Trovagene’s investigational oral therapy onvansertib helps overcome resistance to Zytiga (abiraterone acetate) in men with metastatic castration-resistant prostate cancer (mCRPC), latest data from a Phase 2 clinical trial show.
These results also highlighted that adding onvansertib to a standard Zytiga (by Janssen Biotech) and prednisone combination led to treatment responses in patients carrying markers associated with resistance to Zytiga and other androgen receptor signaling (ARS) inhibitors.
“Observing efficacy in patients that have tumors exhibiting known mechanisms of resistance to ARS inhibitor, Zytiga, suggests that onvansertib’s activity could extend to overcoming resistance to other ARS inhibitors, such as Xtandi and Erleada,” Mark Erlander, MD, Trovagene’s chief scientific officer, said in a press release.
A poster with the data, “A phase II study of onvansertib in combination with abiraterone and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC),” was presented at the 2020 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, held Feb. 13-15 in San Francisco.
Onvansertib is an oral investigational therapy that blocks the activity of PLK1, an enzyme found at higher levels in multiple cancers and that plays a key role in tumor growth and spread (metastases). By suppressing PLK1, onvansertib is designed to stop cancer cells from proliferating, eventually leading to their death.
Preclinical data suggested that onvansertib significantly boosts the efficacy of Zytiga in animal models of mCRPC.
Trovagene launched a Phase 2 clinical trial (NCT03414034) to evaluate whether adding onvansertib to the standard Zytiga combination could halt cancer progression and extend survival. It is enrolling up to 64 men with mCRPC showing signs of disease progression while on Zytiga at three sites in Massachusetts.
Disease progression and resistance to Zytiga in these patients are defined as two rises in their prostate cancer antigen (PSA) levels (a marker of prostate cancer progression), with at least a one-week interval between measures, while using the Zytiga-prednisone combo.
In addition to the standard Zytiga combo, participants will receive one of two different onvansertib dosing regimens: 24 mg/m2 of onvansertib daily for five consecutive days in a three-week cycle (group A), or 18 mg/m2 of onvansertib daily for five consecutive days in a two-week cycle (group B).
The study’s primary goal is to assess the proportion of patients achieving disease control, measured by a stabilization or reduction in PSA levels after three months of treatment. Secondary goals include other PSA level measures, radiographic response, and safety.
Previous trial data, on the first 15 patients who finished three months of treatment, found 72% of these people had lower PSA levels after one treatment cycle, and 60% achieved at least stable disease. Notably, these benefits were also seen in patients with markers of ASR inhibitor-resistance.
Newly presented data covered 19 patients (14 in group A and five in group B) after at least three months of treatment. Six men were treated for seven or more months. Seven had markers of resistance to ARS inhibitors, such as Zytiga.
Results showed that 12 men (63%) — eight (57%) in group A and four (80%) in group B — achieved a radiographic treatment response (stable disease or partial response) at three months. At this time point, five men (36%) in group A and three patients (60%) in group B also achieved the primary goal of at least stabilized PSA levels.
Among the seven men with markers of ARS inhibitor resistance, the onvansertib triple combo led to immediate PSA reductions in six (86%) of them. After three months of treatment, four (57%) showed stable disease or partial response, and three (43%) had at least stable PSA levels.
Researchers also looked at the number of circulating tumor cells (CTCs) in these patients, since it is a predictor of survival in castration-resistant prostate cancer. Of the 32 men enrolled, 25 (78%) showed an unfavorable CTC count (five or more CTCs per 7.5 mL of blood) at the study’s beginning.
Of the 10 men whose CTC count was redone at three months, five (50%) had at least an 80% reduction in CTCs, including two patients with markers of ASR inhibitor resistance. Four (40%) of these patients converted from an unfavorable to favorable CTC count (less than five CTCs/7.5 mL of blood), while three (30%) had no detectable CTCs.
A drop in CTC numbers was also associated with a prolonged response to treatment with no signs of disease progression, the researchers noted.
“We are very encouraged by the significant decreases in circulating tumor cells (CTCs) with the addition of onvansertib, given that these changes in CTCs are an accepted surrogate prognostic factor for efficacy and survival,” Erlander said.
The onvansertib triple combo was found to be safe and well-tolerated in both patient groups.
“These data show that adding onvansertib to [Zytiga] in metastatic castration-resistant prostate cancer patients with an early resistance to [Zytiga] validates pre-clinical studies and shows potential as a new therapeutic option,” said David Einstein, MD, the trial’s principal investigator, with the Genitourinary Cancer Program at Beth Israel Deaconess Medical Center in Boston.
Trovagene is now planning to explore the safety and effectiveness of a more continuous onvansertib dosing regimen in a third patient study arm (group C): 12 mg/m2 of onvansertib for 14 consecutive days in a three-week cycle.
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