Trovagene’s investigational oral therapy onvansertib may help overcome resistance to Zytiga (abiraterone acetate) in men with metastatic castration-resistant prostate cancer (mCRPC), updated Phase 2 data continue to suggest. The trial (NCT03414034) is testing onvansertib as an add-on to Zytiga (by Janssen Biotech) and prednisone in men who experienced a rise in their prostate cancer antigen (PSA) levels while receiving the Zytiga-prednisone combination. Findings showed that 72% of patients experienced a drop in their PSA after one cycle of treatment — indicating a positive response to treatment — including all patients positive for the AR-V7 variant, a known marker of resistance to Zytiga and other androgen receptor inhibitors. The data "builds upon the encouraging clinical response seen to date when onvansertib is added to treatment in patients who have developed resistance to androgen receptor signaling inhibitor [ARS] Zytiga," Mark Erlander, PhD, chief scientific officer of Trovagene, said in a press release. “We believe the addition of onvansertib has the potential to deliver transformative benefit to patients with mCRPC by extending the duration of response to treatment with ARS inhibitors," he said. The results were presented at the recent European Multidisciplinary Congress on Urological Cancers in Vienna, Austria, in a poster, titled “A phase 2 study of the combination of PLK1 inhibitor, onvansertib, with abiraterone and prednisone in patients with metastatic castration-resistant prostate cancer.” Onvansertib works by inhibiting the PLK1 enzyme, which is over-expressed in multiple cancers and plays a key role in tumor cell proliferation. By binding to PLK1, the treatment stops cancer cells from proliferating, eventually leading to their death. Studies in animal models of mCRPC have suggested that onvansertib significantly boosts the efficacy of Zytiga. Thus, the researchers designed a Phase 2 trial to observe the effects of onvansertib in men with mCRPC showing signs of disease progression and resistance to Zytiga — defined as two rising PSA levels, with at least a one-week interval between measures, while on the treatment. Patients continued receiving their prior Zytiga regimen, and were assigned to oral, once-daily onvansertib, given for five consecutive days in two- or three-week cycles. Among the first 15 patients who completed three months of treatment, 60% achieved at least stable disease (based on PSA levels and radiographic scans), and 72% of patients experienced a reduction in their PSA levels after one treatment cycle. Six patients have been receiving treatment for at least four months. Patients with mCRPC typically develop resistance to standard-of-care medications such as Zytiga within nine to 15 months after starting treatment. In some cases, resistance develops when cells produce a variant of the androgen receptor, called AR-V7, which lacks the domain targeted by current androgen receptor inhibitors. The five participants who tested positive for AR-V7 all showed a decrease in their PSA levels following one cycle of treatment with onvansertib. Three of four patients available for efficacy measurements also achieved disease control, the study’s primary efficacy goal. "Of particular significance are the positive results we are observing in patients who harbor the highly aggressive, resistant variant of the androgen receptor (AR-V7). These patients are resistant to ARS inhibitors including Zytiga and Xtandi (enzalutamide, by Astellas and Pfizer) and their therapeutic options are not only limited, but often ineffective,” Erlander said. Onvansertib add-on therapy was generally safe and well-tolerated. The most frequent adverse events were anemia, low levels of neutrophils and platelets, and reduced number of white blood cells, all of which were related to onvansertib's mechanism of action and easily managed. The ongoing trial is expected to reach a total of 64 participants across sites at Massachusetts General Hospital, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute. Find more information about the trial here.