FDA Approves Lifyorli Combo for Platinum-Resistant Ovarian Cancer, Showing Survival Gain

When ovarian cancer returns within months of chemotherapy, doctors know the odds are grim. For years, women with so-called platinum-resistant disease have cycled through single-agent chemotherapies that add only a few months of life, if that, with no drug conclusively proven to help them live longer.

On March 25, federal regulators cleared a new option that for the first time appears to move that survival needle.

The Food and Drug Administration approved relacorilant (sold as Lifyorli) in combination with the chemotherapy drug nab-paclitaxel for adults with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. Eligible patients must have received one to three prior systemic treatments, including the targeted therapy bevacizumab.

The decision—granted about three and a half months before the agency’s scheduled target review date—is based on a global study showing the drug combination helped patients live several months longer on average than chemotherapy alone. It also marks the first approval of a cancer drug that works by blocking the body’s receptor for cortisol, the hormone often associated with stress.

“Platinum-resistant ovarian cancer has long been an area where outcomes are poor and treatment advancements have been limited,” Dr. Rob Coleman, a gynecologic oncologist at Texas Oncology and special adviser to the GOG Foundation, said in a statement released by the drug’s maker, Corcept Therapeutics. He called the survival improvement “clinically meaningful” and said the regimen “is well positioned to become a new standard treatment” for appropriate patients.

A first in a high-risk population

Ovarian cancer is diagnosed in roughly 20,000 women and causes more than 12,000 deaths each year in the United States. It is the fifth leading cause of cancer death among women.

Most patients initially receive surgery plus platinum-based chemotherapy, often with both a taxane and biologic drugs such as bevacizumab. When the disease returns less than six months after the last platinum dose, it is considered platinum-resistant, a category associated with limited treatment options and median overall survival of about a year or less.

In this setting, guidelines have typically recommended single-agent regimens such as weekly paclitaxel, pegylated liposomal doxorubicin, topotecan, or gemcitabine, sometimes paired with bevacizumab. Newer therapies, including the antibody-drug conjugate mirvetuximab soravtansine and the immune drug pembrolizumab in certain combinations, are available only for patients whose tumors meet specific biomarker criteria.

By contrast, Lifyorli does not require a molecular test. Patients qualify based on their clinical course—resistance to platinum, prior exposure to bevacizumab, and the number of prior treatment lines—as long as they can tolerate nab-paclitaxel and do not need life-saving systemic corticosteroids.

What the ROSELLA trial showed

The FDA approval rests on the phase 3 ROSELLA trial, which enrolled 381 women at more than 100 sites across 14 countries. Participants had platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancers and had received one to three prior systemic regimens, including bevacizumab.

Patients were randomly assigned to receive weekly nab-paclitaxel plus oral relacorilant or nab-paclitaxel alone. Relacorilant was given as a 150-milligram tablet once daily on the day before, the day of, and the day after each infusion.

The study had two primary endpoints:

• Progression-free survival, or how long patients lived before their disease grew or spread
• Overall survival

Women who received the combination had a median progression-free survival of 6.5 months, compared with 5.5 months for those on nab-paclitaxel alone—a 30% reduction in the risk of progression or death.

The difference in overall survival was larger. Median survival was 16.0 months in the combination arm and 11.9 months in the control arm, a 35% reduction in the risk of death over the course of the trial.

While the absolute gains measured in months may sound modest, oncologists say this is the first randomized study in platinum-resistant ovarian cancer to demonstrate a statistically significant overall survival benefit over a standard chemotherapy regimen.

Subgroup analyses suggested women whose disease recurred very quickly after platinum—within one to six months—also derived benefit, an especially challenging group to treat.

How a cortisol blocker became a cancer drug

Relacorilant belongs to a class of compounds known as selective glucocorticoid receptor antagonists. Cortisol, which binds to the glucocorticoid receptor, helps regulate metabolism, immune responses, and the body’s reaction to stress.

In oncology, glucocorticoids are commonly administered to control nausea and allergic reactions related to chemotherapy. At the same time, preclinical research has suggested cortisol signaling through its receptor can make certain tumor cells more resistant to chemotherapy-induced cell death.

By occupying the glucocorticoid receptor, relacorilant is designed to prevent cortisol from activating it. Corcept’s scientists have argued this can enhance the ability of taxane chemotherapies such as nab-paclitaxel to induce apoptosis—programmed cell death—in tumor cells, without blocking other steroid hormone receptors.

Lifyorli is the first drug targeting the glucocorticoid receptor pathway to receive an oncology approval. Corcept previously brought a related drug, mifepristone (Korlym), to market for Cushing’s syndrome, a disorder of excess cortisol.

“This approval is the first important step in bringing the benefits of cortisol modulation to patients with cancer,” Corcept Chief Executive Joseph Belanoff said after the FDA’s decision. He added that there is “much more to explore” for this therapeutic approach in other tumor types.

Benefits and risks

The survival gains in ROSELLA came with added toxicity. According to the FDA’s prescribing information, 35% of patients who received relacorilant plus nab-paclitaxel experienced serious adverse reactions, and 2.1% had fatal events, including septic shock, cardiac arrest, ischemic stroke, and intestinal perforation.

Common side effects occurring in at least 20% of patients treated with the combination included decreases in hemoglobin and neutrophil counts, fatigue, nausea, diarrhea, low platelet counts, rash, and decreased appetite. Neutropenia and severe infections were among the most significant concerns, with one fatal case of septic shock reported.

The label warns of potential adrenal insufficiency, worsening of conditions treated with systemic steroids, and embryo-fetal toxicity. Lifyorli is contraindicated in patients who require glucocorticoids for life-saving indications, such as some transplant recipients and individuals with certain severe autoimmune diseases.

Because the pivotal trial enrolled women with good performance status—Eastern Cooperative Oncology Group scores of 0 or 1—how well frailer patients will tolerate the regimen outside controlled studies remains to be seen.

Cost and access pressures

Corcept has set the wholesale acquisition cost for Lifyorli at about $37,900 for a 28-day cycle, not including the price of nab-paclitaxel or clinic and hospital services. A course of treatment over several months can easily reach six figures.

The company has launched a patient support program to assist with insurance coverage and co-pay issues. Even so, oncologists and patient advocates say the high list price, combined with the need for weekly infusions and frequent blood tests, may limit access in rural areas and for patients with limited insurance coverage.

Payers will weigh the demonstrated survival benefit against the cost and the availability of less expensive generic chemotherapies. Formal cost-effectiveness analyses, which estimate the cost per life-year or quality-adjusted life-year gained, are still pending.

Sarah DeFeo, chief program officer at the Ovarian Cancer Research Alliance, described the approval as “very welcome news” for patients facing platinum-resistant disease.

“Women with this diagnosis urgently need better options,” she said in a statement. “We are grateful to the patients and clinicians who participated in the clinical trials that made this much-needed treatment option possible.”

A new player in a crowded field

The Lifyorli approval comes as the treatment landscape for recurrent ovarian cancer grows more complex. In recent years, drugs targeting folate receptor alpha and immune checkpoint pathways have joined traditional chemotherapy, PARP inhibitors, and anti-angiogenic agents.

Unlike some of those therapies, relacorilant can be used regardless of tumor biomarker status, though it is restricted to patients who have already received bevacizumab. Specialists expect clinical guidelines to address how to sequence Lifyorli relative to other agents, and whether it can ultimately be combined with emerging antibody-drug conjugates or immunotherapies.

Outside ovarian cancer, Corcept is testing relacorilant in other malignancies, including endometrial, cervical, pancreatic, and prostate cancers. In endocrinology, the company is working to resolve issues raised in a recent complete response letter from the FDA regarding relacorilant’s use in Cushing’s syndrome.

For now, clinicians and patients confronting platinum-resistant ovarian-type cancers will be the first to see whether blocking a stress hormone receptor can reliably tip the balance in their favor.

“Any extension of survival in this setting is important,” Coleman said. “This approval gives us an additional tool where for a long time there have been very few.”