NEW YORK – Researchers have moved quickly from preclinical research to human trials to determine whether a BET inhibitor paired with androgen therapy can make prostate cancer patients with Rb deficiency and immunologically "cold" tumors responsive to immune checkpoint inhibition.
Prostate cancer patients are often resistant to immunotherapy, and researchers from Emory University, the University of Chicago, and elsewhere are interested in exploring the prevalence of Rb deficiency in this context, its association with a non-T-cell-inflamed tumor microenvironment, and how these cold tumors can be sensitized to immunotherapy.
In a preclinical study published in Molecular Cancer Therapeutics this month, the researchers found that BET inhibitors could increase the infiltration of immune cells into the tumor microenvironment in mouse models. They have since translated these findings to a Phase II trial evaluating Zenith Epigenetics' BET inhibitor ZEN-3694 with Merck's checkpoint inhibitor Keytruda (pembrolizumab) and Astellas/Pfizer's androgen receptor inhibitor Xtandi (enzalutamide) in metastatic castration-resistant prostate cancer patients harboring an Rb deficiency.
Response rates to immunotherapy are already low among prostate cancer patients, around 10 percent, said Akash Patnaik, senior author of the study and assistant professor of medicine at the University of Chicago Medicine. On top of that, Rb-deficient prostate cancer is a very aggressive molecularly defined subtype of the disease. Rb deficiency is "one of the most frequent alterations in human cancer," Patnaik said. "It drives a particularly aggressive form of [prostate cancer] that exhibits a lack of response to conventional hormonal or androgen deprivation therapies, as well as chemotherapies."
Rb loss is present in up to 75 percent of patients with metastatic castration-resistant prostate cancer. In an analysis of the University of Michigan's MET500 database, which includes samples from metastatic tumors, the researchers found that 62 percent of metastatic prostate cancer samples were immunologically non-T-cell-inflamed, or cold tumors. Among those cold tumors, around 30 percent were also Rb deficient. In comparison, only around 4 percent of "hot" tumors that are inflamed or have the intermediate T-cell-inflamed phenotype had Rb deficiency.
The researchers then explored whether Rb deficiency was partially responsible for the non-inflamed tumor microenvironment in vitro and in vivo, finding that Rb deficiency was associated with a decrease in CD45, CD4, and CD8 T cells in the tumor microenvironment.
"When you target these Rb-deficient cancers with BET inhibitors, we can induce DNA damage in these tumors, and this DNA damage drives an innate immune sensing program through NF-κB signaling, called the STING pathway," Patnaik said. "That pathway, in turn, can recruit T cells and macrophages into the tumor microenvironment, which can essentially convert these cold tumors to hot tumors."
The hot tumors are more sensitive to immune checkpoint inhibitors, which work by helping T cells to target and kill tumor cells, Patnaik said. "These Rb-deficient tumors need to be reprogrammed to make the checkpoint inhibitors better," he added.
Since Rb-deficient prostate cancer patients often quickly become resistant to hormone therapy, that leaves them with either chemotherapy or a clinical trial as their only treatment options. There are currently no checkpoint inhibitors approved to treat prostate cancer.
Studies exploring the efficacy of checkpoint inhibitors in prostate cancer haven't always been successful. For example, the Phase II NEPTUNES study of Bristol Myers Squibb's Opdivo (nivolumab) and Yervoy (ipilimumab), which enrolled prostate cancer patients with a certain immunogenic signature, failed to show a benefit. However, when BMS evaluated the same combination in the CheckMate-650 trial in prostate cancer patients, early results suggested prostate cancer patients with high tumor mutational burden may derive greater benefit from the regimen.
Based on their preclinical findings, Patnaik and his colleagues have begun a Phase II trial evaluating the BET inhibitor and checkpoint inhibitor combination in patients. The researchers are enrolling patients into two cohorts: those with Rb-deficient metastatic castration-resistant prostate cancer and those with transdifferentiated treatment-emergent small cell neuroendocrine prostate cancer, which is characterized by Rb deficiency. This latter group of patients are the ones who "develop this more aggressive Rb-deficient disease as a consequence of androgen deprivation therapy," Patnaik said.
Patients in both cohorts will receive Keytruda on the first day of treatment, followed by the combination of the BET inhibitor ZEN-3694 and Xtandi for three weeks. The trial's primary endpoint is composite response rate, which means investigators are tracking whether patients have an objective response by radiographic imaging or a greater than 50 percent decline in serum prostate-specific antigen at four weeks from baseline. Patnaik said investigators are recruiting patients at trial sites at the University of California, San Francisco and the University of Michigan.
Zenith is also studying the activity of ZEN-3694 with checkpoint inhibitors in other disease settings, including in a Phase I study in combination with Keytruda and chemo in triple-negative breast cancer patients and in combination with Opdivo and Yervoy in patients with solid tumors and ovarian cancer.
Patnaik said his group collaborated with researchers at UCSF to try to accelerate the timeline from mouse studies to a Phase II clinical trial. In fact, the start of clinical trial overlapped the preclinical research of the BET inhibitor-immunotherapy combination. "[The trial] is essentially mirroring exactly what we did in the mice and where we showed that BET inhibitors can indeed sensitize these cancers to immune checkpoint inhibitors," Patnaik said.
His group is hoping that this strategy of overlapping preclinical research with clinical studies is a model that more researchers will try as a way of accelerating drug development, instead of the standard process where they first complete all the preclinical studies before starting clinical research.
With more than 95 percent of oncology drugs failing to progress into clinical studies, changes to the drug development paradigm are much needed, in Patnaik's view. "You spend a tremendous amount of time and resources to bring a drug from chemistry to [regulatory] approval without necessarily any significant success," he continued. "Clearly, that system is not efficient, so this paradigm of doing [these studies] in parallel significantly accelerates drug development and that's exactly what we did here."