Cancer Drug Trials That Should, But Won't, Be Done

Nick Mulcahy

April 24, 2014

UPDATED April 25, 2014 — Clinical trials comparing older, cheaper cancer drugs with newer, more expensive agents that are only marginally more effective would make a lot of economic sense, according to an essay published in the April 17 issue of the New England Journal of Medicine.

But conducting such comparative-effectiveness trials is blocked by, among other things, the high cost of purchasing the pricier drugs for trial participants, according to Sham Mailankody, MB BS, and Vinay Prasad, MD, from the National Cancer Institute.

The average price of 1 year of treatment with a new cancer drug now exceeds $100,000, making comparative trials prohibitively expensive, they write.

The comparative trials, which would pit a new pricey drug against an older, typically off-patent product, are unlikely to be sponsored by pharmaceutical companies, and companies are unlikely to provide the newer drug for free.

"High prices protect a drug's market share, precluding challenges from cheaper alternatives," the essayists claim.

They list 5 different tumor types for which a head-to-head drug comparison would be valuable.

The hypothetical trials would compare currently available more expensive "next-generation" cancer drugs with cheaper "parent" drugs that were an earlier treatment choice.

Table. Hypothetical Head-to-Head Comparisons

Setting Next-Generation Agent Parent Agent
Metastatic pancreatic cancer nab-paclitaxel (Abraxane, Celgene) paclitaxel
Renal cell carcinoma temsirolimus (Torisel, Pfizer) sirolimus (Rapamune, Pfizer)
Metastatic breast cancer everolimus (Afinitor, Novartis) sirolimus
Metastatic prostate cancer abiraterone (Zytiga, Janssen) ketoconazole
Metastatic colorectal cancer regorafenib (Stivarga, Bayer) sorafenib (Nexavar, Bayer)


The costs of the drugs alone in these would-be trials would range from $28 to $68 million, the essayists calculate.

Each hypothetical trial shares a number of key principles, they say.

First, the newer drug was approved by the US Food and Drug Administration (FDA) after comparison against placebo (or in 1 case, interferon alfa).

Second, the benefit of the new drug is "marginal"; median improvement in overall survival was 2.0 months and in progression-free survival was 2.7 months.

Third, preclinical or early-phase trial evidence on the next-generation agent supports a comparison with the parent drug.

Fourth, equivalent efficacy, if demonstrated, would result in "substantial savings" to society.

Prostate Cancer Illustration: A Strong Case?

To illustrate their point about cost savings, Drs. Mailankody and Prasad review, in considerable detail, the hypothetical trial of abiraterone and ketoconazole in the treatment of prostate cancer.

Notably, both drugs come from the same pharmaceutical company, Janssen/Johnson & Johnson. Abiraterone was launched in 2011, whereas ketoconazole (first discovered in 1979) has been off-patent for some years.

Abiraterone acetate is an inhibitor of the cytochrome P450c17 (CYP17) class of enzymes, which fuel prostate cancer progression. Abiraterone's mechanism of action is "remarkably similar" to that of ketoconazole, the older generic drug that also inhibits CYP17. The essayists point out that ketoconazole, originally developed and marketed as an antifungal agent (Nizoral, Janssen), has been used off-label in men with castration-resistant prostate cancer.

In the pivotal phase 3 COU-AA-301 trial that secured approval for abiraterone, the drug was used in combination with prednisolone and compared with prednisolone alone. The combination provided superior median survival in men with advanced castration-resistant prostate cancer (14.8 vs 10.9 months).

Ketoconazole was not the comparator in this study, because its survival benefit had not been established, the essayists explain. However, the drug has been shown to improve response rates in this setting.

Drs. Mailankody and Prasad emphasize that ketoconazole costs $500 to $700 per month as a prostate cancer treatment, whereas abiraterone costs more than $7000 per month.

"Conducting a noninferiority, randomized controlled trial comparing abiraterone with ketoconazole is one logical next step," they note.

A principal investigator of abiraterone agrees with the essayists.

"At some point, it is and will be important to show that the 'newly approved' drugs directed to targets and pathways for which older and less costly drugs are available provide incremental benefit," said Howard Scher, MD, from the Memorial-Sloan Kettering Cancer Center in New York City.

But Dr. Scher told Medscape Medical News in an email that he believes abiraterone would be the superior drug.

"Based on my own clinical experience, I believe abiraterone plus prednisone would prove superior in terms of efficacy and safety," he said. "But this is not a substitute for definitively proving that this is indeed the case."

Dr. Scher also explained the pluses and minuses of ketoconazole.

"All of us in the field have seen patients who respond well to ketoconazole plus hydrocortisone, but it is not an 'easy' drug from a toxicity point of view, from a drug interaction point of view, and the trial data available, while very promising, are not definitive vis-à-vis survival benefit," he said.

These points about ketoconazole have also been made by other experts (N Engl J Med. 2011;364:2055-2058).

If and when a comparative trial ever takes place, the makers of abiraterone would not likely provide the drug for free in such a clinical trial because it is not in their economic interest.

"A third party would probably need to purchase both drugs, in addition to incurring the fixed costs of running a trial," the essayists explain. But abiraterone alone would cost approximately $68 million for an appropriately powered trial.

That is a shame, according to the essayists. They speculate that "if just half of the 32,000 patients who die of prostate cancer annually in the United States were treated with ketoconazole instead of abiraterone," payers would save more than $1 billion per year.

Drs. Mailankody and Prasad conclude that innovations are needed to get this kind of trial done, including collaborations between the large oncologic cooperative groups and large payers that "could generate the revenue needed for such trials."

N Engl J Med. 2014;370:1478-1481. Abstract


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