Add-on Onvansertib Overcomes Resistance to Zytiga in mCRPC, Early Data Show

Add-on Onvansertib Overcomes Resistance to Zytiga in mCRPC, Early Data Show
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Adding the investigational oral therapy onvansertib to a regimen of Zytiga (abiraterone acetate) and prednisone overcomes resistance to Zytiga in men with metastatic castration-resistant prostate cancer (mCRPC), according to early results of a Phase 2 clinical trial.

The study (NCT03414034) is testing whether a once-daily dose of Trovagene’s onvansertib is beneficial in adults with mCRPC who experienced cancer progression on Janssen’s Zytiga and prednisone. Patient enrollment is ongoing, for a planned total of 64 participants. (More information about contacts and the three U.S. locations is available here.)

Patients with mCRPC typically develop resistance to standard-of-care medications such as Zytiga — an androgen-receptor signaling (ARS) inhibitor — within nine to 15 months of beginning treatment.

In some cases, resistance develops when cells produce a variant of the androgen receptor, called AR-V7, that lacks the domain targeted by current androgen receptor inhibitors. In other cases, cancer cells overproduce the androgen receptor.

In the ongoing Phase 2 trial, patients are receiving a blood test to determine if they have the AR-V7 variant. So far, the four patients who tested positive for AR-V7 showed an immediate decrease in serum PSA levels, indicating a positive response to treatment. Two of these patients also achieved disease control, the study’s primary efficacy goal.

Interestingly, one of the AR-V7-positive patients had experienced a greater than fivefold increase in his PSA level within two months while on Zytiga.

“We have discovered that adding onvansertib to daily ARS inhibitor therapy changes the trajectory of resistance in patients harboring AR-V7,” Mark Erlander, PhD, Trovagene’s chief scientific officer, said in a press release.

Early data of the first three patients on two-week dosing cycles — instead of the three-week cycles of the first group — and with 50% greater exposure to onvansertib, showed stabilized or reduced PSA levels. No unexpected, off-target toxicities have been reported. This suggests that a shorter dosing schedule may improve treatment response, according to Trovagene.

The results were presented in August at the 20thAsia-Pacific Prostate Cancer Conference in Melbourne, Australia. Earlier findings, presented last April at the American Association for Cancer Research Annual Meeting, had shown PSA reductions in two of six patients and disease stabilization in one.

Onvansertib works by inhibiting the PLK1 enzyme, which is over-expressed in multiple cancers. It has a 24-hour half-life (the time needed for the body to reduce a compound’s concentration by half) and has only mild-to-moderate side effects reported, the company says.

“The inhibition of the PLK1 enzyme by onvansertib appears to enhance the efficacy of Zytiga by repressing the ARS pathway, which is consistent with preclinical data,” Erlander said.

Its selective targeting of PLK1, along with the favorable safety and tolerability profile, and the possibility of using a more beneficial dose/scheduling regimen, may be significant for patients with acute myeloid leukemia (AML) using a former non-selective PLK inhibitor in prior studies, the company says.

Preclinical studies have suggested that using onvansertib boosts the effectiveness of several chemotherapies and targeted therapies for lymphoma, leukemia, and solid tumors. Besides mCRPC and AML, Trovagene believes such combinations may benefit difficult-to-treat cancers such as non-Hodgkin’s lymphoma, colorectal cancer, and triple-negative breast cancer.

Ongoing Phase 1b/2 trials of onvansertib include a study (NCT03829410) on a combination with Avastin (bevacizumab, by Genentech) and the chemotherapy regimen FOLFIRI in metastatic colorectal cancer, and a trial (NCT03303339) of a combination with low-dose cytarabine or Dacogen (decitabine) in patients with relapsed or refractory AML. Both these studies are still enrolling.

Onvansertib has been granted orphan drug designation in the U.S. and the European Union for the treatment of AML patients. The potential therapy was licensed from Italy-based Nerviano Medical Sciences.

José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
Total Posts: 287
Inês holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Ciências e Tecnologias and Instituto Gulbenkian de Ciência. Inês currently works as a Managing Science Editor, striving to deliver the latest scientific advances to patient communities in a clear and accurate manner.
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José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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