ARV-110, an investigational oral therapy that degrades the androgen receptor, has a favorable safety profile and showed promising anti-tumor activity in heavily pretreated men with metastatic castration-resistant prostate cancer (mCRPC), updated Phase 1 data suggests.
The approach worked particularly well in a population with specific mutations in the androgen receptor, the researchers said. But it also was found to have promising efficacy in a group of patients without genetic alterations in the receptor.
Arvinas, its maker, is therefore advancing the development of ARV-110 for these two indications.
“It is exciting to see that ARV-110 continues to be active and well tolerated in what we believe is the most heavily pretreated patient population that has ever been studied with an [androgen receptor]-directed therapy,” Ron Peck, PhD, chief medical officer at Arvinas, said in a press release.
While medicines that target the androgen receptor — such as Zytiga and Xtandi — are a mainstay for the treatment of advanced prostate cancer, tumors often develop a resistance to such treatments and continue to grow.
One of the mechanisms linked with resistance is the production of a variant of the androgen receptor, called AR-V7, that is able to escape the action of androgen receptor inhibitors. In other cases, cancer cells overproduce the androgen receptor.
ARV-110 is a potential oral candidate that targets the androgen receptor — a nuclear receptor that regulates the development and growth of the prostate — for degradation. The medicine, developed using Arvinas’ PROTAC protein degradation platform, delivers small tags to the androgen receptor, triggering its destruction by the cells’ natural protein degrading system.
An ongoing Phase 1 trial (NCT03888612) is investigating the safety and tolerability of daily escalating doses of ARV-110 in mCRPC patients whose disease progressed after being treated with a minimum of two standard-of-care therapies (including Zytiga or Xtandi).
Patients enrolled in the dose-escalating study had received a median of five prior lines of therapy. More than three-quarters (76%) had been treated with chemotherapy, and 82% were previously treated with both Zytiga and Xtandi.
Genetic profiling of the tumors revealed a high genetic variability, with 84% of patients harboring mutations in genes other than those coding for the androgen receptor. These mutations normally reduce the tumor’s dependence on androgen receptor signaling, suggesting that such patients would not respond to ARV-110.
However, results from the 15 patients with a normal androgen receptor demonstrated that two patients (13%) experienced a more than 50% drop in their prostate-specific antigen (PSA) levels. PSA is a marker of prostate cancer.
When considering all 28 participants with exposures above the minimum threshold predicted for efficacy, four (14%) had PSA reductions above 50%.
In both groups, these PSA responses were higher than what would be expected for such pretreated patients. Standard-of-care treatments targeted at the androgen receptor generally provide similar PSA responses in 8-15% of less pretreated patients.
The genetic profiling also revealed a group of patients with a particularly strong response to ARV-110: 40% of patients carrying T878 or H875 mutations in the androgen receptor gene showed reductions above 50% in PSA levels. One such patient had a partial response, with an 80% reduction in tumor size.
According to Arvinas, these interim results support the development of ARV-110 for two key mCRPC indications. One is for heavily pretreated patients with the T878 or H875 mutations, and the other is for a less heavily treated population with a normal androgen receptor.
An extension part of the trial, called ARDENT, is now being conducted by Arvinas and will continue to assess the safety and efficacy of ARV-110 at a daily dose of 420 mg in those two indications. A total of 100 patients are expected to enroll, with recruitment ongoing at multiple sites in the U.S.
The trial will include two subgroups of patients, including one that is expected to support the treatment’s accelerated approval for heavily treated patients with T878 or H875 mutations.
The second group will involve less pretreated patients who received no prior chemotherapy and only one second-generation androgen receptor inhibitor, such as Zytiga or Xtandi. This group is expected to have less genetically diverse tumors, more dependent on the androgen receptor, and therefore more likely to respond to ARV-110.
“Our recently initiated ARDENT Phase 2 cohort expansion is specifically designed to investigate the potential of a precision medicine approach in molecularly defined, late-line patients with few available treatment options, while also fully characterizing the safety and activity of ARV-110 in earlier line patients irrespective of molecular profile, setting ARV-110 on a potential two-pronged registrational path,” Peck said.
Interim data from the ARDENT Phase 2 trial is expected by December, according to Arvinas. The company also is planning to launch a Phase 1b combination trial testing ARV-100 together with a standard-of-care prostate cancer therapy.