What's Wrong With Cancer Clinical Trials? Look at Olaparib

Bishal Gyawali, MD, PhD


June 01, 2023

I recently came across the report of the 7-year survival results from the SOLO1 trial in ovarian cancer.

This is a trial of maintenance olaparib vs placebo among patients with advanced ovarian cancer who have responded to first-line platinum-based chemotherapy. Responding to first-line chemotherapy is a good prognostic marker. Unsurprisingly, almost half of the patients are alive at 7 years.

The final overall survival (OS) data are planned at 60% maturity, and these results provided an early look at the OS data. Accordingly, the criterion for significance was stringent at P < .0001. The results showed that the median OS was not reached in the olaparib arm and was 75.2 months in the placebo arm (P = .004).

Because this P value was higher than the study's criteria for significance, OS was not statistically significant.

When a patient's prognosis is so good that it is measured in years, a maintenance therapy needs to improve OS definitively to have a meaningful clinical benefit. Otherwise, patients would be subjected to years of taking a potentially toxic drug, adding substantial therapeutic burden and cost with no benefit.

If OS can also be improved by taking the drug in subsequent lines of therapy, patients may as well take it at that time, if deemed necessary, and gain the same benefit.

So when I read this trial's conclusion, I squirmed. It reads:

"Results indicate a clinically meaningful, albeit not statistically significant according to prespecified criteria, improvement in OS with maintenance olaparib in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation and support the use of maintenance olaparib to achieve long-term remission in this setting; the potential for cure may also be enhanced."

I then remembered some other trials of olaparib and realized that many, irrespective of tumor type, are riddled with major flaws in trial design and reporting. Let me give some other examples of problematic reporting of olaparib trials.

In pancreatic cancer, the POLO trial asked patients who were fortunate enough to respond to chemotherapy to abruptly stop their treatment after 4 months and be randomly assigned to receive either olaparib or placebo. Yes, you read that right: The control arm was placebo alone for patients with advanced pancreatic cancer. In this case, olaparib improved progression-free survival but failed to improve OS or quality of life.

A detailed commentary on these problematic issues with this trial has been published. However, these issues didn't prevent experts from celebrating these results or the US Food and Drug Administration (FDA) from approving olaparib for this indication. This deserves repeating: The drug had failed to improve survival against placebo in a lethal cancer.

Turning to the PROfound trial in prostate cancer, patients with BRCA mutations did show some OS advantage. However, the control arm of this trial was problematic. Patients who had already progressed on abiraterone or enzalutamide were asked to take these drugs again in the control arm. I would say that this is worse than being randomly assigned to placebo because these patients had already progressed on these agents, and by being randomly assigned to the control arm, they were denied other drugs, like cabazitaxel, which would have been effective. My colleagues and I have published our detailed criticisms of this trial elsewhere.

In metastatic breast cancer, the OlympiAD trial enrolled patients with advanced HER2-negative BRCA-positive breast cancer who had progressed on up to two lines of therapy and randomly assigned them to receive olaparib or physician's choice of treatment. However, the control arm choices excluded platinum agents, which would have likely been the preferred choice for many. Despite being a third-line therapy trial, the primary endpoint was progression-free survival, which improved, whereas OS was similar between the groups.

I have detailed my concerns about this trial in an earlier publication, but I think my conclusion from that editorial is worth repeating here: "Although olaparib seems to have won the Gold with OlympiAD, patients probably have not. Patients deserve a real gold. We need to stop celebrating a gold-plated bronze as a true gold so that one day our patients can finally get the gold they deserve."

To be fair, the adjuvant olaparib breast cancer trial called OlympiA seems cleaner than do the other olaparib trials discussed. The drug improved OS. The control arm did not allow capecitabine, which has a proven OS advantage, but this OS benefit was demonstrated in the 2017 CREATE-X trial; the OlympiA trial started in 2014.

I would argue that olaparib trials are not outliers. Most new cancer drug trials are similarly problematic and suffer from one or the other of the issues in trial design, analysis, and interpretation.

Despite these flaws, all olaparib trials discussed led to approval for the drug in the given indication. That's right. Every single one of these trials led to an FDA approval. Keep in mind, the monthly cost of the drug is $17,000 USD per patient.

We, the patients, physicians, policymakers, guideline writers, ethics review committees, journalists, public, and stakeholders of the cancer care ecosystem, should ask ourselves: Is this what we should be accepting of new cancer drugs? Is this the innovation that our patients deserve? More importantly: Should we accept trial designs that are stacked in favor of the new drug and not in favor of the patients?

It bears repeating: "Trials are there to serve patients, not the other way around."

Bishal Gyawali, MD, PhD, is an associate professor in the Departments of Oncology and Public Health Sciences and a scientist in the Division of Cancer Care and Epidemiology at Queen's University in Kingston, Ontario, Canada, and is also affiliated faculty at the Program on Regulation, Therapeutics, and Law in the Department of Medicine at Brigham and Women's Hospital in Boston. His clinical and research interests revolve around cancer policy, global oncology, evidence-based oncology, financial toxicities of cancer treatment, clinical trial methods, and supportive care. He tweets at @oncology_bg .

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