Androgen Receptor Axis Research Articles

ENCORE: A phase 2 trial of enfortumab vedotin (EV) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

TPS294 Background: EV, an antibody-drug conjugate (ADC), consists of a fully human antibody directed against the extracellular domain of Nectin-4 (N4), which is conjugated to a microtubule-disrupting agent, monomethyl auristatin E (MMAE), by a protease-cleavable linker. MMAE disrupts tubulin polymerization leading to mitotic arrest and apoptosis. N4 RNA is expressed in prostate tissue, but its expression levels in mCRPC are currently unknown. In animal models of prostate, metastatic lesions showed a very high (++++) membranous N4 expression and correlated with advanced disease (PMID: 30767361). In prostate cancer cell lines engineered to express N4 (PC3-Nectin-4), the hybridoma version of EV: AGS-22M6E, demonstrated potent dose-dependent cytotoxicity (PMID: 27013195). MMAE destabilizes microtubules in contrast to stabilization by taxanes and has shown anti-tumor activity in taxane refractory cell lines and in mCRPC pts with prior taxane therapy (PMID: 31742767). We initiated a phase 2 trial of EV in pts with mCRPC. Methods: This IRB approved, investigator-initiated, single-arm, single-center, non-randomized, open-label study will enroll 34 pts. EV will be administered at 1.25 mg/kg IV on days 1, 8, and 15 of 28- day cycle. Key eligibility criteria: ≥18 years age, mCRPC with histologically/cytologically confirmed adenocarcinoma without small cell histology, ECOG performance status ≤ 1, adequate organ function, prior treatment with ≥3 cycles of docetaxel, at least one androgen-receptor axis targeting agent, received/refused all therapies shown to improve overall survival (OS) except cabazitaxel which is exclusionary. Primary objective: To assess the antitumor activity of EV as determined by one of the following: objective response by RECIST 1.1, confirmed conversion of circulating tumor cell count (CTC) to <5/7.5 mL blood, PSA decline of ≥ 50% (per PCWG3) and stable disease for ≥ 6 months per PCWG3 modified RECIST 1.1. Simon’s two-stage design will be used. The null hypothesis (H0) that true response rate (RR) is 25% will be tested against a one-sided alternative. In first stage if ≤3 responses are observed of 11 pts, the study will be stopped. Otherwise, 23 additional pts will be accrued (total 34). H0 will be rejected if ≥13 responses are observed in 34 pts. This design yields type I error rate of 0.046 and power of 0.854 when true RR is 50%. Secondary endpoints: safety, tolerability, progression-free survival (radiological, clinical and PSA), OS, duration of PSA50% response, CTC conversion rate from ≥5/7.5 ml at baseline to <5/7.5 ml, PSA% change from baseline to 12 weeks and maximum PSA% decline from week 12 until treatment discontinuation. 3 patients have been enrolled. Clinical trial information: NCT04754191 .

Comparison of prognostic characteristics between vintage and novel androgen receptor-axis-targeted drug among Japanese patients with non-metastatic castration-resistant prostate cancer: A multi-institutional study of Japanese Urological Oncology Group (JUOG).

163 Background: We conducted a multicenter study, 1) to verify the prognostic difference between novel androgen receptor-axis–targeted (ARAT) drug and vintage drug (Vintage) and, 2) to identify the prognostic PSA doubling time (PSADT) among Japanese non-metastatic castration-resistant prostate cancer (nmCRPC) patients. Methods: Of 515 patients diagnosed and treated for nmCRPC at 25 JUOG participating centers, including Chiba University Hospital, 489 patients with complete clinical characteristics were included. The association between each clinical factor, including drug types, PSADT, progression-free survival (PFS), and overall survival (OS) were analyzed, retrospectively. Results: The median age at nmCRPC diagnosis was 72 years, PSA was 3.24 ng/ml, and the observation period was 980 days. nmCRPC PFS and OS were 22 and 95 months, respectively. nmCRPC first-line therapy included Vintage + LH-RH alone: 197 cases/ARAT: 285 cases /Docetaxel (DOC): 7 cases. In the search for optimal PSADT (3-12M), PFS and OS correlated best at 10M (HR 1.64, p=0.005) and 4M (HR 2.63, p<.0001), respectively. ARAT(DOC) significantly prolonged PFS (HR 3.15, p<.0001) compared to Vintage, however, did not affect OS (HR 1.09, p=0.697) nor combined PFS (HR 0.94, p=0.733). The result was consistent, even after adjustment of the patient`s background by the propensity score matched analysis (n=145 in each arm), such as PFS (HR 0.35, p<.0001), OS (HR 1.16, p=0.598) and Combined PFS (HR 0.66, p=0.133). Multivariate analysis showed that PSADT was an independent prognostic factor for PFS (PSADT 10M: HR 3.1 p<.0001) and OS (PSADT 4M: HR 2.8, p=0.002). Conclusions: ARAT(DOC) prolonged PFS, but not OS, compared to Vintage in Japanese nmCRPC patients. PSADT (4-10M) may represent a useful tool in predicting prognosis and constructing treatment strategies for Japanese nmCRPC patients. [Table: see text]

Unraveling the Peculiar Features of Mitochondrial Metabolism and Dynamics in Prostate Cancer

Prostate cancer (PCa) is the second leading cause of cancer deaths among men in Western countries. Mitochondria, the "powerhouse" of cells, undergo distinctive metabolic and structural dynamics in different types of cancer. PCa cells experience peculiar metabolic changes during their progression from normal epithelial cells to early-stage and, progressively, to late-stage cancer cells. Specifically, healthy cells display a truncated tricarboxylic acid (TCA) cycle and inefficient oxidative phosphorylation (OXPHOS) due to the high accumulation of zinc that impairs the activity of m-aconitase, the enzyme of the TCA cycle responsible for the oxidation of citrate. During the early phase of cancer development, intracellular zinc levels decrease leading to the reactivation of m-aconitase, TCA cycle and OXPHOS. PCa cells change their metabolic features again when progressing to the late stage of cancer. In particular, the Warburg effect was consistently shown to be the main metabolic feature of late-stage PCa cells. However, accumulating evidence sustains that both the TCA cycle and the OXPHOS pathway are still present and active in these cells. The androgen receptor axis as well as mutations in mitochondrial genes involved in metabolic rewiring were shown to play a key role in PCa cell metabolic reprogramming. Mitochondrial structural dynamics, such as biogenesis, fusion/fission and mitophagy, were also observed in PCa cells. In this review, we focus on the mitochondrial metabolic and structural dynamics occurring in PCa during tumor development and progression; their role as effective molecular targets for novel therapeutic strategies in PCa patients is also discussed.

Dependence on MUC1-C in Progression of Neuroendocrine Prostate Cancer.

Castration resistant prostate cancer (CRPC) is responsive to androgen receptor (AR) axis targeted agents; however, patients invariably relapse with resistant disease that often progresses to neuroendocrine prostate cancer (NEPC). Treatment-related NEPC (t-NEPC) is highly aggressive with limited therapeutic options and poor survival outcomes. The molecular basis for NEPC progression remains incompletely understood. The MUC1 gene evolved in mammals to protect barrier tissues from loss of homeostasis. MUC1 encodes the transmembrane MUC1-C subunit, which is activated by inflammation and contributes to wound repair. However, chronic activation of MUC1-C contributes to lineage plasticity and carcinogenesis. Studies in human NEPC cell models have demonstrated that MUC1-C suppresses the AR axis and induces the Yamanaka OSKM pluripotency factors. MUC1-C interacts directly with MYC and activates the expression of the BRN2 neural transcription factor (TF) and other effectors, such as ASCL1, of the NE phenotype. MUC1-C also induces the NOTCH1 stemness TF in promoting the NEPC cancer stem cell (CSC) state. These MUC1-C-driven pathways are coupled with activation of the SWI/SNF embryonic stem BAF (esBAF) and polybromo-BAF (PBAF) chromatin remodeling complexes and global changes in chromatin architecture. The effects of MUC1-C on chromatin accessibility integrate the CSC state with the control of redox balance and induction of self-renewal capacity. Importantly, targeting MUC1-C inhibits NEPC self-renewal, tumorigenicity and therapeutic resistance. This dependence on MUC1-C extends to other NE carcinomas, such as SCLC and MCC, and identify MUC1-C as a target for the treatment of these aggressive malignancies with the anti-MUC1 agents now under clinical and preclinical development.

Quantitative In Vivo Imaging of the Androgen Receptor Axis Reveals Degree of Prostate Cancer Radiotherapy Response.

hK2 expression in prostate cancer tissue is a proxy of EBRT-induced AR activity that can noninvasively be detected using [89Zr]11B6-PET; further clinical evaluation of hK2-PET for monitoring response and development of resistance to EBRT in real time is warranted.

Novel inhibition of AKR1C3 and androgen receptor axis by PTUPB synergizes enzalutamide treatment in advanced prostate cancer.

Castration-resistant prostate cancer (CRPC) is the main driving force of mortality in prostate cancer patients. Among the parameters contributing to the progression of CRPC and treatment failure, elevation of the steroidogenic enzyme AKR1C3 and androgen receptor variant 7 (AR-V7) are frequently reported. The AKR1C3/AR-V7 complex has been recognized as a major driver for drug resistance in advanced prostate cancer. Herein we report that the level of AKR1C3 is reciprocally regulated by the full-length androgen receptor (AR-FL) through binding to the distal enhancer region of the AKR1C3 gene. A novel function of PTUPB in AKR1C3 inhibition was discovered and PTUPB showed more effectiveness than indomethacin and celecoxib in suppressing AKR1C3 activity and CRPC cell growth. PTUPB synergizes with enzalutamide treatment in tumor suppression and gene signature regulation. Combination treatments with PTUPB and enzalutamide provide benefits by blocking AR/AR-V7 signaling, which inhibits the growth of castration relapsed VCaP xenograft tumors and patient-derived xenograft organoids. Targeting of the ARK1C3/AR/AR-V7 axis with PTUPB and enzalutamide may overcome drug resistance to AR signaling inhibitors in advanced prostate cancer.

Prostate-specific Antigen Kinetics During Androgen-deprivation Therapy Predict Response to Enzalutamide in Metastatic Castration-resistant Prostate Cancer.

No practical predictive biomarkers exist to date for the response to androgen receptor-axis targeted (ARAT) therapies in metastatic castration-resistant prostate cancer (mCRPC). This study investigated whether prostate-specific antigen (PSA) kinetics in primary androgen-deprivation therapy for advanced hormone-sensitive prostate cancer may be associated with the response to ARAT agents in mCRPC. This study assessed 102 patients with mCRPC treated with enzalutamide or abiraterone to evaluate the associations between clinical outcomes and PSA kinetics, including the ratio of initial to nadir PSA (I/N PSA) level in primary combined androgen blockade. The PSA response was defined as a ≥50% decrease at 3 months from baseline in patients with mCRPC. In patients treated with enzalutamide, the optimal cut-off I/N PSA value for PSA response was 531 ng/ml (sensitivity=66.7%, specificity=88.2%, area under the curve=0.73, using a receiver operating characteristic curve). The PSA response was 83.3% and 25.0% in the high and low I/N PSA groups, respectively. The median overall survival and radiographic progression-free survival from enzalutamide initiation were longer for the high compared to the low I/N PSA group. Multivariate analysis revealed I/N PSA (hazard ratio=0.275, p=0.026) as an independent risk factor for overall survival in the patients treated with enzalutamide. In contrast, I/N PSA showed no predictive ability for PSA response in patients treated with abiraterone. In patients with mCRPC, I/N PSA can be a practical predictive biomarker for response to the ARAT agent enzalutamide.

The testosterone paradox of advanced prostate cancer: mechanistic insights and clinical implications.

The discovery of the benefits of castration for prostate cancer treatment in 1941 led to androgen deprivation therapy, which remains a mainstay of the treatment of men with advanced prostate cancer. However, as early as this original publication, the inevitable development of castration-resistant prostate cancer was recognized. Resistance first manifests as a sustained rise in the androgen-responsive gene, PSA, consistent with reactivation of the androgen receptor axis. Evaluation of clinical specimens demonstrates that castration-resistant prostate cancer cells remain addicted to androgen signalling and adapt to chronic low-testosterone states. Paradoxically, results ofseveral studies have suggested that treatment with supraphysiological levels of testosterone can retard prostate cancer growth. Insights from these studies have been used toinvestigate administration of supraphysiological testosterone to patients with prostate cancer for clinical benefits, a strategy that is termed bipolar androgen therapy (BAT). BAT involves rapid cycling from supraphysiological back to near-castration testosterone levels over a 4-week cycle. Understanding how BAT works at the molecular and cellular levels might help to rationalize combining BAT with other agents to achieve increased efficacy and tumour responses.

UnCHAARTED territory: The role of docetaxel rechallenge following chemohormonal therapy for metastatic castration-sensitive prostate cancer.

To assess the effectiveness of docetaxel rechallenge (DR) for metastatic castration-resistant prostate cancer (mCRPC) following chemohormonal therapy for metastatic castrate-sensitive prostate cancer (mCSPC). Additionally, we sought to define clinical factors predicting treatment response. Retrospective analysis of men treated with docetaxel for mCSPC and then rechallenged in the mCRPC setting from four cancer centers in Ontario, Canada. Prostate specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS) following DR were evaluated. Fifty five patients were identified between 2015 and 2020. Prior to DR, 94.5% of patients received androgen-receptor axis targeted therapy, 20% received radium-223, and 1.8% received cabazitaxel. Among 54 evaluable patients, 27.8% had a PSA decline ≥50%. Median PFS was 4.1 months (95% CI, 2.1-4.8) and median OS from androgen deprivation therapy initiation was 38.3 months (95% CI, 32.9-41.0). A Gleason Score of ≥8 was an independent predictor of prolonged PFS (HR 0.32, 95% CI, 0.12-0.81; P=0.02). DR following chemohormonal therapy for mCSPC produced a meaningful PSA response in approximately one-quarter of patients, with relatively short PFS. The impact of Gleason Score on docetaxel response warrants further investigation.

Statin Use and Survival Among Men Receiving Androgen-Ablative Therapies for Advanced Prostate Cancer

Epidemiological evidence supports a role for statins in improving survival in advanced prostate cancer, particularly among men receiving androgen-ablative therapies. To study the association between statin use and survival among men with prostate cancer receiving androgen deprivation therapy (ADT) or androgen receptor axis-targeted therapies (ARATs). This systemic review and meta-analysis used sources from MEDLINE, EMBASE, Epub Ahead of Print, Cochrane Clinical Trials, Cochrane Systematic Reviews, and Web of Science from inception to September 6, 2022. Observational studies reporting associations of concurrent statin use and survival outcomes (in hazard ratios [HRs]). Two authors independently abstracted all data. Summary estimates pooled multivariable HRs with 95% CIs using the generic inverse variance method with random-effects modeling. A priori specified subgroup and sensitivity analyses were undertaken, and heterogeneity, study quality, and publication bias were evaluated. Confidence in the evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Overall mortality and prostate cancer-specific mortality (PCSM). Twenty-five cohorts of 119 878 men (65 488 statin users [55%]) with more than 74 416 deaths were included. Concurrent statin use was associated with a 27% reduction in the risk of overall mortality (HR, 0.73 [95% CI, 0.66-0.82]; I2 = 83%) and a 35% reduction in the risk of PCSM (HR, 0.65 [95% CI, 0.58-0.73]; I2 = 74%), with substantial heterogeneity in both estimates. Subgroup analyses identified a PCSM advantage associated with statins for men receiving ARATs compared with ADT alone (HR, 0.40 [95% CI, 0.30-0.55] vs 0.68 [95% CI, 0.60-0.76]; P = .002 for difference). Confidence in the evidence was rated low for both outcomes. The findings of this meta-analysis show that concurrent statin use was associated with reduced overall mortality and PCSM among men receiving androgen-ablative therapies for advanced prostate cancer. These findings are limited by the observational nature of the data and residual unexplained interstudy heterogeneity. Randomized clinical trials are warranted to validate these results.

Alpinumisoflavone Exhibits the Therapeutic Effect on Prostate Cancer Cells by Repressing AR and Co-Targeting FASN- and HMGCR-Mediated Lipid and Cholesterol Biosynthesis.

Prostate cancer (PCa) is the most common cancer in men, and this has been mainly noticed in Western and Asian countries. The aggregations of PCa and castration-resistant PCa (CRPC) progression are the crucial causes in the mortality of patients without the effective treatment. To seek new remedies for the lethal PCa diseases is currently an urgent need. In this study, we endeavored to investigate the therapeutic efficacy of alpinumisoflavone (AIF), a natural product, in PCa. LNCaP (androgen- sensitive) and C4-2 (CRPC) PCa cells were used. An MTT-based method, soft agar colony forming assay, biological progression approaches were applied to determine cell viability, migration, and invasion. A fatty acid quantification kit, a cholesterol detection kit and oil red O staining were conducted to analyze the intracellular levels of lipids and cholesterols. Apoptosis assays were also performed. AIF reduced cell viability, migration, and invasion in PCa cells. The expression of androgen receptor (AR), fatty acid synthase (FASN), and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) was substantially inhibited by AIF treatment in PCa cells. Furthermore, by inhibiting FASN and HMGCR expression, AIF decreased the amounts of intracellular fatty acids, cholesterols, and lipid droplets in PCa cells. Significantly, through coordinated targeting FASN- and HMGCR-regulated biosynthesis and the AR axis, AIF activated the caspase-associated apoptosis in PCa cells. These results collectively demonstrated for the first time the potential of AIF as a novel and attractive remedy and provided an alternative opportunity to cure PCa malignancy.

Extensive Alteration of Androgen Precursor Levels After Castration in Prostate Cancer Patients and Their Association With Active Androgen Level.

Dihydrotestosterone and testosterone are thought to be major contributors of prostate cancer progression and resistance. We studied the modulation of 15 circulating steroids by castration and their association with dihydrotestosterone and testosterone levels. A total of 116 serum samples were collected from 99 prostate cancer patients and categorized as eugonadal, castration-sensitive prostate cancer, castration-resistant prostate cancer, or castration-resistant prostate cancer under abiraterone acetate. Serum levels of 15 steroids were measured using mass spectrometry and compared between groups using analysis of variance. Intrapatient association of steroid levels and the androgens testosterone and dihydrotestosterone were assessed using Pearson correlation and linear regression. Testosterone, dihydrotestosterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androsterone, androstenediol, estrone, estrone-sulfate, estradiol, and androsterone/3α-diol-3/3α-diol-17-glucuronide levels were significantly decreased in castration-sensitive prostate cancer (castrated) compared to eugonadal patients. Testosterone levels were strongly associated with multiple steroids under eugonadal conditions, whereas they were weakly affected by precursor steroids in castrated patients. By contrast, dihydrotestosterone levels under androgen deprivation therapy were associated with testosterone and the backdoor pathway metabolite androsterone. In castration-resistant prostate cancer patients, levels of androstenedione were significantly associated with testosterone level, while testosterone was the only steroid associated with dihydrotestosterone levels. Androgen deprivation therapy significantly reduces the levels of 13 circulating steroids. Upon androgen deprivation therapy initiation, the backdoor pathway metabolite androsterone are strongly associated with dihydrotestosterone levels. Under castration-resistant prostate cancer conditions, androstenedione was significantly associated with testosterone levels, suggesting the presence of tumor-related circulating androgens in these patients. These results provide further rationale to intensify treatments with androgen receptor axis signaling pathway inhibitors in patients with prostate cancer.

SPOP Mutations as a Predictive Biomarker for Androgen Receptor Axis-Targeted Therapy in De Novo Metastatic Castration-Sensitive Prostate Cancer.

Intensification of androgen deprivation therapy (ADT) with either docetaxel or androgen receptor axis-targeted therapies (ARAT) are the current standard of care for patients with metastatic castration-sensitive prostate cancer (mCSPC). However, biomarkers guiding treatment selection are lacking. We hypothesized that ADT intensification with ARAT, but not with docetaxel, would be associated with improved outcomes in patients with de novo (dn)-mCSPC harboring SPOP mutations. Patient-level data from a deidentified nationwide (U.S.-based) prostate cancer clinico-genomic database between January 2011 and December 2021 were extracted. Eligibility criteria: diagnosis of metastatic disease within 30 days of original prostate cancer diagnosis, genomic profiling of a tissue biopsy collected within 90 days of original diagnosis, and initiation of ARAT or docetaxel within 120 days of initial diagnosis. The log-rank test and Cox proportional hazards models were used to compare time to castration-resistant prostate cancer (TTCRPC) and overall survival (OS) for patients with and without SPOP mutations undergoing ADT intensification with ARAT or docetaxel. In the ARAT cohort, presence of SPOP mutation compared with wild-type was associated with more favorable TTCRPC [not reached (NR) vs. 16.7 months; adjusted HR (aHR), 0.20; 95% confidence interval (CI), 0.06-0.63; P = 0.006] and OS (NR vs. 27.2 months; aHR, 0.19; 95% CI, 0.05-0.79; P = 0.022). In contrast, SPOP mutation status was not associated with TTCRPC or OS in docetaxel-treated cohort. In real-world settings, SPOP mutations were associated with improved outcomes to ADT plus ARAT (but not ADT plus docetaxel) in patients with dn-mCSPC. This may serve as a predictive biomarker to guide treatment selection for patients with mCSPC.

1413P Tumor transcriptomic profiling of patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) who do not achieve optimal PSA response to intensified androgen deprivation therapy (ADT-I)

Pts with mCSPC undergoing ADT-I and achieving a PSA nadir ≤0.2 ng/mL (PSA-L) any time after start of therapy was associated with improved overall survival (OS) versus those with a PSA nadir >0.2 ng/mL (PSA-H) (HR: 0.17, P<0.0001) (Chi AUA 2021, abstract 1281). We hypothesized that tumor gene expression profiling in PSA-H would be distinct from PSA-L. Eligibility: confirmed mCSPC on ADT-I with Androgen Receptor Axis Targeted Therapy (ARAT) and availability of RNAseq profiling performed by a CLIA-certified lab using primary prostate biopsies collected before treatment. DEseq2 package was used to identify differentially expressed genes in PSA-H versus PSA-L cohorts. Gene Set Enrichment Analysis (GSEA) was used to identify pathways enriched in each cohort. All analyses were done using R v4.2. Eligible pts= 33 (11 PSA-H, 22 PSA-L) had a median age 65 years, median baseline PSA of 23.3 ng/ml, Gleason ≥8 ∼79%, de novo 55% and high-volume disease per CHAARTED criteria ∼52%. Pts with PSA-H had downregulation of the androgen response, estrogen response, and TNF-α signaling pathway, and upregulation of the interferon-alpha and coagulation pathway (Table).Table: 1413PGSE Scores contrast PSA-H versus PSA-LPathwayNormalized enrichment score (NES)P-valueQ-valuesTNFA_Signaling via_NFKB-2.04632<<<0.001<<<0.001Androgen response-1.67726<0.0010.005Estrogen response late-1.64446<<0.0010.001Coagulation1.5609930.0010.005Interferon-alpha response1.890529<<0.0010.001Positive NES = upregulation in PSA-H pts, and negative NES = downregulation in PSA-H pts Open table in a new tab Positive NES = upregulation in PSA-H pts, and negative NES = downregulation in PSA-H pts mCSPC pts not achieving an optimal response to ADT-I have downregulated pre-treatment tumor AR signaling and TNF-α signaling and upregulation of inflammatory molecular pathways characterized by increased angiogenesis, adhesiveness, and invasiveness (PMIDs: 34696780, 12429291). After external validation, these data may provide upfront identification of patients who may not respond to intensified ADT, and aid with counselling, prognostication, and trial enrollment.

1380P High Sonic Hedgehog (HH) signalling activity, low androgen receptor activity and clonal evolution are associated with resistance to androgen-receptor axis inhibitors in patients with metastatic prostate cancer

The androgen-receptor pathway inhibitors (ARPI) are standard treatment of metastatic castration-resistant prostate cancer (mCRPC). However, the mechanisms of both primary and acquired resistance remain largely unknown.

Maintenance of androgen deprivation therapy or testosterone supplementation in the management of castration-resistant prostate cancer: that is the question

PurposeWhether or not androgen receptor (AR) axis could still be targetable in castration resistant prostate cancer (CRPC) patients with disease progression to next generation hormonal agents (NGHAs) is a controversial issue.ResultsSerum testosterone in CRPC patients has a positive prognostic role and increasing testosterone levels after androgen deprivation therapy (ADT) withdrawal or testosterone supplementation, as part of a bipolar androgen therapy (BAT) strategy, has been shown to potentially restore sensitivity to previous lines of NGHAs.ConclusionThese data suggest that maintenance of ADT in CRPC patients receiving further lines of treatment, as recommended by current international guidelines, could be questionable. Conversely, testosterone supplementation aimed to re-sensitize CRPC to further hormonal manipulation is a strategy worth to be explored in future clinical trials.

Survival of Patients with Metastatic Prostate Cancer After Disease Progression on an Androgen Receptor Axis–Targeted Therapy Given in the Metastatic Castration-Sensitive Versus Metastatic Castration-Resistant Prostate Cancer Setting

Androgen receptor axis–targeted therapies (ARATs; androgen receptor or androgen synthesis inhibitors) have been approved for the treatment of patients with metastatic castration-sensitive and castration-resistant prostate cancer (mCSPC and mCRPC) on the basis of improved overall survival (OS) in randomized clinical trials. However, it is not clear whether the OS for patients after progression on first-line ARAT differs if the first ARAT was administered in the mCSPC versus mCRPC setting and what its estimates are. We assessed the OS after disease progression on ARAT given as first-line therapy in mCSPC versus mCRPC. Patient-level data were collected retrospectively, and only those treated with first-line ARAT for mCSPC or mCRPC were included. For patients receiving ARAT in the mCRPC setting, no prior ARAT was allowed in the mCSPC setting. The median OS and hazard ratio (HR) were determined via Kaplan-Meier analysis from the time of progression on ARAT. Of 382 patients treated with first-line ARAT, 172 (44 mCSPC and 128 mCRPC) had experienced disease progression and were included in the analysis. Median OS was similar in the mCSPC (23 mo) and mCRPC (17 mo) settings (HR 0.99, 95% confidence interval 0.62–1.56; p = 0.95). A total of 138 patients received subsequent systemic therapy after progression. Our results suggest that median OS is similar after progression on one ARAT, whether given in the first-line mCSPC or first-line mCRPC setting, and is estimated to be <2 yr. These data have implications for patient prognostication and the design of clinical trials in the post-ARAT setting for further drug development. Patient summaryWe investigated whether the survival benefit differs between metastatic castration-sensitive and castration-resistant prostate cancer for patients who have already experienced cancer progression after first-line treatment with one drug targeting the androgen receptor pathway (called ARAT). We found that the median survival benefit was less than 2 years and was similar for the two groups.

P35-7 Analysis of BRCA1/2 mutations for metastatic castration resistant prostate cancer in clinical practice

Olaparib can be used for patients with metastatic castration resistant prostate cancer (mCRPC) who have altered BRCA1 or BRCA2. For the analysis of gene alterations, Foundation One CDx and BRACAnalysis are available in Japan. All patients with mCRPC who become resistant to 1st line androgen receptor axis targeted therapy are advised to receive the analysis. However, it is still unclear how these two analyses are recommended. In this study, we report the current status of BRCA1/2 analysis and examined the optimal strategy for detecting BRCA1/2 alterations in patients with mCRPC.

MO20-3 Caffeic acid phenethyl ester suppresses drug resistance of enzalutamide or abiraterone in prostate cancer cells

Enzalutamide (ENZ) and Abiraterone acetate (AA) are drugs targeting androgen receptor axis for treatment of metastatic castration-resistant prostate cancer (mCRPC). However, a majority of patients receiving these treatments will eventually acquire drug resistance, which is caused by multiple mechanisms including the activation of AR splice variant 7 (AR-V7). We determined if caffeic acid phenethyl ester (CAPE) can suppress the signaling of AR-V7 and tumor growth of ENZ-resistant or AA-resistant mCRPC cells.

Is docetaxel-free interval a predictive factor for castration-resistant prostate cancer?

ObjectiveProstate cancer (PCa) is the second most common solid tumor in men and the fifth leading cause of cancer-related death. In advanced stage, palliative treatments are used instead of curative therapies. Therefore, finding predictive indicators seems crucial. Patients with castration-resistant prostate cancer (CRPC) that received Dx chemotherapy have been retrospectively reviewed. The aim of this study was to investigate whether docetaxel (Dx)-free interval could have a predictive value for PCa and influence other sequential therapies. Material and methodsThis clinical trial study was performed on 104 patients at Medeniyet University Oncology Clinic in 2018−2020. All CRPC patients had metastases, received Dx as first-line treatment and underwent androgen receptor axis targeted (ARAT) therapy after disease progression. We analyzed patients’ progression time after Dx therapy and the effects on sequential treatment. ResultsAfter Dx therapy, all patients received ARAT (abiraterone (ABI) n: 49 (47.1%) and enzalutamide (ENZ) n: 54 (51.9%)) as a second-line treatment, except for one patient who received cabazitaxel. There was a statistically significant relationship between the Dx-free interval and duration of response to ARAT (p<0.001). The response time of ARAT treatment was <10.5 months in all patients whose Dx-free interval period was <9 months. ConclusionsOur findings support the theory that Dx-free interval can be a predictive factor for CRPC. CRPC disease can be classified as Dx-sensitive disease or Dx-resistance disease, based on the Dx-free interval. Decision on subsequent treatments could be made considering this information.