Expert Point of View: Charles Drake, MD, PhD

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IN A SEPARATE interview with The ASCO Post, Charles Drake, MD, PhD, commented on the clinical implications of the ENZAMET and TITAN trials, as well as studies of apalutamide, abiraterone acetate, and docetaxel used in metastatic hormone-sensitive prostate cancer. Dr. Drake is Director of Genitourinary Oncology at Columbia University Medical Center’s Herbert Irving Comprehensive Cancer Center in New York.

Charles Drake, MD, PhD

Charles Drake, MD, PhD

“ENZAMET and TITAN are not unique,” Dr. Drake began. “All five trials in this space (ie, ARCHES, LATITUDE, STAMPEDE, TITAN, and ENZAMET) asked the same question: If you were parched with thirst in the desert and had a bottle of water, would you drink it right away? Perhaps a more important question is whether you should drink it now or later. The real question is not whether to use second-generation hormones in hormone-sensitive prostate cancer. The question is whether to use them early or later,” Dr. Drake stated. “All five trials do not ask that question. They just compare using them vs not using them early.”

‘Fundamental Issue’

DR. DRAKE considered this a “fundamental issue” in being able to interpret these trial data. “What if patients do not want these drugs upfront,” he asked. “We need to know how to sequence these drugs and whether we should always use them right out of the gate. In some of the studies, LATTITUDE for example, the vast majority of patients never got a next-generation agent, ie, they never got any water. But in some of the studies, especially ENZAMET—a fair number of patients did go on to receive those agents. I think that many of us would like to see overall survival data on men who received enzalutamide later on. Unfortunately those data were not presented,” according to Dr. Drake.

For example, in the ENZAMET study, the investigators showed that 141 patients received subsequent enzalutamide at disease progression. However, overall survival data on those patients were not shown. “So, 141 patients ‘drank the water later,’ and we didn’t get the information on their outcomes. Perhaps we'll see those data later,” Dr. Drake opined.

“The clinical relevance of early vs late treatment has not been addressed,” continued Dr. Drake. “The studies address early treatment vs no early treatment. This creates a bit of a bias, as patients who progress on the placebo arm are not crossed over to the study drug in a controlled manner. Instead they receive a variety of agents in an uncontrolled manner. It’s important to realize that these drugs are all active, but that starting an active drug early vs not starting an active drug early is almost inevitably likely to lead to a successful trial,” he noted.

Many Treatment Choices: Role of Shared Decision-Making

“IF A PATIENT with metastatic hormone-sensitive prostate cancer comes in to see me, he could receive androgen-deprivation therapy (ADT) in the form of a luteinizing hormone-releasing hormone antagonist alone, or ADT plus chemotherapy (CHAARTED, STAMPEDE trials), ADT plus abiraterone acetate (LATITUDE trial), ADT plus apalutamide (TITAN trial), or ADT plus enzalutamide (ENZAMET, ARCHES trials). We now have all these choices, so this will involve shared decision-making with the patient,” Dr. Drake stated.

“For some patients, chemotherapy is anathema, but docetaxel is given over 18 weeks, and the payoff in survival is a median [increase in survival] of 1.8 years compared with ADT alone. Plus, it is covered by insurance. But many patients prefer an oral treatment.”

Clinically, the hormone therapies may be used similarly in the real world, Dr. Drake noted. The choice of agent should consider risks versus benefits, side effects, insurance coverage, and potential contraindications.

“With abiraterone acetate, steroids are needed, but there are contraindications to that regimen, such as cardiovascular disease or diabetes. With enzalutamide, the major contraindication is seizure disorder, and a few patients do experience debilitating fatigue. Apalutamide may be better tolerated, and darolutamide will probably be approved—there are some who feel that’s even better tolerated. Of course, without head-to-head comparisions, those observations can be experiential rather than data-driven,” Dr. Drake concluded.

DISCLOSURE: Dr. Drake has served as a consultant/advisor for AstraZeneca/MedImmune, Bristol-Myers Squibb, Compugen, Roche/Genentech, Janssen Oncology, Pfizer, Tizona Therapeutics, Potenza Therapeutics, Merck, and Pierre Fabre; has received institutional research funding from Bristol-Myers Squibb; has institutional patents with Bristol-Myers Squibb and Potenza Therapeutics; has stock/ownership interests with Compugen, Harpoon Therapeutics, Kleo Pharmaceuticals, Potenza Therapeutics, and Tizona Therapeutics; and has received travel/accommodations/ expenses from Roche/Genentech, AACR, and ASCO.

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