Arvinas to Expand Development of Resistance-Busting Cancer Drug

Arvinas is moving forward with its plans to expand the development of its ARV-766 potential for the treatment of prostate cancer into earlier-line contexts. The biotechnology company connected the protein degrader to decreases in the PSA biomarker as well as partial responses in a phase 1/2 study, which provided early signs of its capacity to combat resistance mechanisms. 

Arvinas, located in Connecticut, developed ARV-766 to break down wild-type androgen receptors (AR) as well as therapeutically important LBD mutations. These mutants are associated with prostate cancer medication resistance. ARV-766 has the potential to improve health outcomes by degrading LBD mutants,through which it can combat the resistance to drugs faced by individuals who use AR inhibitors like Xtandi and Zytiga, manufactured by Astellas and Pfizer, respectively. 

Arvinas is currently putting that hypothesis to the test in a clinical investigation that recruited 34 patients for the phase 1 section of the study and, as of the most recent data cutoff, 13 patients for the phase 2 portion of the study. Participants in the trial must have had at least one line of therapy with a new hormonal medication, such as Xtandi or Zytiga.

Arvinas is particularly interested in the 13 individuals, spanning both portions of the research, who exhibit the AR LBD mutations targeted by ARV-766.  Arvinas revealed in their most recent update that 42% of individuals with AR LBD mutations showed a reduction in PSA of 50% or more, which is an important biomarker. Two of the four LBD-mutated individuals who could be evaluated experienced partial responses; however, one of these responses was not validated. 

Ron Peck, M.D., the Chief Medical Officer at Arvinas, stated, “The patients in this trial received extensive prior therapy for mCRPC and had limited alternative treatment options. These data increase our confidence in our ability to bring innovative treatment options to a patient population with significant unmet need.”

Arvinas investigated the types of AR LBD mutations that were present in the individuals whose PSA levels dropped by half. Three of the five individuals who had the L702H mutation saw a 50% reduction in PSA. The data point demonstrates that ARV-766 may be able to treat a mutation that is becoming increasingly significant. Arvinas released information indicating that the incidence of L702H mutations grew from 2% to 11% from 2016 to 2023.

ARV-766 is not only meant to target T878X and H875Y, but also less common mutations. PSA levels dropped by at least 50% in each of the three individuals who possessed the simultaneous presence of the H875, T878 and L702H mutations.

Arvinas interprets the proof of effectiveness as adequately encouraging to begin preparing for an investigation that will test ARV-766 among individuals who have not yet taken hormonal agents such as Xtandi and Zytiga. This is because the safety data has been coming in clean—no patients have had treatment-related adverse reactions or dose-limiting toxicities of grade 4 or 5. The candidate will be evaluated alongside Zytiga throughout the course of the study, which is scheduled to get underway in this year.

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