PURPOSE This phase I/II study (which, to our knowledge, is the first such study in humans) evaluated the safety and efficacy of bavdegalutamide (ARV-110), a proteolysis-targeting chimera (PROTAC) androgen receptor (AR) degrader, in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS Eligible patients were adult (18 years and older) males with mCRPC previously treated with an AR pathway inhibitor (ARPI). In phase I, patients received escalating doses of oral bavdegalutamide to determine the recommended phase II dose (RP2D). In phase II, patients received bavdegalutamide at the RP2D in 28-day cycles. Antitumor activity, including prostate-specific antigen (PSA) response rate (≥50% [PSA 50 ] or ≥30% [PSA 30 ] decline from baseline) and radiographic progression-free survival (rPFS), was assessed in three AR molecular profile–defined subgroups and a less-pretreated (one prior ARPI without prior chemotherapy) subgroup. RESULTS In phase I (N = 95), bavdegalutamide 420 mg once daily was the RP2D. In phase II, PSA 50 and PSA 30 rates, respectively, were 60.0% and 70.0% among patients with tumors harboring AR T878 and/or H875 mutations (n = 20), 4.3% and 6.5% among those with wild-type AR or other AR alterations (n = 46), and 3.1% and 6.3% among those with AR L702H mutations or AR splice variant 7 expression (n = 32); the median rPFS was 11.1, 4.2, and 5.1 months in the respective subgroups. Among less-pretreated patients (n = 42), the PSA 50 rate was 21.4%, the PSA 30 rate was 23.8%, and the median rPFS was 11.1 months. Among phase II patients (n = 144), 72.3% experienced grade 1/2 treatment-related adverse events (TRAEs) and 17.4% experienced grade 3 TRAEs; no grade ≥4 TRAEs occurred. TRAEs led to dose reduction and discontinuation in 11.8% and 11.1% of patients, respectively. CONCLUSION Bavdegalutamide had a manageable safety profile and showed promising clinical activity in patients with mCRPC, particularly those with tumors harboring AR T878/H875 mutations.
Immunomodulatory drugs (IMiDs) have fundamentally reshaped multiple myeloma therapy, extending survival and establishing durable backbones across induction, relapse, and maintenance. Cereblon's identification as a druggable E3 ligase substrate receptor created the mechanistic path to next-generation modulators, whereas widespread frontline lenalidomide exposure created the clinical need for scalable oral agents active in IMiD-refractory, triple-class-exposed disease. In this review, we link the clinical evolution of the IMiD class to its mechanistic foundation. We trace the path from thalidomide's serendipitous repurposing to lenalidomide's establishment of the Rd backbone and maintenance paradigm and to pomalidomide's ability to retain efficacy after lenalidomide failure. We integrate structural and biochemical insights showing how medicinal chemistry reshaped cereblon engagement and selective neosubstrate degradation, producing tumor-intrinsic and immune-mediated effects. We then focus on next-generation cereblon E3 ligase modulators (CELMoDs), including iberdomide and mezigdomide, designed to deepen cereblon modulation and overcome resistance. We summarize early clinical experience and ongoing randomized programs, discuss rational combinations with monoclonal antibodies, bispecific T-cell engagers, and chimeric antigen receptor T-cell therapies, and propose a pragmatic framework for positioning CELMoDs in an immunotherapy-rich treatment era.
Women with stage II to III human epidermal growth factor receptor 2 (HER2)-positive breast cancer commonly receive neoadjuvant therapy. Recent trials have substantially expanded treatment options for these individuals. Randomized trial data indicate that carboplatin can be safely omitted from neoadjuvant therapy for most patients with stage II HER2-positive early-stage breast cancer, with comparable pathological complete response rates and reduced toxicity. Here, we review evidence supporting de-escalation in the neoadjuvant setting from docetaxel or paclitaxel, carboplatin, trastuzumab, pertuzumab to docetaxel or paclitaxel, trastuzumab, pertuzumab with weekly paclitaxel and examine biomarker-guided strategies for further de-escalation, including chemotherapy-free approaches. DESTINY-Breast11 and DESTINY-Breast05 have established the use of neoadjuvant and postneoadjuvant fam-trastuzumab deruxtecan-nxki, respectively, as new options for high-risk disease, with both indications recently granted approval from the U S Food and Drug Administration. We propose a framework for risk-adapted treatment optimization, highlighting the potential of circulating tumor DNA monitoring and functional imaging as response-adapted strategies and identifying them as priorities for future investigation. Together, these advances support a more precise, individualized approach to caring for patients with early-stage HER2-positive breast cancer.
