5 minute read
A One-Two Punch to Treat Advanced Prostate Cancer
BY JANE KOLLMER
A drug that held great promise in advanced prostate cancer failed in clinical trials. Several years later, a discovery made in a University of Chicago research laboratory renewed hope in its potential.
Prostate cancer is the second most frequent cancer diagnosis made in men and the fifth leading cause of mortality, accounting for approximately 360,000 deaths worldwide in 2018. Men with metastatic castration-resistant prostate cancer (mCRPC), or cancer that has spread and is not responding to standard hormonal treatments, face a poor prognosis.
Currently, researchers are looking for new ways to address this longstanding treatment challenge by testing novel therapeutic options, including cancer
therapies that identify and attack specific types of cancer cells. One such drug is cabozantinib, a type of tyrosine kinase inhibitor (TKI). The drug has been traditionally thought to work by blocking certain proteins that drive the rapid increase and survival of cancer cells, thus inhibiting the growth of the tumor. It may also prevent angiogenesis, the growth of new blood vessels that tumors need to grow.
This new drug was tested on advanced prostate cancer through a large, phase III clinical trial named COMET-1. The trial was halted in 2014 when early results showed the drug did not extend survival in a heavily pre-treated mCRPC patient population.
In the wake of these disappointing results, the drug’s manufacturer, Exelixis, laid off about 70% of its workforce.
RENEWED HOPE
The results of that study were puzzling to Akash Patnaik, MD, PhD, an accomplished physicianscientist and national expert in prostate cancer research at the UChicago Medicine Comprehensive Cancer Center. The Comprehensive Cancer Center is a major center for conducting prostate cancer research through the National Cancer Institute and private sponsors.
Akash Patnaik, MD, PhD, published a study showing that the drug cabozantinib has powerful effects against metastatic prostate cancer.
Patnaik focuses on translating novel therapies from the laboratory to early-stage clinical trials. He was curious about why cabozantinib showed promising activity in a phase II trial of patients with mCRPC but did not extend survival in a larger phase III trial. He reasoned that a better understanding of the drug’s mechanism of action and its impact on the unique immune environment within the tumor would help identify patients who may respond to it.
At that point, Patnaik’s laboratory began studying cabozantinib’s effects in a mouse model of advanced prostate cancer. His team first saw that the antitumor effects of the drug did not depend upon the MET signaling pathway, one of the proteins targeted to hold back cell growth and angiogenesis. Instead, Patnaik’s team observed that cabozantinib stimulated tumor cells to release immune cell trafficking molecules called chemokines. These proteins send out a signal to attract
neutrophils, a type of white blood cell that helps heal damaged tissues and resolve infections. This resulted in neutrophils swarming into the tumor and clearing out cancer cells.
The study was the first to demonstrate that a TKI can switch on neutrophil-mediated antitumor immunity, resulting in widespread cancer clearance. The research was published in Cancer Discovery in 2017.
“We were excited to have more evidence supporting how cabozantinib has powerful effects against metastatic prostate cancer,” said Patnaik. “But this was only the beginning because we still needed to figure out how this applies to humans and what other drugs were needed to induce a powerful immune response.”
A major breakthrough in cancer is immunotherapy, or treatments that use a patient’s own immune system against cancer. One type of immunotherapy uses monoclonal antibodies that target an interaction between the cell-surface receptors— programmed cell death protein 1 (PD-1) and (PD-L1), which are “checkpoints” that tumors exploit to turn off the immune response. By blocking this interaction, PD-1 checkpoint inhibitors can open the gates for T cells, restoring the desired immune response against cancer cells.
These new therapies have shown incredible promise, yet they only work for approximately 20% of all cancer patients and are not effective in certain specific tumor types. In particular, the responses to immune checkpoint blockade in advanced prostate cancer have been few and far between. Therefore, researchers are exploring ways to improve immunotherapy responses. They have found that pairing immunotherapies with other treatments may be an effective approach for eliciting a better clinical response than either treatment by itself.
The published work generated in Patnaik’s lab opened the door to investigating 16 combination trials with cabozantinib (innate immune activation) and checkpoint inhibitors in multiple advanced solid tumors. At the 2020 American Society of Clinical Oncology Genitourinary Cancers Symposium in February 2020 in San Francisco, researchers shared exciting results from a trial that tested cabozantinib in combination with atezolizumab in patients with mCRPC, as part of a larger study called COSMIC-021. Atezolizumab is a monoclonal antibody that attaches to PD-L1 and “blocks” its checkpoint function, thus releasing the hold on the immune system, to attack cancer cells.
The study cohort included 44 patients, who were followed for a median of 12.6 months. The results showed that 32% of the patients experienced an overall response on the treatment, including two who had complete responses and 12 who had partial responses. For 80% of the patients, their disease was controlled during the study period.
Among 12 patients who had an objective response and at least one prostate-specific antigen (PSA) evaluation following the initiation of treatment, 67% had a PSA decline of at least 50%. OF THE PATIENTS HAD THEIR DISEASE CONTROLLED DURING THE STUDY PERIOD.
Patnaik said, “Given the 0% and 5% prior response rates for atezolizumab and cabozantinib singleagent trials, respectively, these data are very exciting, and a big step forward for the development of immunotherapy combinations in advanced prostate cancer.”
He continued, “It’s gratifying to see that our laboratory discovery demonstrating cabozantinib’s innate immune anti-cancer mechanism is holding true in patients.”
NEXT STEPS
These promising, newly emerging clinical data set the stage for phase III trials involving this drug combination. With funding from various federal and private sources, Patnaik is also developing clinical trials involving combinations of cabozantinib with other immune checkpoint inhibitors. He will serve as co-principal investigator and national correlative science chair for an investigator-initiated clinical trial of cabozantinib with nivolumab, a PD-1 checkpoint inhibitor, run through the Prostate Cancer Clinical Trials Consortium.
The unprecedented speed at which progress is being made continues. As early as 2021, Exelixis plans to collect enough positive supporting clinical data to apply for accelerated FDA approval in metastatic CRPC.
It all started with the discovery of cabozantinib’s immune mechanism in the laboratory that paved the way for the drug’s resurrection and redemption.
“The fact that a mechanistic discovery made in the laboratory in 2017 led to a clinical trial reporting positive results in 2020 is an incredibly rapid drug development timeline, a prime example of how bench-to-bedside research is able to generate promising new treatments,” Patnaik said. “We hope this strategy will alleviate suffering and improve survival for our patients with aggressive mCRPC.”
