Androgen Receptor Signaling Inhibitors Research Articles

Androgen Receptor Signaling Inhibitors and Cardiovascular Events in Advanced Prostate Cancer: A Systematic Review and Meta-Analysis

Androgen Receptor Signaling Inhibitors and Cardiovascular Events in Advanced Prostate Cancer: A Systematic Review and Meta-Analysis

Epigenetic regulation of neuroendocrine prostate cancer

Neuroendocrine prostate cancer (PCa), an aggressive subtype of PCa, can arise de novo or from pre-existing castration-resistant PCa, especially after treatment with new-generation androgen receptor signaling inhibitors (ARSIs); thus, it is a major cause of resistance to ARSIs. Lineage plasticity drives the transformation of adenocarcinoma cells from the androgen receptor-driven luminal cell program to an alternative neuroendocrine transdifferentiation phenotype, which has been recognized as a key mechanism in neuroendocrine PCa development. Although genetic alterations can promote lineage plasticity, this process is primarily orchestrated through epigenetic regulation, including DNA methylation, chromatin modifications, and long noncoding RNA. Notably, epigenetic regulators are amenable therapeutic targets, offering the potential not only to address lineage plasticity but, more crucially, also to overcome resistance to ARSIs in PCa. In this review, we aim to elucidate the pivotal epigenetic factors driving the plasticity of the PCa lineage, providing a foundation for the development of treatment strategies to effectively combat resistance to ARSIs driven by lineage plasticity.

Androgen Receptor Mediates Dopamine Agonist Resistance by Regulating Intracellular Reactive Oxygen Species in Prolactin-Secreting Pituitary Adenoma.

Aims: Dopamine agonists (DAs) are the first-line treatment for patients with prolactin-secreting pituitary adenoma (PRL adenoma). However, a subset of individuals exhibits poor responses, known as DA resistance. Previous studies have reported that DA resistance is more prevalent in male patients. This study aims to investigate the relationship between androgen receptor (AR) expression and DA resistance, as well as to explore underlying mechanisms of AR-mediated DA resistance. Results: Our results demonstrated that patients with higher AR expression exhibit greater resistance to DA in our cohort of DA-resistant PRL adenoma. Furthermore, AR was found to be involved in cell proliferation, PRL secretion, and resistance to bromocriptine (BRC) both in vitro and invivo. Mechanistically, we demonstrated that intracellular reactive oxygen species (ROS) function as upstream mediators of apoptosis and ferroptosis following BRC treatment. As a ligand-dependent transcription factor, AR could translocate to the nucleus and transcriptionally promote NFE2-like bZIP transcription factor 2 (NRF2) expression, which regulates intracellular ROS levels, thereby enhancing cell viability and conferring DA resistance to pituitary adenoma (PA) cells. Finally, AR targeting agents were used to inhibit AR signaling, downregulate NRF2 transcription, and sensitize PA cells to BRC treatment. Conclusion and Innovation: We demonstrated that AR plays a crucial role in mediating DA resistance in PRL adenoma. Mechanistically, AR promotes cell proliferation and PRL secretion and confers drug resistance by transcriptionally regulating NRF2 expression to maintain redox homeostasis in PA cells. Finally, combining AR targeting agents with BRC shows promise as a therapeutic strategy for treating PRL adenomas. Antioxid. Redox Signal. 00, 000-000.

Androgen Receptor Signaling Inhibitor Withdrawal Syndrome After Castration-resistant Prostate Cancer.

Androgen-deprivation therapy is an extremely effective treatment for progressive prostate cancer. Previously, the first-line treatment for progressive prostate cancer was combined androgen blockade (CAB). If the disease progressed to castration-resistant prostate cancer, the administration of androgen receptor signaling inhibitors (ARSIs) was recommended. When elevated serum prostate-specific antigen (PSA) levels are seen during CAB treatment, it is important to suspect antiandrogen withdrawal syndrome (AWS), discontinue CAB, and monitor the changes in the serum PSA levels. If a reduction in the patient's PSA levels is subsequently observed, antiandrogens should be discontinued and the patient should be followed, but if their PSA level rises they should be transitioned to ARSI treatment. Recently, there have been reports of withdrawal syndrome (WS) after ARSI treatment. With the increased use of ARSIs, such as abiraterone acetate, enzalutamide, apalutamide, and dalorutamide, it is necessary to consider ARSI WS when a patient's serum PSA level increases during ARSI treatment. Unnecessary treatment can be avoided if the confirmation of ARSI WS is prioritized. Conversely, if it is not confirmed there is a risk that second-line treatment will be delayed. This is a review of recent studies of ARSI WS. It also discusses future prospects in this field.

PSA Kinetics Affect Prognosis in Patients With Castration-resistant Prostate Cancer Treated With Enzalutamide.

There is little evidence regarding the predictive value of prostate-specific antigen (PSA) kinetics in patients with castration-resistant prostate cancer treated with an androgen receptor signaling inhibitor. This study investigated the correlation between PSA kinetics and prognosis in patients with castration-resistant prostate cancer treated with enzalutamide. We analyzed data from 103 patients who received enzalutamide as primary treatment for castration-resistant prostate cancer at our hospital, focusing on the associations between overall survival and PSA kinetics variables, such as maximal PSA response, PSA nadir, and time to PSA nadir. The median PSA level at the initiation of enzalutamide was 18.1 ng/ml (interquartile range=7.9-61.2 ng/ml). The median maximal PSA response rate was 88% (interquartile range 55-98), and the median PSA nadir was 1.84 (interquartile range (IQR)=0.38-14.7) ng/ml. The median time to PSA nadir was 19 (IQR=6-28.5) weeks. Maximal PSA response rate <90% [hazard ratio (HR)=2.28, 95% confidence interval (CI)=1.03-5.03, p=0.0413], PSA nadir >2 ng/ml (HR=2.30, 95%CI=1.05-5.07, p=0.0379), time to nadir <19 weeks (HR=2.48, 95%CI=1.15-5.35, p=0.0204) were all independently predictive of shortened overall survival even after adjusting for pre-treatment factors. Maximal PSA response, PSA nadir, and time to PSA nadir correlated with survival in patients with castration-resistant prostate cancer receiving enzalutamide as a first-line therapy.

Development and validation of prognostic model for metastatic castration-resistant prostate cancer patients treated with first-line abiraterone or enzalutamide.

IntroductionOver the years, several prognostic models were developed in patients receiving chemotherapy for metastatic castration resistant prostate cancer (mCRPC), while data on androgen-receptor signaling inhibitors (ARSI) in a real-world setting are limited. Patients and methodsWe compared a consecutive series of 565 mCRPC patients receiving first-line ARSI at four high-volume Italian Centers (development set) to an external series of 180 patients receiving the same treatment at another Italian high-volume Center (training set), between 2011 and 2022.Sixteen clinical and baseline laboratory variables were selected to develop a prognostic model. Patients were categorized into risk groups according to the number of independent factors positively associated with overall survival (OS). ResultsIn the development cohort, after a median follow-up of 21.1 months, the median OS was 30.4 months (95% CI 27.5-33.4). At the multivariate analysis, seven variables [age, prostate specific antigen (PSA) doubling time, baseline levels of hemoglobin, PSA, time to castration resistance, ECOG PS and bone metastases number) were included into the final model.The median OS was 13.4, 25.7 and 46.4 months in poor (0-2 factors), intermediate (3-4 factors) and good (≥5 factors) prognosis group, respectively.The application of the model to the validation set confirmed its ability to prognosticate for OS. The model c-indexes were 0.68 (95% CI 0.64-0.72) and 0.75 (95% CI 0.68–0.81) in the development and validation cohort, respectively. ConclusionsOur model, based on clinical and laboratory variables readily assessable in clinical practice, might prognosticate the OS of mCRPC patients receiving first-line ARSI. Micro AbstractA retrospective study comparing a development to a validation cohort of mCRPC patients receiving ARSI found a new prognostic model. It included seven clinical and baseline laboratory variables and confirmed its ability to prognosticate for OS.

PARP inhibitors in prostate cancer: clinical applications.

Despite recent advancements in the treatment of metastatic castrate-resistant prostate cancer (mCRPC), this disease remains lethal. A novel family of targeted pharmaceuticals known as poly-ADP-ribose polymerase (PARP) inhibitors has been developed to treat mCRPC patients with homologous recombination repair (HRR) gene alterations. The FDA recently approved olaparib and rucaparib for treating mCRPC patients with HRR gene alterations. Ongoing trials are investigating combination therapies involving PARP inhibitors combined with radiation, chemotherapy, immunotherapy, and androgen receptor signaling inhibitors (ARSIs) to improve the effectiveness of PARP inhibitors and broaden the range of patients who can benefit from the treatment. This review provides an overview of the development of PARP inhibitors in prostate cancer and analyzes the mechanisms underlying their resistance.

Sequential versus concomitant treatment of androgen receptor signaling inhibitors and docetaxel for metastatic hormone-sensitive prostate cancer: an network meta-analysis.

Androgen receptor signaling inhibitors (ARSis), when administered sequentially or in combination with docetaxel and androgen deprivation therapy (ADT), have been shown to enhance overall survival (OS) and progression-free survival (PFS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Nonetheless, the optimal sequence for administering chemotherapy and ARSis remains to be determined. To compare the efficacy of ARSis sequential therapy with ARSis combined therapy for mHSPC, and to evaluate the efficacy and safety of different combination regimens. The PubMed, Embase, Cochrane Central, and ClinicalTrials.gov databases were searched from their inception through 14 July 2024, to identify eligible phase III randomized clinical trials (RCTs) evaluating the combination or sequential use of docetaxel + ADT with abiraterone, enzalutamide, apalutamide, or darolutamide. The outcomes of interest included OS, PFS, time to prostate-specific antigen (PSA) progression, grade 3-5 adverse events (AEs), and serious adverse events (SAEs). Five RCTs involving 2836 patients were included in the analysis. When comparing ARSis sequential therapy to ARSis combined therapy, no significant differences were observed in OS (Hazard Ratio (HR): 1.17, 95% Confidence Interval (CI): 0.69-1.96), PFS (HR: 1.03, 95% CI: 0.47-2.22), or time to PSA progression (HR: 0.48, 95% CI: 0.03-7.69). Within the different ARSis combined regimens, the triple therapies involving enzalutamide, abiraterone, and darolutamide demonstrated comparable efficacy and safety profiles in the overall population, and their efficacy in patients with high-volume disease or low-volume disease was also similar. ARSis sequential therapy did not significantly differ from ARSis combined therapy in improving OS and PFS among patients with mHSPC, and thus can be considered as a viable treatment option.

Predicting time to castration resistance with androgen-receptor signaling inhibitors in hormone-sensitive prostate cancer: data from ULTRA-Japan Consortium.

Androgen-receptor signaling inhibitors (ARSIs) become the new standard of care for metastatic hormone-sensitive prostate cancer (mHSPC). It is unknown whether time to castration resistance (TTCR), when using the first-line ARSIs, offers predictive value in mHSPC. We sought to assess the clinical outcomes for mHSPC patients treated with first-line ARSIs focusing on the TTCR. Data from the ULTRA-Japan study cohort from five academic institutes (496 mHSPC patients) were retrospectively analyzed. The median overall survival (OS) in the total cohort was 80months with a median follow-up of 18months. Of 496 patients, 332 (67%), 82 (16.5%), and 82 (16.5%) were treated with first-line abiraterone acetate + prednisone, enzalutamide, and apalutamide, respectively. During the follow-up, a total of 155 (31%) were diagnosed with mCRPC with a median TTCR of 10months. In those 155 patients, TTCR > 12months is an independent predictor of longer OS from the first-line ARSIs. Cox regression analysis of the TTCR from initiating first-line ARSI in 496 mHSPC patients revealed three variables as independent predictors of shorter TTCR, including Gleason's score (GS) ≥ 9, the extent of disease (EOD) ≥ 2, and the presence of liver metastasis. Our results indicate that mHSPC patients with those three features are likely to have primary resistance to first-line ARSIs (doublet therapy), thus requiring consideration of other options, such as the recent triplet approach.

Optimal timing for initiating androgen receptor signaling inhibitor therapy in patients with nonmetastatic castration-resistant prostate cancer: a multicenter collaborative study.

We determined the optimal timing for initiating androgen receptor signaling inhibitor (ARSI) therapy in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) and assessed its impact on oncological outcomes. This retrospective study included 145 nmCRPC patients who received enzalutamide, apalutamide or darolutamide at the Jikei University Hospital or its affiliated institutions between May 2014 and November 2022. Patients were stratified based on prostate-specific antigen (PSA) doubling time (PSADT) at CRPC diagnosis and PSA levels at ARSI initiation. Oncological outcomes, including progression-free survival (PFS), metastasis-free survival (MFS), cancer-specific survival and overall survival, were assessed using the Kaplan-Meier curve and Cox regression analysis. The median age of the patients was 73 (interquartile range [IQR]: 52-88) years, and the median follow-up duration was 36 (IQR: 2-104) months. The median PSA level at ARSI initiation was 5.4 (IQR: 2.2-48) ng/ml, and 44.8% of patients had a PSADT <3months. Multivariate analysis revealed that PSADT and PSA levels at ARSI initiation were independent MFS predictors. Patients with a PSADT ≤3months and a PSA level≥5.4ng/ml experienced significantly reduced PFS and MFS. Notably, ARSI initiation at a PSA level ≥5.4ng/ml was associated with worse outcomes, suggesting the potential benefit of earlier intervention. Patients with rapid PSADT are at increased risk of early disease progression, suggesting that immediate treatment may be warranted. In addition, initiating therapy at a PSA level <5.4ng/ml may be associated with improved patient outcomes in patients with low PSADT.

The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1.

Lineage plasticity is a hallmark of cancer progression that impacts therapy outcomes, yet the mechanisms mediating this process remain unclear. Here, we introduce a versatile in vivo platform to interrogate neuroendocrine lineage transformation throughout prostate cancer progression. Transplanted mouse prostate organoids with human-relevant driver mutations (Rb1-/-; Trp53-/-; cMyc+ or Pten-/-; Trp53-/-; cMyc+) develop adenocarcinomas, but only those with Rb1 deletion advance to aggressive, ASCL1+ neuroendocrine prostate cancer (NEPC) resistant to androgen receptor signaling inhibitors. Notably, this transition requires an in vivo microenvironment not replicated by conventional organoid culture. Using multiplexed immunofluorescence and spatial transcriptomics, we reveal that ASCL1+ cells arise from KRT8+ luminal cells, progressing into transcriptionally heterogeneous ASCL1+;KRT8- NEPC. Ascl1 loss in established NEPC causes transient regression followed by recurrence, but its deletion before transplantation abrogates lineage plasticity, resulting in castration-sensitive adenocarcinomas. This dynamic model highlights the importance of therapy timing and offers a platform to identify additional lineage plasticity drivers.

Genomic and epigenomic analysis of plasma cell-free DNA identifies stemness features associated with worse survival in lethal prostate cancer.

Metastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor signaling inhibitors (ARSIs) is often lethal. Liquid biopsy biomarkers for this deadly form of disease remain under investigation, and underpinning mechanisms remain ill-understood. We applied targeted cell-free DNA sequencing to 126 mCRPC patients from three academic cancer centers, and separately performed genome-wide cell-free DNA methylation sequencing on 43 plasma samples collected prior to the initiation of first-line ARSI treatment. To analyze the genome-wide sequencing data, we performed nucleosome-positioning and differential methylated region analysis. We additionally analyzed single-cell and bulk RNA sequencing data from 14 and 80 mCRPC patients, respectively, to develop and validate a stem-like signature, which we inferred from cell-free DNA. Targeted cell-free DNA sequencing detected AR/enhancer alterations prior to first-line ARSIs which correlated with significantly worse PFS (p = 0.01; HR = 2.12) and OS (p = 0.02; HR = 2.48). Plasma methylome analysis revealed that AR/enhancer lethal mCRPC patients have significantly higher promoter-level hypomethylation than AR/enhancer wild-type mCRPC patients (p < 0.0001). Moreover, gene ontology and CytoTRACE analysis of nucleosomally more accessible transcription factors in cell-free DNA revealed enrichment for stemness-associated transcription factors in lethal mCRPC patients. The resulting stemness signature was then validated in a completely held-out cohort of 80 mCRPC patients profiled by tumor RNA sequencing. We analyzed a total of 220 mCRPC patients, validated the importance of cell-free AR/enhancer alterations as a prognostic biomarker in lethal mCRPC and showed that the underlying mechanism for lethality involves reprogramming developmental states toward increased stemness.

Androgen-ablative therapies inducing CXCL8 regulates mTORC1/SREBP2-dependent cholesterol biosynthesis to support progression of androgen receptor negative prostate cancer cells.

Treatment with androgen-ablative therapies effectively inhibited androgen receptor (AR)-positive (AR+) prostate cancer (PCa) cell subtypes, but it resulted in an increase in AR-negative (AR-) PCa cell subtypes. The present study aimed to investigate the debated mechanisms responsible for the changing proportion of cell types, identifying CXCL8 as a synthetic essential effector of AR- PCa cells. AR- PCa cells were found to be susceptible to CXCL8 depletion or inhibition, which impaired their survival. Mechanistically, androgen-ablative therapies resulted in the suppression of AR signaling, leading to the upregulation of CXCL8 gene transcription. CXCL8, in turn, activated the mTORC1 pathway, which increased de novo cholesterol synthesis by activating sterol regulatory element-binding protein-2 (SREBP2). Together, these results suggested that the CXCL8-mTORC1-SREBP2 axis contributed to the exacerbation of tumorigenicity in AR- PCa cells under androgen-ablative therapies.

Docetaxel Versus Androgen-Receptor Signaling Inhibitors (ARSI) as Second-Line Therapy After Failure of First-Line Alternative ARSI for the Elderly ≥ 75 Years Old With Metastatic Castration-Resistant Prostate Cancer (mCRPC): A SPARTACUSS—Meet-URO 26 Real-World Study

BackgroundAndrogen receptor signalling inhibitors (ARSIs) abiraterone acetate (AA) enzalutamide (Enza), are currently the standard first-line (L1) treatments for metastatic castration-resistant prostate cancer (mCRPC), and docetaxel (D) is reserved as second-line (L2) after ARSI failure. Nonetheless, D use in men ≥ 75 years old is restricted owing to treatment toxicities and patient comorbidities, and a L2 alternative ARSI is frequently used. We aimed to evaluate real-life survival and toxicity outcomes of these elderly patients after failure of L1 ARSI treatment. Material and MethodsWe retrospectively evaluated efficacy and safety in a real-world international cohort of consecutive patients ≥ 75 years old when starting L1 ARSI for mCRPC according to the choice of L2 treatment (D versus alternative ARSI). ResultsOf the 122 identified patients, 57 (46.7%) had received L2 ARSI and 65 (53.3%) L2 D. No difference was found in the L1 overall survival (OS) for the ARSI and D groups (32.8 vs. 30.0 months, respectively; Hazard ratio [HR] = 1.22; 95% CI, 0.77-1.95; P = .40) or in the L2 OS (18.5 vs. 17.8 months, respectively; HR = 1.09; 95% CI, 0.69-1.74; P = .71). No difference was observed for rPFS from L2 (P = .12), although a trend was observed for a numerically improved rPFS on D. ConclusionWithin the limitations of a retrospective design and small population, our study suggests that D or ARSI after failure of L1 alternative ARSI are clinically comparable L2 options for elderly patients with mCRPC.

A boost or a redundancy? on the value of combination of androgen receptor signal inhibitor and PARP inhibitor for advanced prostate cancer

AbstractPoly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), as a novel endocrine therapy, has been investigated in patients with metastatic castration-resistant prostate cancer (mCRPC) in recent years. Multiple large-scale clinical trials have consistently demonstrated that various PARP inhibitors, including olaparib, rucaparib, niraparib, and talazoparib, confer longer radiographic progression-free survival (rPFS) compared to new hormonal agents (NHA) in mCRPC patients with homologous recombination deficiency (HRD). Moreover, the incidence of grade 3 and above adverse events did not significantly increase. Additionally, when combined with androgen receptor signaling inhibitors (ARSI), olaparib, niraparib, and talazoparib have shown significant extension of rPFS but also an increased occurrence of serious adverse events in HRD-positive patients. Only PROpel yielded positive results among the homologous recombination repair (HRR) mutation negative population. Therefore, it remains uncertain whether ARSI-PARPi combination therapy should be considered as first-line treatment for mCRPC patients without HRR mutations. In this review article, we aim to elucidate the necessity and feasibility of combination therapy versus monotherapy specifically within the HRR mutant population while exploring its potential applicability to other non-HRR mutant subtypes. Furthermore, we conducted a comprehensive search on registered clinical trials at present to summarize the research progress of PARP inhibitors in prostate cancer patients at different disease stages.

Efficacy and Toxicity of [177Lu]Lu-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: Results from the U.S. Expanded-Access Program and Comparisons with Phase 3 VISION Data.

The phase 3 VISION trial demonstrated that [177Lu]Lu-PSMA-617 prolonged progression-free survival and overall survival (OS) in prostate-specific membrane antigen [PSMA]-positive metastatic castration-resistant prostate cancer (mCRPC) patients who progressed on taxane-based chemotherapy and androgen receptor-signaling inhibitors (ARSIs). The U.S. expanded-access program (EAP; NCT04825652) was opened to provide access to [177Lu]Lu-PSMA-617 for eligible patients until regulatory approval was obtained. This study aimed to evaluate the efficacy and safety profile of [177Lu]Lu-PSMA-617 within the EAP and compare the results with those from the VISION trial. Methods: Patients enrolled in the EAP at 4 institutions in the United States with available toxicity and outcome data were included. Outcome measures included OS, a prostate-specific antigen (PSA) response rate (RR) of at least 50%, and incidences of toxicity according to Common Terminology Criteria for Adverse Events version 5.0. Differences in baseline characteristics, outcome data, and toxicity between the EAP and VISION were evaluated using t testing of proportions and survival analyses. Results: In total, 117 patients with mCRPC who received [177Lu]Lu-PSMA-617 within the EAP between May 2021 and March 2022 were eligible and included in this analysis. Patients enrolled in the EAP were more heavily pretreated with ARSI (≥2 ARSI regimens: 70% vs. 46%; P < 0.001) and had worse performance status at baseline (Eastern Cooperative Oncology Group score ≥ 2: 19% vs. 7%; P < 0.001) than VISION patients. EAP and VISION patients had similar levels of grade 3 or higher anemia (18% vs. 13%; P = 0.15), thrombocytopenia (13% vs. 8%; P = 0.13), and neutropenia (3% vs. 3%; P = 0.85) and similar PSA RRs (42% vs. 46%; P = 0.50) and OS (median: 15.1 vs. 15.3 mo; P > 0.05). Conclusion: Patients with PSMA-positive mCRPC who received [177Lu]Lu-PSMA-617 within the EAP were later in their disease trajectory than VISION patients. Patients enrolled in the EAP achieved similar PSA RRs and OS and had a safety profile similar to that of the VISION trial patients.

Bipolar androgen therapy for treatment of metastatic castration‐resistant prostate cancer: A case series

AbstractIntroductionAdvanced prostate cancer treatment has improved with androgen receptor signaling inhibitors (ARPI), yet many patients develop metastatic castration‐resistant prostate cancer (mCRPC), characterized by sustained androgen receptor (AR) signaling. Bipolar androgen therapy (BAT) introduces supraphysiologic testosterone levels to inhibit tumor growth, offering novel treatment for mCRPC by exploiting AR‐dependent mechanisms.Case PresentationsCase 1: A 53‐year‐old man with mCRPC, post multiple systemic therapies, initiated BAT and pembrolizumab, achieving PSA reduction and improved quality of life before progression. The patient exhibited AR amplification, which may have contributed to favorable response to BAT.Case 2: A 73‐year‐old man with recurrent prostate cancer, stable on ADT and abiraterone, experienced PSA decline with BAT to an undetectable level, maintaining stability post‐therapy discontinuation.Case 3: A 73‐year‐old man with metastatic prostate cancer, initially resistant to enzalutamide, achieved clinical benefit and disease control with BAT, although he did not meet PSA response criteria, patient had remarkable response upon enzalutamide rechallenge.Case 4: A 90‐year‐old man with localized prostate cancer, refractory to multiple treatments, experienced symptom relief and PSA reduction with BAT before progression.ConclusionBAT represents a promising treatment strategy for mCRPC. This case series underscores BAT's potential to induce significant clinical and biochemical responses, resensitize tumors to ARPIs, and improve patients' quality of life. Despite eventual progression in some cases, BAT offers a period of disease control. Further research is needed to optimize patient selection and understand the molecular determinants of BAT responsiveness.

Novel Treatment Strategies for Low-Risk Metastatic Castration-Sensitive Prostate Cancer.

The treatment strategy for metastatic castration-sensitive prostate cancer (mCSPC) has changed significantly in recent years. Based on various guidelines, an upfront androgen receptor signaling inhibitor (ARSI) is the first choice, but in patients of Asian descent, including Japanese patients, there are a certain number of cases in which androgen deprivation therapy (ADT) and CAB are more effective. If patients can be identified who show a marked response to ADT within 12 weeks after the initiation of ADT, which is the inclusion criterion for ARSI clinical trials targeting mCSPC, it would be valuable from an economic standpoint. A total of 218 patients with pure prostate adenocarcinoma and treated with ADT at the Kanazawa University Hospital between January 2000 and December 2020 were included in this study. As a risk classification for mCSPC, in addition to the LATITUDE and CHAARTED criteria, we used the castration-sensitive prostate cancer classification proposed by Kanazawa University (Canazawa), developed by the Department of Urology of Kanazawa University. The Canazawa classification was based on three factors: Gleason pattern 5, bone scan index (BSI) ≥ 1.5, and lactate dehydrogenase (LDH) ≥ 300 IU/L. It defined patients with one factor or less as low-risk and patients with two or three factors as high-risk. The overall survival (OS) and time to castration resistance (TTCR) were estimated retrospectively using the Kaplan-Meier method, and factors associated with TTCR were identified using univariate and multivariate analyses. The median follow-up period was 40.4 months, the median OS period was 85.2 months, and the median TTCR period was 16.4 months. The Canazawa risk classification provided the clearest distinction between the OS and TTCR in mCSPC patients. Multivariate analysis revealed a decrease in PSA levels of <95% at 12 weeks after ADT initiation and was a predictor of short TTCR in low-risk, low-volume patients across all risk classifications. The Canazawa classification differentiated the prognosis of mCSPC patients more clearly. A PSA reduction rate of <95% at 12 w after starting ADT in low-risk, low-volume patients of all risk classifications was significantly shorter than the TTCR. We propose a new treatment strategy, in which patients with low-risk mCSPC are treated with ADT and switched to ARSIs based on the rate of PSA reduction at 12 w.

Deep PSA response and extended time‐to‐nadir as robust predictors of survival in Asian patients with de novo metastatic hormone‐sensitive prostate cancer receiving upfront intensified treatment

AbstractIntroductionIn de novo metastatic hormone‐sensitive prostate cancer (mHSPC) treated with upfront intensification using androgen receptor signaling inhibitor or chemotherapy (Docetaxel), achieving a PSA nadir less than 0.2 ng/mL, indicative of superior survival in trials, may often be unattainable in real‐world settings. We explored the predictive value of the degree of PSA decline and time to PSA nadir (TTPN) on oncological outcomes.MethodsA prospectively maintained database of consecutive prostate cancer cases in Hong Kong was accessed. Patients diagnosed with de novo mHSPC from 2016 to 2022 and treated with upfront intensification were included in this analysis. Landmark analysis on PSA kinetics at 6‐months following treatment intensification was performed. They were classified based on 1) TTPN (≥6 months vs. &lt;6 months), and 2) a combined response (deep responders achieving both ≥95% PSA decline and TTPN ≥ 6 months vs. shallow responders). Multivariable regression analysis was employed to identify the effects of confounders.FindingsA total of 131 patients were included in this analysis. Classifying patients by combined response best predicted survival outcomes. Deep responders had better progression‐free survival (HR = 0.56; 95%CI = 0.34–0.91; p = 0.019), overall survival (HR = 0.50; 95%CI = 0.26–0.97; p = 0.036), and cancer‐specific survival (HR = 0.43; 95%CI = 0.19–0.99; p = 0.042). Difference in overall survival remained significant after adjustment in multivariable regression analysis.ConclusionOur analysis demonstrates that alternative PSA targets can predict treatment response and survival outcomes in de novo mHSPC patients in a real‐world setting, providing valuable information for patient counselling and potentially guiding future trial design.

BCL2 expression is enriched in advanced prostate cancer with features of lineage plasticity.

The widespread use of potent androgen receptor signaling inhibitors (ARSIs) has led to an increasing emergence of AR-independent castration-resistant prostate cancer (CRPC), typically driven by loss of AR expression, lineage plasticity, and transformation to prostate cancers (PCs) that exhibit phenotypes of neuroendocrine or basal-like cells. The anti-apoptotic protein BCL2 is upregulated in neuroendocrine cancers and may be a therapeutic target for this aggressive PC disease subset. There is an unmet clinical need, therefore, to clinically characterize BCL2 expression in metastatic CRPC (mCRPC), determine its association with AR expression, uncover its mechanisms of regulation, and evaluate BCL2 as a therapeutic target and/or biomarker with clinical utility. Here, using multiple PC biopsy cohorts and models, we demonstrate that BCL2 expression is enriched in AR-negative mCRPC, associating with shorter overall survival and resistance to ARSIs. Moreover, high BCL2 expression associates with lineage plasticity features and neuroendocrine marker positivity. We provide evidence that BCL2 expression is regulated by DNA methylation, associated with epithelial-mesenchymal transition, and increased by the neuronal transcription factor ASCL1. Finally, BCL2 inhibition had antitumor activity in some, but not all, BCL2-positive PC models, highlighting the need for combination strategies to enhance tumor cell apoptosis and enrich response.