Phase 1/2 study of ARV-110, an androgen receptor (AR) PROTAC degrader, in metastatic castration-resistant prostate cancer (mCRPC).

Abstract

17 Background: ARV-110 is a first-in-class, oral PROteolysis TArgeting Chimera (PROTAC) protein degrader that selectively targets AR. Patients (pts) with mCRPC have limited treatment (tx) options due to decreasing AR dependence of tumors upon successive therapies. Previous phase 1 data indicated clinical activity for ARV-110 in heavily pretreated pts with mCRPC and suggested enhanced activity in pts with specific molecular profiles, eg, AR T878 and H875 mutations, leading to a phase 2 expansion (ARDENT) to further characterize ARV-110 in biomarker-defined pt subgroups. We report results of the ongoing phase 1/2 study. Methods: In phase 1, pts with mCRPC and disease progression after ≥2 prior therapies (enzalutamide and/or abiraterone required) received ARV-110 orally once or twice daily (QD or BID) in sequential cohorts (3 + 3 dose escalation design). Primary objectives were to assess ARV-110 safety and select the recommended phase 2 dose (RP2D). Phase 2 pts with mCRPC and 1–2 prior novel hormonal agents (NHAs) ± chemotherapy were assigned to 3 biomarker-defined subgroups: 1) AR T878 and/or H875 mutations, 2) AR L702H mutation or AR-V7 (variants not degraded by ARV-110 in nonclinical studies), and 3) wild-type AR or other AR alterations. A fourth subgroup enrolled pts based on clinical history of less prior tx: ≤1 therapy for mCRPC, 1 NHA, and no chemotherapy. Primary objective is to assess ARV-110 antitumor activity. Results: As of Aug 26, 2021, 173 pts were enrolled (67 in phase 1; 106 in phase 2). In phase 1, ARV-110 doses ranged from 35–700 mg QD or 210–420 mg BID; 420 mg QD was selected as the RP2D based on safety, pharmacokinetics, and efficacy. Across 140 biomarker-evaluable phase 1/2 pts with ≥1 month of prostate-specific antigen (PSA) follow-up, 26 with AR T878A/S and/or H875Y mutations had best PSA declines ≥50% (PSA50) and ≥30% (PSA30) of 46% and 58%, respectively, vs 10% and 23% in 114 pts without these mutations. Of 7 RECIST-evaluable pts with AR T878A/S and/or H875Y mutations, 6 had tumor shrinkage (2 with confirmed partial responses), and 4 remain on tx. Five of 19 (26%) PSA-evaluable pts in the fourth subgroup (only 1 prior NHA; no prior chemotherapy) achieved PSA50. Overall PSA50 and PSA30 response rates were 16% and 29%, respectively. There were no grade ≥4 tx-related adverse events (TRAEs) in 113 pts treated at the RP2D. The most common any grade TRAEs at the RP2D were nausea (42%; grade 3: 1%), fatigue (27%; grade 3: 1%), vomiting (23%; grade 3: 1%), decreased appetite (19%; grade 3: 0), diarrhea (15%; grade 3: 2%), and alopecia (11%). Conclusions: ARV-110, a novel AR protein degrader, demonstrates clinical activity in a post-NHA, heavily pretreated mCRPC pt population, with greatest PSA50 activity and RECIST responses in pts with AR T878 and/or H875 mutations, likely representing a particularly ARV-110–sensitive population. ARV-110 merits further investigation in pts with mCRPC. Clinical trial information: NCT0388861.

Treatment-mediated selection of lethal prostate cancer clones defined by copy number architectures

“…Similarly, CA34, CA79 and CA43 clusters had at least two different patientunique AR genomic architectures achieving similar levels of AR copy number gain, and in CA34, we identified different frequencies of distinct break-points suggesting multiple sub-clones that had independently acquired structural change associated with similar levels of AR amplification. This could justify classification of patients by AR gene class for therapeutic intervention, as for example is being attempted for patients harboring AR mutations (7, 8). Overall, whilst we identified greater intra-patient diversity than described previously, the uniformity across clusters of metastases dominated by a single clone contextualizes these previous results that might have primarily obtained samples from the same cluster (34).…”

“…Selection of clones harboring AR amplification or mutations (2,3), structural rearrangements, splice variants and a plethora of events consistent with treatmentmediated selection to maintain AR activity despite medical efforts to inhibit it result in an often rapidly lethal state that remains poorly understood (1). AR alterations in liquid or tissue biopsies associate with shorter responses to second-line next-generation hormonal treatments (4,5) and new drugs are in development to target aberrant AR (6)(7)(8). However, heterogeneity of AR alterations across metastases could create a challenge that complicates their utility as a biomarker or therapeutic target.…”

Highlights in Prostate Cancer from ASCO GU 2022

“…ARV-110 is being assessed in an ongoing phase II expansion study (ARDENT), which included patients with confirmed mCRPC who had previously received 1−2 NHAs with ≤1 chemotherapy regimen. 21 In the biomarker-evaluable group, 46% of patients with AR T878A/S and/or H875Y mutations (n=28) had best PSA declines ≥50%. Data further showed that PSA declines ≥50% were seen across all subgroups including wild-type and less pretreated patients.…”

“…Another novel agent presented at the 2022 ASCO Genitourinary Cancers Symposium was ARV-110 (bavdegalutamide), a proteolysis-targeting chimera (PROTAC) protein degrader that is directed against wild-type AR and clinically relevant mutations. 21 PROTAC molecules differ from classical inhibitors in their mode of action as they direct the target to the ubiquitin-proteasome system. 22 They are currently explored as a treatment option in prostate and breast cancer, as well as for non-oncology indications.…”

CRL4CRBN E3 Ligase Complex as a Therapeutic Target in Multiple Myeloma

“…To date, degronimids and other PROTACs are being studied extensively in a broad spectrum of hematologic malignancies and other cancers in preclinical studies [ 104 , 105 , 106 ]. In 2019, the first potential PROTAC-based drugs entered the first-in-human clinical trial in metastatic and castration-resistant prostate cancer (ARV-110; NCT03888612) and advanced breast cancer (ARV-471; NCT04072952), resulting in acceptable toxicity profile and the first evidence of the PROTACs’ clinical activity [ 107 , 108 ]. In August 2022, clinical trials with ARV-110 (ADRENT, NCT0388861) and ARV-471 (VERITAC, NCT04072952) are running phase 2 trials.…”