AUSTIN, TX—An interim analysis of the randomized, Phase II P-19 trial of maintenance treatment with the PARP inhibitor olaparib in patients with platinum-sensitive relapsed serous ovarian cancer shows the drug is still not improving overall survival compared with placebo.
Median overall survival reported here at the Society of Gynecologic Oncology's Annual Meeting on Women's Cancer was 29.7 months for olaparib and 29.9 for placebo.
Because of this, the drug's manufacturer is not moving forward with a Phase III trial in this disease.
The Phase II study did show, however, that maintenance therapy with olaparib does increase progression-free survival. First reported at the 2011 ASCO Annual Meeting and subsequently published as a full study in the 4/12/12 issue of the New England Journal of Medicine (2012; 366:1382–1392), the trial showed an improvement in median progression-free survival of 3.6 months: 8.4 months for olaparib versus 4.8 months for placebo.
The latest data were presented at the SGO meeting by first author Jonathan Ledermann, MD, Professor of Medical Oncology at University College of London Cancer Institute.
Ledermann emphasized that the data are still immature and that 38 percent of the patients in the study had died. The planned final survival analysis will be done at 60 percent maturity, he said, which is likely to occur towards the end of the year.
The 295 participants entering the P19 study had completed platinum chemotherapy with a response that was either complete or a maintained partial response before randomization. Treatment was continued until disease progression.
“The future of olaparib is uncertain,” Ledermann confirmed in an interview after his presentation. “Following the first interim survival analysis showing no difference against placebo, the manufacturer decided not to pursue development of the drug for high-grade serous ovarian cancer.”
Problems with Capsule Formulation
He noted that there were also problems with the capsule formulation, and that the company has gone ahead with a reformulation to tablets. A trial is underway in Europe using the tablet form for breast and ovarian cancers with BRCA mutations.
“We're still waiting for further news from AstraZeneca, but the studies with the new formulation are going ahead now so it is likely the drug will be reformulated and used some other way,” he said.
“The take-away message is that PARP inhibitors are active drugs, as we can see from the statistically significant progression-free survival; the problem is that we just don't know quite how to use them.
“We have to determine how important overall survival is compared with progression-free survival,” he continued. “And we need to know if we can modify the use of the drug or use it in different groups of patients, such as those with BRCA mutation.”
The entry criteria for the study did not require BRCA mutation, but did require high-grade serous histology.
PARP inhibitors are targeted specifically to patients who have defects in the way in which they repair DNA. This is most clearly seen in patients with BRCA mutations, he said, “but we now know that high-grade serous ovarian cancer patients have similar defects—homologous recombination deficiency—and therefore are sensitive to PARP inhibition.”
Hoping for Further Ovarian Cancer Research
SGO's Immediate Past President, John Curtin, MD, Director of the Division of Gynecologic Oncology at New York University Medical Center, commented in an interview that the PARP inhibitors seem to have the most promise for patients who have the BRCA mutations.
“I'm hoping the pharmaceutical company that developed the drug is only planning to withhold further development until they can better characterize their formulation and that it is not a matter of giving up on it all together,” he said.
He speculated that one reason for the similarity in overall survival for patients receiving olaparib versus those receiving placebo is that patients can continue on different treatments after they enrolled in this clinical trial, so even if they show disease progression they might have significant response to subsequent therapies, which would blur the ability to detect a survival benefit.
Ledermann said candidly that statisticians are doubtful the trial will become positive over the long term regarding overall survival—“but you have to remember that the primary endpoint of this study was progression-free survival, and that endpoint has been well met,” he added.
He said while overall survival was a secondary endpoint, overall survival is important as far as the company is concerned for taking the development forward, “particularly on this side of the Atlantic with the FDA wanting overall survival in order to license a drug.”
The European Medicines Agency (EMA), he said, is not quite so rigid about survival and progression-free survival in terms of licensing.
“Purists will say that overall survival is the final endpoint, and it is, but I think there is more that goes on between progression and death, [such as] time off treatment and quality of life, and we are not particularly good at measuring those,” Ledermann said.
“We tend to give a treatment, measure the response, and that's it, but I think we need to see the whole pathway of care and where new drugs might fit in that.”