PROTAC Shrinks Mutated Prostate Tumors

The most clinically advanced proteolysis-targeting chimera (PROTAC), a small-molecule drug that destroys proteins rather than inhibiting its target, looks to be particularly active against certain molecularly defined subtypes of advanced prostate cancer.

According to data presented at the 2022 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium in February, treatment with the androgen receptor (AR) protein-degrader bavdegalutamide (ARV-110; Arvinas) dramatically lowered PSA levels in nearly half of patients with two mutant forms of AR—a somewhat unexpected result given that the drug was not designed to be selective for these alterations.

Trial participants had previously received abiraterone (Zytiga; Janssen) or another hormonal therapy, after which few effective drugs are available. “That's why this is exciting,” says trial investigator Jacqueline Vuky, MD, of Oregon Health & Science University's Knight Cancer Institute in Portland. “It's a proof of concept that [AR degraders] can work in heavily pretreated patients.”

Based on phase I/II study findings—and bavdegalutamide's manageable tolerability profile—Arvinas plans to initiate a registration-enabling trial of the oral, once-daily PROTAC for patients with metastatic castration-resistant prostate cancer who harbor T878X or H875Y mutations.

Although prostate cancer specialists have not traditionally based treatment recommendations on the presence of AR mutations, that could change with bavdegalutamide, says Xin Gao, MD, of Massachusetts General Hospital in Boston, who presented the trial data at the ASCO meeting. “This is certainly one of the first studies to show that there can be a benefit with a biomarker-selected approach to targeting the androgen receptor,” he says.

Bavdegalutamide harnesses the cell's waste disposal system to destroy the AR, a protein vital to the survival of prostate tumors. A bifunctional compound, the drug binds to AR with one arm and to an E3 ubiquitin ligase with the other. This brings the target protein into close contact with the ligase enzyme, which in turn promotes the selective degradation of AR via the cell's proteasomal machinery.

Patients with T878X or H875Y mutations seem to be especially sensitive to bavdegalutamide treatment—the assumption being that these two mutations “may be a signature for tumors that are still AR-dependent,” says Arvinas's President and CEO John Houston, PhD.

Among 28 trial participants with either of these two genetic alterations, 13 had PSA reductions greater than 50%; another three had PSA levels drop between 30% and 50%. Imaging data were available for seven patients; all but one experienced tumor shrinkage, and two had confirmed partial responses.

Response rates, whether judged by PSA or radiographic assessments, were lower in other subgroups, including among patients whose tumors contained wild-type forms of AR—a result that Ramesh Narayanan, PhD, MBA, of the University of Tennessee Health Science Center in Memphis, describes as “really surprising.”

Preclinical studies did not foreshadow this outcome, and unlike other PROTACs that Arvinas's founders created to induce mutant-selective degradation, bavdegalutamide was not designed in this way. As such, Narayanan points out: “No one expected this curve ball.”

Whether other AR degraders show similar mutational biases remains to be seen. In addition to bavdegalutamide, two other AR-targeted PROTACs—AR-LDD (Bristol Myers Squibb) and ARV-766 (Arvinas)—are in early human testing for prostate cancer, with more AR degraders that deploy different technologies, including Narayanan's ONCT-534 (Oncternal Therapeutics), in preclinical development.

Arvinas is advancing ARV-766 in the hope that it will prove more effective than bavdegalutamide against a larger number of mutated AR forms. According to a recent Arvinas corporate update, ARV-766 works better than bavdegalutamide at blunting the growth of cancer cells with L702H alterations, the most frequent mutation associated with resistance to abiraterone and other AR-targeted therapies.

The company is also exploring opportunities to develop bavdegalutamide more broadly, including as a treatment for localized disease and for use with hormonal therapies. –Elie Dolgin