Most patients with ovarian cancer are diagnosed at late stage as symptoms at early stages are minimal making it difficult to differentiate from common diseases.
Once patients reach these late stages, standard of care (SOC) is primary debulking surgery (PDS) followed by a course of chemotherapy. Recurrence is common in this patient population and then another round of chemotherapy. However after time, patients build up platinum resistance and the tumour does not respond to treatment.
There are several trials investigating candidates with different mechanisms of action (MoA) to be used in conjunction with other therapies or alone help patients better respond to first line therapies while other therapies are targeting patients who have developed platinum resistance.
GlobalData estimates that the value of the ovarian cancer market for the seven major pharmaceutical markets (7MM: US, France, Germany, Italy, Spain, UK, and Japan) will reach $4.05bn by 2032. GlobalData is the parent company of Clinical Trials Arena.
ADC associated AE’s must be monitored in farletuzumab ecteribulin
Eisai and Bristol Myers Squibb are running a Phase II trial of its antibody-drug conjugate (ADC) farletuzumab ecteribulin. Although still a relatively novel concept, the candidate is trailing behind its biggest rival – AbbVie’s Elahere (mirvetuximab sorvatansine), an ADC recieved approval from the FDA on 25 March 2024.
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In the trial (NCT05613088) the candidate is being pitted against the investigator’s choice of chemotherapy in patients with platinum-resistant high-grade serious ovarian, primary peritoneal, or fallopian tube cancer.
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By GlobalDataPrimary endpoints will evaluate objective response rate (ORR) of up to two years and proportion of participants with adverse events (AEs) leading to study discontinuation of up to two years. The primary completion date for the trial is June 2024.
The candidate acts by targeting tubulin and cells expressing folate receptor alpha. After binding to cancer cells, the candidate delivers its erubilin payload. Erubilin inhibits the polymerisation of tubulin at the targeted site and causes anti neoplastic activity.
Dr. Pamela Munster, director of the Early Phase Clinical Trials Unit at the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, says that there are concerns with ocular toxicity with Elahare, adding it is vital for these kinds of toxicities to be monitored and addressed in all ADC candidates.
“It’s an incredibly central and vital functional organ for people and has huge impact on quality of life if affected,” Munster explains. “While the folate receptor antagonist is an important target and the antibody drug conjugate, managing ocular toxicity is important – but it is very exciting.”
While ocular toxicity remains less of a concern with farletuzumab ecteribulin than with Elahare, having only occurred in two (9%) of patients at Phase I at Grade I, it is something being monitored closely.
“We have to look for another way to attack this disease,” says Dr. Armon Amit, director of the Gyneco-Oncology Unit at Rambam Medical Center in Israel. “I would need to consider the adverse events of this drug, but if these are manageable, I would definitely want to try it. The mechanism of action is logical and innovative.”
Combination of Merck’s flagship Keytruda and Lynparza
Merck is conducting a Phase III trial of its flagship drug Keytruda (pembrolizumab), in combination with carboplatin/paclitaxel chemotherapy, followed by Merck and AstraZeneca’s poly-ADP ribose polymerase (PARP) inhibitor Lynparza (olaparib) as a first-line treatment of women with breast cancer gene (BRCA) non-mutated advanced epithelial ovarian cancer.
Patients on the trial will have just undergone PDS or be eligible for PDS.
The Phase III trial (NCT03740165) is due to enrol 1084 patients. The primary completion for the Keylynk-001 is set for August 2024. The primary endpoint is progression-free survival (PFS) with monitoring of up to 57 months.
“The long-expected duration of response stems from the fact that these women are platinum sensitive so there’s a hope that patients will do well,” Muster says.
There are concerns about the possibility of high-grade AEs. Lynparza’s label includes detail about the possibility of events including myelodysplastic syndrome (MDS) of acute myeloid leukaemia (AML) in some patients.
“What we don’t know and hope not to see is that MDS occurs in this early-stage setting,” comments Munster.
There are also associated AEs with Keytruda but due to clinicians having a lot of experience with this candidate, they can usually be addressed at an early enough stage.
“In most patients we can identify the beginning of AEs and stop the drug which avoids significant events. Used properly, I think this is a better treatment than chemotherapy alone,” adds Amit, principal investigator on the trial.
Genelux hopes to bring gene therapy to treatment paradigm
Genelux Corp is investigating its olvimulogene nanivacirepvec, called olvi-vec, in a Phase III trial, called OnPrime.
The Phase III trial (NCT05281471) is investigating the efficacy and safety of olvi-vec and platinum-doublet plus bevacizumab compared to platinum-doublet plus bevacizumab. The study has a primary completion date in August 2024.
The trial will enrol 186 patients with histologically confirmed non-resectable, platinum-resistant, or refractory ovarian, fallopian tube or primary peritoneal cancer. The primary endpoint for the trial is PFS of up to 12 months.
Olvi-vec is an oncolytic virus which is distributed through the bloodstream and infects and replicates within tumour cells. The amplifying viral load causes tumour cells to burst and viral progeny to infect neighbouring tumour cells. The process continues until no tumour cells remain.
Oncology analyst for GlobalData, Jasminemay Barcelon says that olvi-vec is the only gene therapy product in late-stage development for ovarian cancer, adding that cell and gene therapies have suffered difficulties breaking into the solid tumour market.
Barcelon says: “If Olvi-vec demonstrates efficacy in this setting, it will provide a novel individualised therapy option and become a commercial success.”
Munster adds that there could be promise with this candidate – but only if it does not cause infection from the virus outside tumour cells.
Relacorilant targets unmet need of platinum-resistance
Platinum resistance is a big issue with ovarian cancer patients, marking a key unmet need to reduce or reverse platinum resistance.
Corcept Therapeutics’ hopes that its Phase III Rosella trial (NCT05257408) investigating the combination of relacorilant and Abraxane (nab-paclitaxel) may demonstrate a substantial improvement without increased toxicity compared with nab-paclitaxel alone.
Relacorilant is an oral selective glucocorticoid receptor modulator in late-stage development for ovarian cancer.
The candidate is being investigated as a combination therapy with Abraxane in platinum-refractory/resistant ovarian cancer patients. The dosing schedule for relacorilant is the day before, day of, and day after Abraxane treatment.
The global trial is estimated to enroll 360 patients with a primary completion date set in June 2024. Patients will be treated until disease progression or unacceptable toxicity.
The primary endpoint is PFS, assessed by blinded independent central review (BICR) of up to 24 months. Secondary endpoints include OS, ORR, duration of response and clinical benefit.
“There’s incredible value in extending the benefits of an effective therapy. If you have a drug that works for a year, we can extend this to 18 months or 24 months and that is a huge accomplishment,” Munster concludes.
