PARP Inhibitors and ADCs Spark Change Across Ovarian and Cervical Cancer Paradigms

Therapies that have broken ground in the cervical and ovarian cancer treatment arenas will also serve as springboards for the development of increasingly effective targeted regimens for patients with these diseases, according to Ritu Salani, MD.

“There are exciting developments on the horizon, but they are just a reminder that we still need to keep looking,” Salani said in an interview with OncLive^® following an Institutional Perspectives in Cancer webinar on gynecologic oncology, which she chaired.

In the interview, Salani highlighted key points that were presented at the meeting on current frontline standards of care for patients with ovarian and cervical cancers, detailing the evolving role of PARP inhibitors in the cervical cancer treatment landscape and antibody-drug conjugates (ADCs) in the ovarian cancer maintenance setting. Salani, the director of Gynecologic Oncology at the University of California Los Angeles, also explained what the future of the post–immuno-oncology (IO) setting in cervical cancer management may look like.

She spotlighted the ongoing phase 3 ARTISTRY-7 trial (NCT05092360), which is examining nemvaleukin alfa (ALKS 4230) in combination with pembrolizumab (Keytruda) vs pembrolizumab vs nemvaleukin alfa vs investigator’s choice of chemotherapy in patients with platinum-resistant epithelial ovarian cancer.¹ This trial is evaluating overall survival (OS) as its primary end point, with objective response rate (ORR), disease control rate, duration of response, time to response, and safety as key secondary end points.

Salani also shared her enthusiasm surrounding a phase 2 trial (NCT06099418) examining the therapeutic DNA vaccine VB10.16 alone or in combination with atezolizumab (Tecentriq) in patients with advanced, HPV16-positive cervical cancer.² This ongoing research builds on findings from a first-in-human phase 1/2a trial (NCT02529930) in patients with confirmed HPV16-positive high-grade cervical intraepithelial neoplasia. In the phase 1/2a trial, investigators observed HPV16-specific T-cell responses in most patients after vaccination with VB10.16 and lesion size reductions occurred in 94% of patients enrolled in the expansion cohort (n = 18).³

OncLive: What do the current frontline treatment paradigms look like for ovarian and cervical cancers?

Salani: In ovarian cancer, we haven’t had many treatment advances. The biggest next area of exploration is [sequencing] PARP inhibitors after PARP inhibitors, particularly for patients who had a good response or an interval between treatment and recurrence. [PARP inhibitors] have revolutionized ovarian cancer care. That is a testament to how successful these therapies have been in certain populations. [However, patients with] homologous recombination–proficient disease, [similar to those] with mismatch
repair–proficient cancer, continue to be a challenge to treat. They don’t have as good of responses [as patients with homologous recombination–deficient disease], so continuing to investigate treatment options for those patients is important.

Regarding cervical cancer, some ADCs are approved now. Tisotumab vedotin-tftv [Tivdak] received full FDA approval in [April 2024 for the treatment of patients with recurrent or metastatic cervical cancer], and fam-trastuzumab deruxtecan-nxki [(Enhertu) is FDA approved] for patients with HER2-positive IHC 3+ [solid tumors]. These are options, but evaluating other agents, including TROP2-directed therapies, and developing HPV16 vaccination targets with immunotherapy in the second line, are exciting developments on the horizon.

What are the next steps for therapies for patients with ovarian cancer?

For patients with homologous recombination–proficient disease, PARP inhibitors such as bevacizumab [Avastin] are an option. There are [additional agents] on the horizon as well. ADCs targeting CDH6 are being studied as a maintenance option for that population. Anything we can do to prevent those patients from recurrence or prolong their disease-free intervals will be important. I’m excited about what’s out there. Our industry sponsors and investigators are all looking at ways to better explore therapies in those patients, particularly.

We’re excited about mirvetuximab soravtansine-gynx [Elahere] coming into the arena. Studies with immunotherapy in ovarian cancer are hopefully going to read out in the next year, including ARTISTRY-7, which is investigating nemvaleukin alfa plus pembrolizumab compared with investigator’s choice of chemotherapy [in patients with platinum-resistant epithelial ovarian cancer].

What novel therapeutic targets are under exploration in cervical cancer?

Cervical cancer continues to be a challenging disease to study. With tisotumab vedotin, we have seen improvements in progression-free survival and OS [compared with chemotherapy in patients with recurrent or metastatic disease in the pivotal phase 3 innovaTV 301 trial (NCT04697628)]. However, the ORR with chemotherapy was 5.2%, and after second-line therapy, we are still left with just chemotherapy [for this population]. There are opportunities to have better therapy options.

I’m involved in a [study evaluating a] HPV16 vaccine with or without atezolizumab, in patients [with advanced, HPV16-positive cervical cancer] after prior IO experience. This trial is [capitalizing on] that IO after IO potential. I like studies that are biologically rational. This study is targeting HPV16, and patients have to have HPV16 positivity. The preliminary data are promising, and hopefully the phase 2 data will help show what the role of this target is.

TROP2 is also highly expressed in cervical cancer, as we know it is in endometrial cancer. Investigating TROP2 as a target in cervical cancer is an exciting area of exploration. Topotecan is a toxic but active drug in cervical cancer, so capitalizing on that activity with an ADC is appealing.

References

1. Phase 3 study of nemvaleukin alfa in combination with pembrolizumab in patients with platinum-resistant epithelial ovarian cancer (ARTISTRY-7) (ARTISTRY-7). ClinicalTrials.gov. Updated June 28, 2024. Accessed August 23, 2024. https://clinicaltrials.gov/study/NCT05092360
2. Efficacy and safety of VB10.16 alone or in combination with atezolizumab in patients with advanced cervical cancer. ClinicalTrials.gov. Updated August 9, 2024. Accessed August 23, 2024. https://www.clinicaltrials.gov/study/NCT06099418
3. Hillemanns P, Denecke A, Woelber L, et al. A therapeutic antigen-presenting cell-targeting DNA vaccine VB10.16 in HPV16-positive high-grade cervical intraepithelial neoplasia: results from a phase I/IIa trial. Clin Cancer Res. 2022;28(22):4885-4892. doi:10.1158/1078-0432.CCR-22-1927