Trial to evaluate TKI and abiraterone treatment combination for prostate cancer

SAP Partner | <b>Cleveland Clinic</b>

“If outcomes are improved for patients who take this combination — or in patients whose cancer is still progressing after being treated with hormone-based chemotherapy alone — this could be a big step forward in caring for these patients," says Moshe Ornstein, MD, MA.

MAVERICK, a phase 2, open-label clinical trial (NCT05361915) to evaluate the efficacy of a new prostate cancer treatment combination of abivertinib and abiraterone acetate (Zytiga), is now underway across 9 sites in the US.1

The therapy for the trial was developed on the basis of research done at Cleveland Clinic2 showing how the gene HSD3B1 is associated with treatment-resistant prostate cancer. The paper was published in the Journal of Clinical Investigation.

Previous research has shown that tumors can produce their own tumor-feeding androgens, dependent on the configuration of the gene HSD3B1, which controls the first step of the androgen creation pathway. In MAVERICK, patients who have the genetic configuration that enables adrenal androgen production will be given abivertinib, a tyrosine kinase inhibitor (TKI), in combination with abiraterone acetate.

MAVERICK includes 100 participants with metastatic castration-resistant prostate cancer as identified by imaging. Patient cohorts include an abiraterone-naïve group and an abiraterone-progressing group. The primary end point is 6-month radiographic progression-free survival. Secondary outcomes include overall response rate, duration of response, prostate-specific antigen progression, safety and tolerability, time to occurrence of first skeletal event, time to first subsequent anti-cancer therapy, 6-month radiographic progression-free survival, and overall survival.3

“If outcomes are improved for patients who take this combination — or in patients whose cancer is still progressing after being treated with hormone-based chemotherapy alone — this could be a big step forward in caring for these patients. Likewise, the lab-based translational data that will be developed from this trial will be critical to further understanding the mechanisms of resistance to abiraterone acetate and the role of abivertinib in prostate cancer,” said Moshe Ornstein, MD, MA, a genitourinary medical oncologist and principal investigator at the Cleveland Clinic site.

Previous findings inform trial

The treatment combination was based on findings from research that investigated the process through which prostate cancer synthesizes androgens. Results showed that a tyrosine kinase called BMX interacted with the enzyme produced by HSD2B1. This interaction was a key part of the phosphorylation process, which activates proteins or enzymes, allowing for androgens to be made.

“Patients who have the genetic configuration that enables adrenal androgen production will be given the TKI in combination with abiraterone acetate,” according to a news release about the research.1

Further research with preclinical models found that knocking out BMX or halting phosphorylation stopped androgen production and cancer growth. These findings identified BMX as the therapeutic target, resulting in the therapy combination in MAVERICK. The treatment is designed to block BMX, the protein that allows the body to continue to produce tumor-feeding androgens even after castration.

“BMX directly interacts with 3βHSD1 [3β-hydroxysteroid dehydrogenase-1] and is necessary for enzyme phosphorylation and androgen biosynthesis. In vivo blockade of 3βHSD1 Y344 phosphorylation inhibits [castration-resistant prostate cancer],” the authors wrote.

References

1. National prostate cancer trial testing therapy based on Cleveland Clinic molecular discovery. News release. Cleveland Clinic. January 17, 2023. Accessed January 19, 2023. https://www.lerner.ccf.org/news/details/?National+prostate+cancer+trial+testing+therapy+based+on+Cleveland+Clinic+molecular+discovery&41360c371947bc464431e56c938806dd92913173&9b9c0801df07368664411f8bb47f21f0e1b06726

2.Li X, Berk M, Goins C, et al. BMX controls 3βHSD1 and sex steroid biosynthesis in cancer. The Journal of Clinical Investigation. 2023;133(2):e163498. doi:10.1172/JCI163498.

3. Study to Assess Abivertinib in Combination With Abiraterone in Metastatic Castration Resistant Prostate Cancer. ClinicalTrials.gov. Updated May 5, 2022. Accessed January 19, 2023. https://clinicaltrials.gov/ct2/show/NCT05361915