AR L702H

In this real-world clinicogenomics database-driven study we explored the development of AR alterations and their association with ARTA treatment outcomes. Our study showed that AR amplifications are associated with longer time to progression on first ARTA treatment. Further prospective studies are needed to optimize therapeutic strategies for patients with AR alterations.

Patients with AR LBD–mutated mCRPC had notably shorter rwOS than those whose tumors did not harbor AR LBD mutations, indicating an unmet need for this population. The prevalence of AR LBD mutations was higher in later lines of therapy, but repeat testing rates were low, suggesting that AR LBD mutations may go undetected.

Our study revealed dynamic shifts in genetic mutations in pts with mCRPC following ARSi, PARPi and taxanes. Additionally, we highlight the prognostic significant of ctDNA burden in mCRPC. These data can help inform personalized sequential tx strategies for pts with mCRPC.

There were no grade ≥4 treatment-related adverse events (TRAEs) with 420 mg bavdeg (n=158 across phase 1/2); any grade TRAEs reported in ≥20% of pts were nausea (54%; 1% grade 3), fatigue (35%; 1% grade 3), vomiting (31%; 1% grade 3), diarrhea (25%; 2% grade 3) and decreased appetite (23%; 0 grade 3). Conclusions Bavdeg had encouraging efficacy in post-NHA pts with mCRPC and AR 878/875 or any AR missense LBD mutation (excluding AR L702H alone) and was tolerable; these pt populations will be analyzed in a phase 3 study of bavdeg.

AR mutations have implications for clinical decision making and drug development in patients treated with abiraterone and/or enzalutamide. >1n (%).

Commonly found mutations include L702H, W742C, H875Y, F877L and T878A, while the F877L mutation can convert second-generation antagonists such as enzalutamide and apalutamide into agonists. However, pruxelutamide, another second-generation AR antagonist, has no agonist activity with the F877L and F877L/T878A mutants and instead maintains its inhibitory activity against them...Additional structural studies suggest that both the L702H and F877L mutations are important for conformational changes. This structural variability in the AR LBD could affect ligand binding as well as the resistance to antagonists.

ARV-766 significantly and dose-dependently inhibits tumor growth in murine LNCaP and VCaP xenograft models, including an enzalutamide-insensitive non-castrated VCaP model. These preclinical data supported the clinical development of ARV-766 for the treatment of men with metastatic CRPC. Selected pre-clinical data along with the chemical structure of ARV-766 will be presented.

Patients enrolled in the cohort expansion must have received 1–3 prior NHAs (eg, abiraterone or enzalutamide) and ≤2 prior chemotherapy regimens. Enrollment in the phase 2 expansion study is ongoing. Clinical trial information: NCT05067140.

In this large database, the overall detection rate of activating AR-LBD mutations in men with mCRPC undergoing ctDNA analysis was 21%, and increased with prior use of 2nd generation ARPi (abiraterone and enzalutamide). Men with AR-LBD mutations were more likely to harbor other alterations relevant to tumor progression. These findings inform on the ctDNA prevalence and impact of AR-LBD mutations in a real-world dataset of mCRPC.

Two early phase trials investigating CYP11A1 inhibitors - CYPIDES (ODM208, NCT03436485) and STESIDES (ODM209, NCT03878823) - recruited mCRPC patients with and without pre-specified AR LBD mutation...Overall, 212 (78%), 202 (74%), and 240 (88%) patients had received previous abiraterone, enzalutamide, and docetaxel respectively... AR LBD mutations were detected in ctDNA in 25% of men with advanced mCRPC treated with at least one ARSI. Their incidence was associated with a longer duration of treatment with enzalutamide and a longer time from CRPC and prostate cancer diagnosis. >

Hormonal therapies including androgen deprivation therapy and androgen receptor (AR) pathway inhibitors such as abiraterone and enzalutamide have been widely used to treat advanced prostate cancer. Currently, precision medicine utilizing genetic and genomic data to choose suitable treatment for the patient is becoming to play an increasingly important role in clinical practice for prostate cancer management. Therefore, monitoring the AR mutation status is a promising approach for providing precision medicine in prostate cancer, which would be implemented through the development of clinically available testing modalities for AR mutations using liquid biopsy.

P20-23 PDOs were derived from a transurethral prostate resection obtained from a patient with metastatic castration-resistant PCa, previously treated with goserelin, docetaxel, and enzalutamide. We have successfully generated two novel PDOX models, which highly resemble the original patients’ tumor and can be further cultured as organoids. These models are representative of relevant clinical and molecular subtypes of advanced PCa, providing further opportunities for translational studies.

Both testosterone and 11KT effectively contribute to AR activation, while selective sensitization positions 11KT as a more prominent activator of AR. Dexamethasone may be a suitable alternative to prednisolone and should be explored in patients bearing the AR.

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). 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.

AR mutations in post-ARTA group were seen at similar rates regardless of prior docetaxel exposure (14.3% vs 18.0%, p = 0.46) and following first abiraterone vs enzalutamide/apalutamide exposure (48.6% vs 48.3%, p = 1.0). AR mutations, unlike amplifications, were associated with shorter TTP on abiraterone. Genomic testing should be considered before second line ARTA.

In this analysis of CRPC patients who were responders and non-responders to 400 mg testosterone cypionate q 3-4 weeks (post-abiraterone and/or enzalutamide), only AR amplifications in ctDNA were predictive of response. In all measured patients, the degree of AR amplification in the ctDNA diminished after testosterone injections.

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). 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.

The goal was to characterize androgen receptor gene (AR) amplifications and mutations detected in circulating tumor DNA (ctDNA) from patients with prostate cancer in relation to non-AR gene alterations detected in the ctDNA landscape. The study included 892 patients with prostate cancer with AR alterations in ctDNA. AR alterations were significantly associated with other gene alterations detected in ctDNA. The common AR mutations found are linked to resistance to abiraterone, enzalutamide, or bicalutamide. Characterization of the circulating AR landscape and gene alterations provides potential additional insight into the somatic genetic heterogeneity of advanced prostate cancer.