AR-V7 positive

VTX-1 enables isolation of CTCs and plasma exosomes from a single blood draw and can be used for detecting AR-V7 and PSMA mRNA in both CTCs and cfRNA in patients with mCRPC and resistance to ARIs. This technology facilitates combining RNA measurements in CTCs and exosomal cfRNA for future studies to develop potentially clinically relevant cancer biomarker detection in blood.

Conclusions The benefit of continuing ENZ beyond progression with Doc vs Doc alone is greatest in patient with no evidence of plasma AR gain or AR-V7+ CTC. Plasma tumor DNA detection after 3 weeks Doc +/- ENZ identifies patients with shorter PFS.

Detection of AR-V7 in intact live CTC isolated by CytoGen's Smart BiopsyTM CTC isolator might overcome limitations of tissue biopsy. In this study, we developed a novel method of detection of AR-V7 in CTC with high sensitivity and specificity by in vitro assay and clinical test will be conducted for validation.

CTC positive/AR-V7 positive status significantly associated with a shorter PFS: 5.9 months (HR 8.56, 95% CI 2.40-30.43, p = 0.0087). -reduction (3 months) and BSI-reduction (on ENZ treatment) were significant response biomarkers, and a negative CTC status was a predictive factor for ENZ efficacy in patients with mCRPC.

These results indicate that AR-SVs are not restricted to CRPC, but also are expressed in primary PCa at higher rate than previously reported. Future investigation of the relative expression of NTD vs. LBD AR-SVs could guide the use of newly developed treatments targeting the NTD earlier in the treatment paradigm.

Owing to its flexibility, we also confirmed that the developed approach can be used to detection of other AR-Vs, including AR-v3 and ARv567es. We expect that the further in-depth analyses including larger samples and clinical outcomes can discover clinical applicability of AR-Vs.

The androgen deprivation therapy (ADT) alone and its combination with hormone therapy that block AR signaling (e.g., enzalutamide or abiraterone) are effective treatments for advanced prostate cancer. No animal was found dead or moribund and no test article-related changes in clinical signs,body weights, food consumption, ophthalmologic examinations, clinical pathology parameters, sperm analysis, urinalysis, organ weights, histopathology. In conclusion, HSK38008 is a promising oral AR-V7 degrader with better efficacy than enzalutamide and ARV-110 in AR and AR-V7 positive, and potential AR mutants mCRPC.

More investigations are still warranted to clarify the association between CRPC and AR-V7 testing. https://www.crd.york.ac.uk/prospero/, identifier CRD42022297014.

AR-V7 positivity predicted poor overall survival (OS). However, cabazitaxel-treated AR-V7 positive patients and those lacking AR-V7 positivity, who received cabazitaxel as standard of care, appeared to have similar OS. Therefore, despite the low response rate, cabazitaxel may still be an effective treatment in this poor prognosis, AR-V7 positive patient population.

Androgen receptor splice variant-7 (AR-V7) expression in circulating tumor cells (CTCs) in metastatic castration-resistant prostate cancer (mCRPC) is associated with abiraterone and enzalutamide resistance...This is the first prospective, open-label, Asian validation study of CBZ in Japanese patients with mCRPC after docetaxel (n = 48; four CBZ cycles; 2017-2020, Juntendo University Hospitals)...AR-V7 was not associated with CBZ resistance in CTCs. Reductions in BSI and PSA in early stages of CBZ treatment may predict OS.

Au-AR pep-PROTAC results in suppression of AR levels and induces tumor regression in both enzalutamide sensitive and resistant prostate cancer animal models. Further optimization of the Au-AR pep-PROTAC can ultimately lead to a new therapy for AR-V7-positive CRPC.

Additionally, AR-V7 level does not correlate with clinical response. Thus, the value of AR-V7 as a clinical biomarker must be considered skeptically.

PKCβ inhibition reduces total AR gene expression, thus reducing AR-V7 protein levels and sensitizing prostate cancer cells to current anti-androgen therapies. We demonstrate that this combination may be a viable therapeutic strategy for AR-V7-positive prostate cancer.

The response of patients with metastatic castration-resistant prostate cancer (mCRPC) to androgen receptor (AR)-directed hormonal treatments (i.e., enzalutamide and abiraterone) is mediated by the expression of a molecular variant of the androgen receptor called androgen receptor variant 7 (AR-V7). Together, the presence and amount of AR-V7 in serum offer predictive and prognostic value to inform selection between two classes of systemic treatments (i.e., hormones or taxanes). Triaging patients that are AR-V7-positive to other systemic treatments (e.g., taxane-based chemotherapy) can improve progression-free survival and overall survival.

At this early stage, independently to ADT administration, AR-V7 positivity is associated to risk classification and it can predict biochemical and radiological progression after surgery. Validation of our findings in a larger cohort will be relevant for further studies to define a subset of PC cases submitted to RP in which intensification of adjuvant treatments could be indicated.

A subgroup analysis of patients treated with androgen receptor signaling inhibitors (ARSi such as abiraterone and enzalutamide) showed a significant association of AR-V7 positivity with poorer OS, PFS, and PSA-PFS. More studies on chemotherapy-treated patients are warranted. PROSPERO, CRD42021239353.

Baseline CTC biomarkers may be prognosticators for cabazitaxel-treated mCRPC patients. Cabazitaxel at lower (20 mg/sqm) dose was associated with poorer outcomes in AR-V7 positive patients compared to AR-V7 negative patients in a post hoc subgroup analysis.

Androgen receptor variant 7 (AR-V7) detection provides important information for the clinical management of abiraterone in metastatic castration-resistant prostate cancer (mCRPC)...The present study showed that the detection of urine-derived exosomal AR-V7 provides a sensitive and feasible clinical workflow. The predicting role of urine-derived exosomal AR-V7 in mCRPC patients should be further verified using studies with greater sample sizes.

P2, N=32, Completed, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | N=15 --> 32

Using ultra-deep targeted RNA-Seq, we provide among the first comprehensive descriptions of the ARV landscape in primary prostate cancer. Moreover, we show that detectable AR-V7 in prostatectomy specimens was associated with inferior outcomes following salvage RT+ADT, suggesting for the first time that AR-V7 may modulate outcomes for localized as well as metastatic disease. Ongoing work includes comparison with Decipher score and validation in independent cohorts.

Interestingly, all patients with AR-V7-positive CTCs also carried TP53 point mutations. Altogether, analysis of cfDNA and CTCs can provide complementary information that may support temporal and targeted treatment decisions and may elucidate the optimal choice within the variety of therapy options for advanced PCa patients.

Using a custom ultra-deep targeted RNA-Seq approach, we provide among the first comprehensive descriptions of the AR splice variant landscape in primary prostate cancer. Moreover, we show that detectable AR-V7 expression in prostatectomy specimens was associated with inferior outcomes following subsequent salvage RT+ADT, suggesting for the first time that AR-V7 may modulate outcomes for localized as well as metastatic disease.

P2, N=15, Completed, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Active, not recruiting --> Completed | Trial completion date: Sep 2022 --> Oct 2021 | Trial primary completion date: Sep 2021 --> Dec 2020

We conclude that positive AR IHC and apocrine morphology are pathologic features that may indicate testing for AR-V7 is warranted in both primary and metastatic BC in the appropriate clinical context. The study findings further encourage the assessment of AR-V7 as a predictive biomarker for AR antagonist benefit in ongoing clinical BC trials.

Here we show that nobiletin, a polymethoxylated flavonoid derived from the peel of Citrus fruits, exerts a potent anticancer activity via inducing G0/G1 phase arrest and enhancing the sensitivity of cells to enzalutamide in AR-V7 positive PC cells...This effect relies on its selective inhibition of the interactions between AR-V7 and two deubiquitinases USP14 and USP22. These findings not only enrich our understanding on the mechanism of AR-V7 degradation, but also provide an efficient and druggable target for overcoming CRPC through interfering the stability of AR-V7 mediated by the interaction between AR-V7 and deubiquitinase.

In the abiraterone (AA)/enzalutamide (E) treatment group, AR-V7 positive patients had worse PSA-PFS (hazard ratio [HR] = 3.40; 95% confidence interval [95%CI] 2.56-4.51; P < 0.05) and worse r-PFS (HR = 2.69; 95%CI 1.70-4.24; P < 0.05) and OS (HR = 3.02; 95%CI 1.73-5.30; P < 0.05). In addition, compared to AA/E, taxane treatment is a protective factor for OS in AR-V7-positive patients. AR-V7 may thus be an effective biomarker for treatment prognosis in patients with mCRPC.

AR-V7 positivity is associated with a higher Gleason score, bone or any site metastasis, pain and worse ECOG performance scores in CRPC. However, it is not correlated with tumor stage or lymph node metastasis. More studies are needed to confirm these findings.

The results of this meta-analysis, the first in literature to be specifically focused on this topic so far, suggest that AR-V7 positivity may be associated with any site metastases and bone metastases; conversely, no association has been highlighted between AR-V7 expression and lymph node or visceral metastases. Although this meta-analysis should be interpreted with caution due to some limitations, our findings confirm that AR-V7 status could designate a unique and peculiar subtype of PC. Further studies aimed at improving and standardizing AR-V7 detection in clinical trials on CRPC patients are warranted.

The presence of AR-V7 in prostate cancer tissue is independently associated with an unfavorable prognosis for PFS, OS and CSS in patients who received AHT.

CTC genomic findings were independently confirmed in a separate cohort of mCRPC men who progressed despite prior treatment with abiraterone/enzalutamide (NCT02204943). Implications: We identified common and reproducible genomic alterations in CTCs from AR-V7 negative mCRPC men associated with poor outcomes during enzalutamide/abiraterone treatment, including CNAs in genes linked to lineage plasticity and epigenetic signaling, DNA repair, AR, TP53/RB1, PTEN, and WNT pathways.

Nivolumab plus ipilimumab demonstrated only modest activity in patients with AR-V7-expressing prostate cancer, and was not sufficient to justify further exploration in unselected patients. Stratification by baseline alkaline phosphatase and cytokines (IL-6, -7, and -17) may be prognostic for outcomes to immunotherapy.

AR-V7 expression in primary cancer tissue is correlated with poor prognosis for mHSPC patients receiving ADT.

This study aimed to evaluate the prognostic role of AR-V7 in terms of prostate-specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS) in CRPC patients treated with novel hormonal therapy (NHT) (Abiraterone and Enzalutamide) or taxane-based chemotherapy (Docetaxel and Cabazitaxel). NHT treatment increased AR-V7 positive proportion whereas chemotherapy decreased it. Moreover, AR-V7 positivity correlated with lower PSA response, poorer PFS, and OS in CRPC treated with NHT, and shorter OS in patients receiving chemotherapy.

Furthermore, the ability of AR-V7 status to predict treatment outcomes varies from different detection methods. The detection of AR-V7 before treatment is important for the selection of treatment modalities for mCRPC patients.

Synergistic effects of DBF were observed in combination with PARP-inhibitor olaparib most likely due to the induction of ROS production by the marine alkaloid. In addition, DBF intensified effects of platinum-based drugs cisplatin and carboplatin, and taxane derivatives docetaxel and cabazitaxel. Finally, DBF inhibited AR-signaling and resensitized AR-V7-positive 22Rv1 prostate cancer cells to enzalutamide, presumably due to AR-V7 down-regulation. These findings propose DBF to be a promising novel drug candidate for the treatment of human PCa regardless of resistance to standard therapy.

Initial treatment responses to hormonal therapies are transient and further management options lie between (1) further hormone therapy or (2) a non-hormonal approach involving additional chemotherapy or molecular radiotherapy (radium-223)...Findings to be disseminated through patient and professional organisations that have expressed their support, media outlets and peer-reviewed journal publication. ISRCTN10246848; pre-results.

Detection of AR-V7 in CTCs by two different blood-based assays is independently associated with shorter PFS and OS with abiraterone or enzalutamide, but such men with AR-V7-positive disease still experience clinical benefits from taxane chemotherapy.

Although CTCs that expressed prostate cancer related genes were eliminated by the given therapy, PSMA+ CTCs significantly identified pts at high risk for relapse. Furthermore, AR inhibition, often discussed for this BC subgroup, might not be successful in the primary setting of the disease since we identified AR-FL+ CTCs together with AR-V7+ CTCs, associated with therapeutic failure.

Legal entity responsible for the study: Hao Zeng. Funding: Has not received any funding.