MUNICH – With more than three years of follow-up, median progression-free survival (PFS) has yet to be reached in the treatment arm of the SOLO-1 study. Patients receiving placebo had a median progression-free survival (PFS) of 13.8 months, making for a hazard ratio of 0.3 and data that seem likely to turn Lynparza (olaparib, Astrazeneca plc) into the front-line standard of care for women with BRCA mutations.

SOLO-1 tested the use of Lynparza in newly diagnosed advanced ovarian cancer patients with a BRCA mutation as maintenance therapy in ovarian cancer following platinum-based chemotherapy. In the trial, 391 patients with high-grade serous or endometrioid ovarian cancer who responded to platinum-based chemotherapy were randomized 2-to-1, to Lynparza tablets 300 mg twice daily or placebo for two years.

Though median PFS has not yet been reached in the olaparib arm, it is on track to be roughly three years longer than for the placebo group.

Principal investigator Kathleen Moore, an associate professor at the University of Oklahoma's Stephenson Cancer Center, University of Oklahoma, presented the results at the European Society of Medical Oncology (ESMO) 2018 Congress, and predicted they "herald a new era in treatment for women diagnosed with advanced ovarian cancer who carry a BRCA mutation."

It's an indication that could use a new era. The current standard of care for ovarian cancer is platinum chemotherapy, which is initially quite successful in inducing remission. Three years later, though, more than 70 percent of patients have relapsed, and the long-term disease-free survival rate is around 15 percent. Lynparza and other poly (ADP) ribose polymerase (PARP) inhibitors are currently approved in recurrent disease.

The data presented at ESMO were in some ways more reminiscent of immunotherapies than other targeted therapies. At 41 months, it is too early to truly know whether front-line olaparib is capable of achieving the same kinds of cures as immunotherapy. But the Kaplan-Meier survival curves of the SOLO-1 trial do seem to show the beginnings of a tail, flattening at a level significantly above zero, that indicates the presence of long-term survivors.

The ability to cure even a small fraction of patients would be unprecedented for targeted therapies, which have collectively not found a way to convert initially strong responses into durable benefit for patients.

That is particularly encouraging given that in women with no evidence of disease, olaparib treatment was discontinued after two years – a trial design that more than one patient protested, and Moore admitted to being initially skeptical about.

To date, though, that skepticism has not been borne out. "It does not seem as if the curves are coming together" after treatment is ended, Moore said, indicating that treatment with Lynparza can have a benefit that endures beyond the duration of treatment.

Lynparza does not directly stimulate the immune system in the way that checkpoint inhibitors do. But because PARP inhibition prevents the repair of damaged DNA, it may raise the neoantigen load, which may make the tumors more visible to the immune system, which could explain its durable effects.

"Is olaparib eradicating the disease, or is something else going on? We don't know yet," Jonathan Ledermann told BioWorld.

Ledermann is at the University College London Cancer Institute and the principal investigator of Study 19, a randomized, double-blind placebo-controlled phase II trial that showed Lynparza improved both PFS and overall survival in women with platinum-sensitive, recurrent, high-grade serous ovarian cancer, and had already shown that some patients are "super-responders" to PARP inhibition, with response rates ongoing at six years.

But while those responses are ongoing, in Study 19, so is the treatment.

"We don't dare take them off therapy," Ledermann said.