Expanding the Treatment Toolbox for Platinum-Resistant Ovarian Cancer

This Clinician’s View is written by AdventHealth Cancer Institute Medical Director of Gynecologic Oncology Robert Holloway, MD, DHc, FACOG, FACS.

Platinum-resistant ovarian cancer (PROC) remains one of the greatest unmet needs in gynecologic oncology. For decades, treatment options were limited, and outcomes remained poor. Although there currently is no one-size-fits-all solution, the landscape is evolving rapidly, creating new opportunities for patients who historically had few.

Over the past five years, the FDA-approval of three new therapies for patients with PROC, coupled with a growing pipeline of investigational agents in clinical development, has meaningfully expanded treatment options. While no single therapy has fundamentally altered the course of the disease in terms of cure, the increasing number of available options is enabling a more personalized approach to care, extending disease control and providing patients with greater potential to benefit from future therapeutic advances.

Delivering the highest quality care requires an expanding therapeutic toolbox that includes access to the latest innovative treatments along with a robust clinical trial portfolio. This approach allows us to match each patient with the most appropriate treatment strategy at every stage of their disease journey.

The evolution of our oncolytic virus program at AdventHealth Cancer Institute (AHCI) exemplifies this toolbox philosophy. What began as a promising scientific concept has progressed into a national Phase 3 clinical trial, demonstrating how clinical leadership, translational research and strategic trial development can accelerate innovation, bringing treatment options directly to patients while helping shape the future of ovarian cancer care.

The Challenge of Platinum Resistance in Ovarian Cancer

Although significant progress has been made in frontline ovarian cancer treatment, disease recurrence and the development of platinum resistance continue to drive outcomes for many patients.

For newly diagnosed patients, standard frontline treatment typically includes a platinum-based chemotherapy agent (carboplatin or cisplatin) combined with a taxane such as paclitaxel. While many initially respond well to this approach, approximately 80% will ultimately experience disease recurrence.

With ovarian cancer, a patient's response to platinum therapy is categorized by the interval between completion of treatment and recurrence:

• Platinum-Sensitive: Cancer returns after 6 months from last platinum therapy.
• Partially Platinum-Sensitive: Cancer returns between 6 and 12 months.
• Platinum-Resistant (PROC): Cancer returns or progresses within 6 months.
• Platinum-Refractory: Cancer continues to progress during or within one month of initial platinum treatment.

These classifications help guide our treatment decisions and provide insight into a patient’s prognosis. For patients with platinum-resistant disease, the challenge is that therapies that were once effective are no longer reliably controlling the cancer, and for those who are platinum-refractory, there was no response at all.

Current National Comprehensive Cancer Network (NCCN) guidelines recommend single-agent, non-platinum chemotherapy with or without bevacizumab (Avastin) for PROC. Bevacizumab, a VEGF (vascular endothelial growth factor) inhibitor, works by disrupting the blood supply tumors need to grow and spread. Among available options, one of the most effective standard approaches combines bevacizumab with weekly low-dose paclitaxel.

While this regimen can provide meaningful disease control and symptom management for some patients, stable disease time is only about 10 months, and overall survival averages 15 to 17 months.

These outcomes underscore the urgent need for therapies that can extend survival, preserve quality of life and provide patients with additional treatment opportunities.

The Evolving Treatment Landscape

Fortunately, there has been rapid acceleration of new drug development for platinum resistance in recent years, including three new FDA-approved therapies that we are now using at AHCI:

• Mirvetuximab (Elahere) is an antibody drug conjugate (ADC) for folate receptor (FR)-alpha positive disease, which accounts for about 30% of patients with ovarian cancer. We've been using this therapy at AHCI since its approval about two years ago. It is yielding a median progression free survival (PFS) of around 8 months, with some patients who have achieved a complete response (approximately 7% by blinded independent central review in the pivotal Phase III MIRASOL trial), and several patients maintaining stable disease well over one year.
• If a patient is FR negative, we look at their PD-L1 (programmed death-ligand 1) status, an immunohistochemical (ICH) marker for interaction of T-cells with the tumor. For patients with PROC who are PD-L1+, we can now use pembrolizumab (Keytruda), a checkpoint inhibitor, combined with weekly paclitaxel with or without bevacizumab. Combining pembrolizumab with both paclitaxel and bevacizumab has produced the best response and overall survival (OS). In the ENGOT-ov65/KEYNOTE-B96 clinical trial that led to pembrolizumab’s approval for PROC, median OS was 18 months, with many patients maintaining stable disease up to two years.
• If a patient is PD-L1-, we can now combine a weekly taxane, nab-paclitaxel (Abraxane), with Relacorilant (Lifyorli), a glucocorticoid receptor antagonist, which prevents tumors from activating survival and growth pathways and can re-sensitize chemotherapy-resistant tumors. In the pivotal Phase 3 ROSELLA trial, this regimen significantly extended patient survival for PROC compared to nab-paclitaxel alone.
• Her-2 is another surface receptor present (IHC 2+ or 3+) in 10% to 20% of patients with high-grade serous cancers of the ovary. Enhertu is a “pan tumor” ADC that is FDA-labeled for 3+ staining, and the NCCN guidelines recommend use in 2+ as well. Responses are often very high for this ADC (40% to 60%), and reported median PFS was 5.9 months with OS at 13.2 months.

Twenty years ago, many patients had only few options beyond palliative chemotherapy and supportive care. Today, we can offer new therapies that may extend survival, often laddering more than one to significantly preserve quality of life. By studying the specific gene mutations and protein expressions in an individual patient’s tumor, we can more precisely personalize therapies, including those on clinical trials, to achieve improvements in survival and quality of life.

Perhaps most importantly, every therapy that extends disease control creates time and the potential for patients to benefit from future therapies or clinical trials. Our experience with oncolytic virus therapy grew from this desire to expand options and improve outcomes by modifying the patient’s immune responsiveness to chemotherapy.

A New Tool Ten Years in the Making: Developing an Oncolytic Virus Clinical Trial

Sometimes a new idea can come from an unlikely place.

More than a decade ago, a community philanthropist asked me to join him at an investor meeting for a new biotech start-up focused on oncolytic viruses. The lab that made the viruses was in Germany, and they had performed a clinical trial in Germany using a new viral therapy called olvimulogene nanivacirepvec (Olvi-Vec) on solid tumors that had ascites and carcinomatosis disease in the abdominal cavity.

Olvi-Vec was designed to selectively infect and destroy cancer cells while sparing healthy tissue. The company had also completed a head and neck oncology trial combining radiation therapy with this virus.

I listened carefully to the science they presented and found it all intriguing.

Afterward, I asked to speak to their lead researcher about an idea for a new clinical trial using Olvi-Vec for PROC. At the time, we didn’t have many options to offer our patients with PROC, and most were going on hospice within a year after their treatment.

Soon after that initial introduction, we began developing concepts.

In 2015, we launched a Phase 1B study evaluating intraperitoneal Olvi-Vec in both platinum-resistant and platinum-refractory ovarian cancer (PRROC). It demonstrated biologic activity, tumor-specific immune activation and encouraging signals of durable disease control, supporting further investigation:

• Intraperitoneal Olvi-Vec was well tolerated.
• The overall response rate (ORR) with monotherapy Olvi-Vec was 9%.
• Stable disease ≥15 weeks was 46%.
• Median PFS was 15.7 weeks.
• Three patients had extended OS from 33.6 to 59+ months following additional cytotoxic therapies.

Soon after, we launched our Phase 2 non-randomized clinical trial of Olvi-Vec in patients with PRROC. This time we followed the intraperitoneal administration of Olvi-Vec with platinum-based chemotherapy with or without bevacizumab as immunochemotherapy. The results were once again, encouraging:

• With a median of 4 prior lines of therapy, 54% of patients experienced an objective response, with a median PFS of 11 months and a manageable safety profile.
• Median PFS was 10 months in the platinum-resistant group and 11.4 months in the platinum-refractory group.
• The median OS was 15.7 months in all patients with a median OS of 18.5 months in the platinum-resistant group and 14.7 months in the platinum-refractory group.

These findings exceeded historically expected outcomes from standard therapies at that time, warranting further clinical evaluation in a larger confirmatory Phase 3 clinical trial, which we were developing just as COVID-19 hit and slowed our efforts.

Seeking National Confirmation – The Current Olvi-Vec Phase 3 Clinical Trial

Despite the delays caused by the national pandemic, Olvi-Vec received fast track designation from the FDA, and we were finally able to open the Phase 3 study in 2022. Commonly known as OnPrime or GOG-3076, it is a multicenter, prospective, randomized and active-controlled trial evaluating whether Olvi-Vec can reverse platinum resistance, effectively resensitizing tumors to standard platinum-based chemotherapy and bevacizumab as an immunochemotherapy in heavily pre-treated women with PRROC. Once again, the aim is to prolong PFS.

When we opened the Phase 3 trial, this group of patients had very few other treatment options. Now we have three new FDA-approved therapies in the past three years that are extending survival and giving them options, so this has slowed enrollment a bit.

However, one of the things that makes the OnPrime/GOG-3076 study unique is that we aren’t limiting the number of prior therapies. This is important because with the newly approved treatments that are extending survival, we are increasingly encountering patients who have had five, six, seven and even eight lines of therapy while still maintaining good performance status.

Additionally, throughout all our Oli-Vec studies, we have allowed platinum refractory patients, which is rarely if ever seen. We believe this is important because these patients often have no other treatment option, and as evidenced in our Phase 2 study, the response rate and survival were nearly identical whether the patient was platinum-refractory or platinum-resistant. Either way, the virus is energizing the immune system, and we are achieving response about 54% of the time.

The Modern PROC Toolbox: Broadening Access Through Clinical Research

I believe the future of PROC care will not be defined by a single breakthrough therapy, but by our ability to offer patients access to diverse and expanding therapeutic options.

In addition to the recently approved therapies that have entered the standard of care and our ongoing work with oncolytic virus immunotherapy, several promising investigational approaches are advancing the treatment landscape for PROC, including bispecific antibodies, WEE1 inhibitors, and antibody drug conjugates (ADCs).

Bispecific antibodies are engineered to perform two functions simultaneously: one arm binds to a target on the cancer cell, while the other engages T-cells. By bringing these cells into proximity, bispecific antibodies are designed to direct the immune system to attack the tumor more effectively. Because approximately 90% of ovarian cancers express the Mucin-16 (MUC16) protein, this approach has generated considerable interest. At AHCI, we currently offer a multi-arm, Phase 2 trial evaluating the bispecific antibody ubamatamab both as monotherapy and in combination with other anti-cancer agents for patients with PROC.

Another promising area of investigation is WEE1 inhibition. Like PARP [poly (ADP-ribose) polymerase] inhibitors, WEE1 inhibitors exploit weaknesses in a cancer cell's ability to repair DNA damage. By blocking the WEE1 protein, these therapies prevent cancer cells from pausing to repair damaged DNA before division, ultimately leading to cell death as genetic damage accumulates. While many previous WEE1 inhibitors were found to be too toxic in patients with PROC, we are participating in a multicenter, Phase 2 study evaluating the investigational WEE1 inhibitor Zn-C3, which has shown a more favorable tolerability profile in early studies.

ADCs represent yet another important advancement. These therapies combine the targeting precision of monoclonal antibodies with highly potent chemotherapy payloads, allowing treatment to be delivered directly to tumor cells while limiting exposure to healthy tissue. In many ways, they function as a "smart bomb," delivering powerful anti-cancer agents precisely where they are needed. AHCI plans to participate in the J5E-MC-JZXB/GOG3133 FRAmework-01 trial, a Phase 3 study evaluating the ADC LY4170156 in PROC and in platinum-sensitive ovarian cancer in combination with platinum-based chemotherapy and bevacizumab.

Not every patient is eligible for every trial, and not every treatment aligns with a patient's goals or preferences. That is why maintaining a broad clinical trial portfolio is so important. The more options we can offer, the better we can personalize care based on a patient's disease characteristics, biomarkers, prior therapies and treatment priorities. To that end, we are very involved with the Phase 1 therapy unit (early drug discovery trials) housed on the AdventHealth Celebration campus. All new targeted therapies pass through Phase 1 testing and offer another important treatment option for many patients.

Ultimately, expanding treatment options is about improving patients' lives. When we can maintain quality of life while controlling disease, patients are more likely to remain on therapy and benefit from additional lines of treatment over time. We are now seeing more patients with PROC that can live five years or more with a diagnosis that only a few years ago carried a much shorter expected survival.

Building the Next Generation of PROC Care

While PROC remains one of the greatest challenges in gynecologic oncology, the pace of progress in the past five years has been remarkable, and the outlook for patients is finally improving. The evolution of our oncolytic virus program illustrates what can happen when scientific curiosity, translational research, institutional commitment and clinical expertise align with patient needs.

Targeted therapies, immunotherapy combinations and promising investigational agents have begun changing what is possible. At the same time, emerging tools such as ctDNA (circulating tumor DNA) and molecular disease monitoring may help us identify resistance earlier and make more informed, individualized treatment decisions that can further impact survival.

Ultimately, our goal is not simply to treat platinum resistance more effectively once it occurs, but to recognize it sooner, intervene earlier and prevent it from becoming clinically significant. Looking ahead, I hope to explore how approaches such as intraperitoneal oncolytic immunotherapy might be incorporated earlier in the disease course, potentially even alongside frontline treatment strategies like cytoreductive surgery in order to engage the patient’s innate immune system earlier in the treatment cycle.

Until then, we must continue building a broad range of treatment and clinical trial opportunities so that we can personalize care as much as possible. For patients and families facing PROC, every additional option represents the potential for more time to enjoy life with those they love, and that is what makes the rapid progress we are achieving in this field so meaningful.