Dismissing Reduced Abiraterone Dose Is 'Absolutely Wrong'

Nick Mulcahy

September 17, 2018

A debate has intensified about cutting the dose — and hence the cost — of the oral prostate cancer drug abiraterone acetate (Zytiga, Janssen) by taking it with food.

A prominent figure in the prostate cancer world has entered the discussion and added withering words for those opposing the idea.

Ian Tannock, MD, PhD, DSc, from Princess Margaret Hospital, Toronto, Ontario, endorses taking one daily pill of abiraterone with a low-fat breakfast (250 mg) — instead of the standard four pills on an empty stomach (1000 mg) — for the treatment of castrate-resistant prostate cancer.

And he said critics who dismissed the take-with-food approach as being "of small consequence" were "absolutely wrong."

The lower dose and reduced cost would make the efficacious drug available to many more men, especially in poor and middle-income countries, and thus is a matter of "enormous consequence," Tannock writes in a letter to the editor published online September 6 in the Journal of Clinical Oncology (JCO).

Tannock was provoked to write the letter after reading an editorial published May in JCO that accompanied publication of the randomized, 72-patient phase 2 study upon which the dose-reduction concept is based.

The editorialists said the evidence of noninferiority of the low-dose was "noncompelling" and use of the primary outcome was "clinically questionable." They also concluded that the low-fat abiraterone food effect was "minimal at best" and of "little consequence."

The phase 2 study findings on the two doses were first reported last year by Medscape Medical News, when they were presented at the 2017 Genitourinary Cancer Symposium. At that time, lead author Russell Szmulewitz, MD, from the University of Chicago, Illinois, said that it was well-known that abiraterone is more efficiently absorbed with food.

However, abiraterone, like many cancer drugs, was tested at fasting levels in clinical trials. "In cancer, there's a belief that fasting will give you better and more predictable drug levels with patients," Szmulewitz told Medscape Medical News at that time.

In his letter to the editor, Tannock acknowledges that a larger phase 3 trial to support the lower dose instead of the higher dose would be ideal, but the current phase 2 study design was wise.

"The authors sensibly chose a widely used proximal endpoint of prostate-specific antigen (PSA) response and progression-free survival (PFS)," he writes.

The study also investigated reduction in androgen dehydroepiandrosterone sulfate (DHEA-S), which is an "important pharmacodynamic (PD) marker" of abiraterone activity, Tannock notes.

"Within reasonable limits of error, the authors showed similar PSA response and PFS, and similar PD effects to reduce DHEA-S between the arms, obtained with a quarter of the recommended dose, despite higher trough levels of abiraterone in the standard arm," he summarizes.

However, in their JCO editorial that accompanied publication of the phase 2 results, Jill Kolesar, PharmD, University of Kentucky, Lexington, and Glenn Liu, MD, University of Wisconsin–Madison, focused on pharmacokinetics data and largely dismissed the trial and concept.

The editorialists are blinded by their methodological purity, Tannock suggests: "They are emphasizing small residual uncertainties and ignoring the global value of the reduced-dose treatment."

They are emphasizing small residual uncertainties and ignoring the global value of the reduced-dose treatment. Dr Ian Tannock

In his letter, Tannock suggests that this one-pill-a-day strategy should be used when men cannot afford the full dose. (In the United States, abiraterone at the full doses costs $8,000 to $10,000 per month).

Currently, "many" men will be denied abiraterone in developed countries as well as poor and middle-income countries, he says.

Abiraterone has "huge potential to improve the duration and quality of survival of millions of men with metastatic prostate cancer worldwide," he writes.

Tannock also has harsh words for the manufacturer of abiraterone, Janssen, a division of Johnson & Johnson. "Sadly," he writes, the drug has "limited global availability, and [this] trial is important, largely because of the greed of a company in setting an inappropriate price that bears no relationship to the cost of development and manufacture of abiraterone."

The drug is "a simple molecule that probably costs about as much to manufacture as aspirin," he commented.

What Janssen Said

When the study was published in May 2018, the authors concluded that "these data warrant consideration by prescribers, payers, and patients." They also called for additional studies to assess the long-term efficacy of the low dose with food approach.

At that time, Janssen issued a statement that said abiraterone should be taken, in accordance with the prescribing information, "on an empty stomach."

The company warned that taking abiraterone with food "may cause more of the medicine to be absorbed by the body than is needed and this may cause side effects."

Further, Janssen noted that "the use of food as a way to increase bioavailability in patients with cancer could present problems and risks."

"Given the variation in the content and composition of meals, the recommendation is to take [abiraterone] exactly as described in the prescribing information,” the company added.

Study Details

For the phase 2 trial comparing the two doses of abiraterone, Szmulewitz and colleagues randomly assigned 72 patients with progressive castrate-resistant prostate cancer to receive either a low dose (250 mg with a low-fat meal) or standard dose (1000 mg during fasting) along with prednisone 5 mg twice daily.

The patients were from seven institutions in the United States and Singapore, and the two groups were well balanced. The median age was around 73 years, and the patients' ECOG (Eastern Cooperative Oncology Group) status was 0 or 1. The only difference was that there were more African Americans in the low-dose group, at 31% vs 14% in the standard arm.

PSA levels were assessed monthly. Every 12 weeks, DHEA-S levels were determined, and disease burden was assessed radiographically. Drug concentrations were calculated from plasma samples.

There was a greater reduction in PSA levels from baseline to week 12 with low-dose abiraterone, at a mean log change of -1.59 vs -1.19 in the standard-dose group. These findings established the noninferiority of low-dose abiraterone on predefined criteria.

At 12 weeks, three patients (9%) on the standard dose experienced primary PSA progression vs one patient (3%) in the low-dose group.

The absolute PSA response rate at 12 weeks was 58% in the low-dose arm and 50% in the standard-dose arm. The duration of response was comparable, at a median PFS of 8.6 months in both arms.

The low-dose intervention yielded changes in androgen levels that were similar to the standard dose; at the end of the study, DHEA-S concentrations were 10.2 µg/dL and 9.1 µg/dL, respectively.

The team found that the maximum plasma concentrations of abiraterone acetate were higher in the standard than the low-dose group (P = .012).

At the time of publication, an expert not involved in the study, Daniel M. Geynisman, MD, assistant professor in the Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, told Medscape Medical News that the study was "important" and "well-designed."

Geynisman also noted caveats: the trial was small, and the endpoint of PSA levels at 3 months used in the trial is not standard.

"But at the same time we know that PSA is great surrogate for all the other endpoints in prostate cancer, and so it's reasonable to assume that it is," he said.

The results will not change practice widely, although they will give clinicians "some wiggle room," he said.

Tannock has reported a financial relationship with Janssen, the makers of abiraterone. Both editorialists have reported ties to industry, including Liu's tie to Johnson & Johnson, the parent company of Janssen. Multiple study authors, including Szmulewitz, have also reported ties to industry.

J Clin Oncol. Published online September 6, 2018. Letter to the editor

Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick

For more from Medscape Oncology, follow us on Twitter: @MedscapeOnc

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