Following the recent flurry of FDA approvals for prostate cancer medications, oncologists are grappling with questions about which combinations or sequences of those therapies might improve outcomes for patients.
Robert Dreicer, MD, MS
Following the recent flurry of FDA approvals for prostate cancer medications, oncologists are grappling with questions about which combinations or sequences of those therapies might improve outcomes for patients. Clinical trials are needed to resolve that uncertainty and ultimately to cure more patients and produce the kinds of cost savings that will soon be demanded by the healthcare reimbursement system, a doctor explained during the 6th Annual Interdisciplinary Prostate Cancer Congress held on March 16 at the Crowne Plaza Times Square in New York, NY.
The doctor, Robert Dreicer, MD, MS, chairman of the Department of Solid Tumor Oncology at the Taussig Cancer Institute and professor of Medicine at the Cleveland Clinic in Ohio, said that trials will be crucial in determining which drugs are synergistic and which are toxic in combination—as was the case with sunitinib and bevacizumab in the treatment of renal cell carcinoma.
In his talk, Dreicer focused on the promise associated with several new drugs, including anti-androgen medications enzalutamide (Xtandi) and abiraterone acetate (Zytiga) and the experimental alpha-emitting radionuclide radium-223.Dreicer cited a recently published case report (Urology. 2013;81(2):381-383) about a man with metastatic castration-resistant prostate cancer (mCRPC) who responded well to enzalutamide as part of a phase I study. When the patient’s prostate-specific antigen (PSA) rose after 14 months, doctors added immunotherapy sipuleucel-T (Provenge) to his treatment regimen. Six months later, the man had an undetectable PSA level and went on to maintain his disease status for a year without radiographic change.
“You would not expect that with sipuleucel-T alone,” Dreicer said. “That begs the question about combination therapies.”
There is also emerging data suggesting a benefit from the combination of next-generation androgen receptor antagonists (ARs), such as enzalutamide, and testosterone-suppressing lyase inhibitors, such as abiraterone, the doctor said. In a study (J Clin Oncol. 2011;29[suppl abstr 4501]), 47 patients with progressive mCPRC were treated with enzalutamide and given serial bone marrow biopsies. Based on rises in mean plasma testosterone and drops in PSA, investigators confirmed that enzalutamide works in CRPC because it potently inhibits AR signaling. Previous research had shown that abiraterone works by a different mechanism that decreases testosterone and increases AR copy number.
“Taken together, these data suggest that these two androgen signaling inhibitors in combination will work synergistically,” Dreicer said.
A phase II safety and tolerability trial of the two drugs in combination in patients with mCRPC (NCT01650194) is being conducted at the University of Texas MD Anderson Cancer Center, with results expected in the fall or winter, he said.The doctor said that another aim of clinical trials should be to determine the order in which drugs should be given, both as a cost-effectiveness measure and in order to avoid toxicities.
One area where that information will be important is in patients with mCRPC who are asymptomatic, Dreicer said. He noted that treatment choices may soon include either abiraterone or enzalutamide, but that there is no information yet on how to sequence the two drugs for maximum effectiveness.
“We have sipuleucel-T as an approved agent in this clinical space,” he added, “but is there a rationale to give it with enzalutamide or abiraterone? Does sequence matter, and does it impact on the immune response? We don’t know.”
Dreicer also suggested that it will be worthwhile to study whether, when using new drugs, oncologists will be able to drop older medications out of combination regimens or sequences for patients with mCRPC.
He noted that, in the phase III AFFIRM (Presented at the European Society for Medical Oncology Congress; September 28-October 2, 2012; Vienna, Austria. Abstract 896O) and COU-AA-301 (Lancet Oncol. 2013;13:1210-1217) studies, respectively, enzalutamide and abiraterone delayed time to first skeletal-related event in patients with mCRPC. That raises questions, the doctor said, about whether such patients also need osteoclast inhibitors.
“If a patient takes abiraterone and then enzalutamide, does he benefit by adding denosumab or zoledronic acid, or are those drugs not needed because there are such effective therapies now?” Dreicer asked.
Because radium-223 also demonstrated a delay in time to first skeletal event in this population in the ALSYMPCA trial (J Clin Oncol. 2012;30 [suppl abstr LBA4512]), and because its non-hematologic toxicity profile is very low, trials of the drug in combination with AR targeted agents will provide important information, Dreicer said.
To support the process of testing potential drug combinations for the treatment of prostate cancer, the FDA should change its stance on what constitutes a valid endpoint in clinical trials, Dreicer asserted.
“Can you continue to anticipate, in an era where multiple trials are going to be done with multiple overlapping mechanisms, that we can still use overall survival as an endpoint?” he asked. “The likelihood, as we begin to start thinking about these new combinations, is that that’s not going to be acceptable.”
Dreicer added that the stage of disease for which agents are currently approved does not necessarily represent the most rational way to use them. “These are drugs with unique mechanisms that most likely will work through the spectrum of disease,” he said of treatments including enzalutamide and radium-223.
A further complication on the horizon is a change in the reimbursement paradigm to favor value-based care, Dreicer said. “Payers will say, ‘Do what you think is best for the patient: Here’s the amount of money you have to do it,’” he said. “Whether a treatment makes scientific sense will be the most cost-effective way to take care of patients, so we have to think differently about trial design. It’s not just, ‘Can we think about adding three drugs together because we can put three drugs together,’ but whether the mechanism and outcome will drive what we want—improved patient outcome.”
Ultimately, new information about how to combine and sequence novel drugs is bound to benefit patients, Dreicer predicted.
In particular, he said, by confirming additive or synergistic activity between enzalutamide and abiraterone and moving them into the adjuvant setting—in high-risk locally advanced patients—it may be possible to “cure some patients that we didn’t cure before.”