Authors

  1. Goodwin, Peter M.

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MUNICH-An "unprecedented improvement" in progression-free survival (PFS) was observed in the randomized, controlled, double-blind, phase III SOLO-1 study of women with newly diagnosed ovarian cancer who had BRCA1/2 mutations and were treated with the PARP inhibitor olaparib after their standard initial platinum-based induction chemotherapy.

  
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A 3-year extension of median PFS and the expectation of a robust superiority in overall survival-compared with the patients who had placebo therapy following their platinum induction chemotherapy-were reported at the 2018 ESMO Annual Congress.

 

"It's practice-changing. Patients are going to be demanding this when these results are made public. I think rightly so," said first author Kathleen Moore, MD, Associate Director for Clinical Research at the Stephenson Cancer Center, University of Oklahoma in Oklahoma City. "We're going to need to get the drug approved in this line-it's not approved in frontline [therapy] in any part of the world."

 

And genetic testing of tissue and tumor samples needed to be done very early in any patient's treatment course, she said, noting that it was not usually done in the first weeks but that this should now be considered mandatory. "We're going to have to move it up so we can make decisions. This is going to challenge some health care systems to accommodate that. So I think there is going to be some work to do."

  
Kathleen Moore, MD. ... - Click to enlarge in new windowKathleen Moore, MD. Kathleen Moore, MD

Big Step Forward

The big challenge for doctors in ovarian cancer-other than not being able to prevent it-had been that the vast majority of patients present with advanced disease. And while this had been very treatable it had been hard to cure, Moore said.

 

Although clinical science had done well by providing new assets to be used at the time of recurrence-giving small incremental improvements in PFS-these had improved the outlook for patients, but the really big steps forward had not been made, she said. "We really [had] not meaningfully prolonged that first disease-free interval to a point that we could start thinking about long-term disease-free survival for women."

 

PARP inhibition with olaparib had already been approved as a component of maintenance therapy for recurrent ovarian cancers that were still sensitive to platinum-based chemotherapy. And Moore said the drug had a meaningful impact on PFS. "So you would think you could incorporate that into front-line therapy."

 

At the time when plans for the SOLO-1 study began in 2011, Moore said patients with BRCA mutations had not yet ever been prospectively studied. "We thought they did better than non-BRCA [mutation carrying] patients. And that's true. But we really didn't know what their disease course was," she stated, noting that there had been trepidation about using maintenance for fear of overtreating patients who might already have been cured.

 

Having mutated BRCA1/2 implied that there was a dysfunctional BRCA protein-one of the key proteins for homologous recombination for double-stranded DNA repair, Moore said.

 

"If you're born with that, it predisposes you to ovarian and breast cancers and some others," she explained. "If you develop one of those cancers, it becomes the Achilles heel for that cancer-because if you treat the cancer with something that causes damage to the tumor's DNA the tumor can't fix its DNA.

 

"So it's got an inherent vulnerability to DNA-damaging agents-synthetic lethality. Patients with a BRCA mutation should be the most sensitive [to PARP inhibition]. So if you're going to try it in frontline in anybody, you [should] try it in a BRCA patient."

 

SOLO-1 Study

The SOLO-1 international phase III study randomized 391 women who had a known BRCA mutation to treatment with olaparib or placebo for their stage III or IV newly diagnosed high-grade serous or endometrioid ovarian cancer, or for primary peritoneal or fallopian tube cancer.

 

In the study, 260 women received olaparib; 130 had placebo therapy. And one did not receive either placebo or olaparib. All patients were given platinum-based chemotherapy and were in clinical complete or partial response. The primary endpoint was investigator-assessed PFS.

 

After a median follow-up of 41 months, primary PFS analysis showed a statistically significant 70 percent reduction in the risk of progression or death with olaparib compared with placebo treatment. Overall survival data were immature.

 

The investigator-assessed PFS was a median of 13.8 months in the placebo arm compared with a median that had not yet been reached in the olaparib arm. The difference between the survival curves gave a hazard ratio of 0.3 with a highly statistically significant confidence interval. "Improvement in progression-free survival as compared to placebo looks to be around 3 years," said Moore.

 

"The benefit of frontline olaparib appears [to be] maintained when you look at PFS2 (the time from randomization into SOLO-1 until the second progression)," she explained. "That hazard ratio is 0.5. So, you decrease the risk of progression on our second therapy by 50 percent if you get frontline olaparib. And that benefit was even more [statistically] significant because there was crossover in the placebo arm. Thirty-five percent of the patients who received placebo on SOLO-1 knew their BRCA status, so they got PARP [inhibition] when they recurred."

 

Adverse events were mostly low-grade. The most common grade 3 or higher toxicities with olaparib were anemia (22%) and neutropenia (8%). Olaparib dose reductions, interruptions, and discontinuations occurred in 28 percent, 52 percent, and 12 percent of patients, respectively. The study found no change in health-related quality-of-life scores with olaparib.

 

Commentary

"These are outstanding results in a worsening disease setting. Not only was olaparib efficacious, but it was also shown to be well-tolerated," said Isabelle Ray-Coquard, MD, PhD, medical oncologist at the Institute for Clinical Science, Centre Leon Berard in Lyon, who is Professor of Medical Oncology in University Claude Bernard Lyon, France. "The findings promise to change practice in this subgroup of patients with a BRCA mutation."

 

Coquard said two questions remained. "Can we expand this benefit to all high-grade serous carcinomas? Looking at existing results in relapse (with PARP inhibitor maintenance in all comers) we can anticipate excellent results for all patients with high-grade serous or endometrioid ovarian carcinoma.

 

"Also, what is the best maintenance therapy?" asked Coquard. Standard first-line therapy in many countries is chemotherapy plus bevacizumab maintenance for the majority of [patients with] advanced disease. But the question remains whether maintenance with olaparib alone or in combination with bevacizumab is preferable?

 

Peter M. Goodwin is a contributing writer.