. N Engl J Med. 2023;389(23):2162-2174. doi:10.1056/NEJMoa2309169
4. Alvarez Secord A, Lewin SN, Murphy CG, et al. The efficacy and safety of mirvetuximab soravtansine in FRα-positive, third-line and later, recurrent platinum-sensitive ovarian cancer: the single-arm phase II PICCOLO trial. Ann Oncol. Published online November 29, 2024. doi:10.1016/j.annonc.2024.11.011
5. Sutro Biopharma announces update from STRO-002, luveltamab tazevibulin (Luvelta), phase 1 dose-expansion study and registrational plans in advanced ovarian cancer. News release. January 9, 2023. Accessed January 31, 2025. https://www.sutrobio.com/sutro-biopharma-announces-update-from-stro-002-luveltamab-tazevibulin-luvelta-phase-1-dose-expansion-study-and-registrational-plans-in-advanced-ovarian-cancer/
6. Jia H, Zhang S, Sun Y, et al. Phase 1 study of BAT8006, a folate receptor α antibody drug conjugate with strong bystander effect, in subjects with advanced solid tumors. J Clin Oncol. 2024;42(suppl 16):5550. doi:10.1200/JCO.2024.42.16_suppl.5550
7. Lee EK, Yeku O, Winer I, et al. A phase 1/2 study of rinatabart sesutecan (Rina-S) in patients with advanced ovarian or endometrial cancer. Ann Oncol. 2024;35(suppl 2):S550. doi:10.1016/j.annonc.2024.08.781