Androgen Receptor Axis-targeted Research Articles

Connecting Gene Variation to Treatment Outcomes in Metastatic Castration-Resistant Prostate Adenocarcinoma: Insights into Second-Generation Androgen Receptor Axis-Targeted Therapies.

Prostate cancer (PC) is one of the most commonly diagnosed tumours among men. Second-generation androgen receptor axis-targeted (ARAT) agents, namely abiraterone acetate (AbA) and enzalutamide (ENZ), are currently used in the management of metastatic castration-resistant PC (mCRPC). However, the treatment is challenging due to the lack of prognostic biomarkers. Meanwhile, single-nucleotide polymorphisms (SNPs) have emerged as potential prognostic indicators of mCRPC. Thus, this study evaluated the impact of relevant SNPs on the treatment outcomes of 123 mCRPC patients enrolled in a hospital-based cohort study. The CYP17A1 rs2486758 C allele was associated with a 50% reduction in the risk of developing castration resistance (hazard ratio (HR) = 0.55; p = 0.003). Among patients without metastasis at tumour diagnosis and under AbA, a marginal association between YBX1 rs10493112 and progression-free survival was detected (log-rank test, p = 0.056). In the same subgroup, significant associations of HSD3B1 rs1047303 (CC/CA vs. AA; HR = 3.41; p = 0.025), YBX1 rs12030724 (AT vs. AA; HR = 3.54; p = 0.039) and YBX1 rs10493112 (log-rank test, p = 0.041; CC vs. AA/AC; HR = 3.22; p = 0.053) with overall survival were also observed, which were confirmed by multivariate Cox analyses. Although validation with larger cohorts is required, these findings suggest that SNPs could enhance the prognosis assessment of mCRPC patients, leading to a more personalised treatment.

Abstract 7629: Association between COMT expression and therapeutic efficacy of androgen receptor-axis targeted in prostate cancer

Abstract Background: The enzyme of catechol-O-methyltransferase (COMT) inhibits the proliferation of prostate cancer (PCa). There has been no obvious biomarker that contributes to the selection of a therapeutic agent among new-generation androgen receptor-axis targeted (ARAT) therapy, such as abiraterone (ABI) or enzalutamide (ENZ). We aimed to assess the possibility of using COMT expression as a biomarker for PCa progression and the criteria for selecting ABI or ENZ. Methods: We retrospectively evaluated 60 patients with PCa treated with ABI or ENZ via needle biopsy or radical prostatectomy. Immunostaining of COMT was performed using formalin-fixed, paraffin-embedded blocks obtained from the initial prostate biopsy for diagnosis or prostatectomy. Immunostaining evaluations were scored by immunostaining intensity (0-3) and staining area (0-3), and the total score ≥4 was defined as "high expression" and the total score <4 was defined as "low expression.” The associations between COMT expression levels and clinical outcomes, including the duration of ENZ or ABI response, were also assessed. Results: Of the 60 cases, nine (15%) showed low expression of COMT. Overall survival was significantly shorter in patients with lower COMT expression (hazard ratio [HR] = 0.24, 95% confidence interval [CI] 0.07-0.83, P= 0.024). When ENZ was administered as the first ARAT, progression-free survival (PFS) was significantly different between patients with COMT expression scores <4 and ≥4 (median 5.9 and 23.3 months, respectively). However, when ABI was administered as the first ARAT, there was no significant difference in the PFS of ARAT between COMT expression scores <4 and ≥4. Conclusion: Patients with lower COMT expression have a significantly poorer prognosis for PCa. In addition, PFS after ENZ administration, as the first ARAT, correlated with COMT expression levels. To our knowledge, this is the first report of an association between COMT expression and the duration of ARAT. Citation Format: Shigekatsu Maekawa, Ryo Takata, Ei Shiomi, Daiki Ikarashi, Tomohiko Matsuura, Renpei Kato, Mitsugu Kanehira, Jun Sugimura, Wataru Obara. Association between COMT expression and therapeutic efficacy of androgen receptor-axis targeted in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7629.

Cardiovascular Toxicity Associated With Androgen Receptor Axis-Targeted Agents in Patients With Prostate Cancer: A Meta-analysis of Randomized Controlled Trials

IntroductionSecond-generation androgen receptor axis-targeting (ARAT) agents have become a standard treatment for patients with advanced prostate cancer (PC), however much remains unknown about the potential cardiovascular toxicities. Patients and MethodsWe performed a systematic search of PubMed, Embase, Web of Science, and Cochrane library for randomized controlled trials of patients receiving ARAT agents for PC from inception to March 2023. The odds ratios (ORs) of all-grade and high-grade cardiovascular adverse events (CVAEs) for patients treated with and without ARAT agents were pooled for meta-analysis. Subgroup analyses based on PC type and treatment regimen were conducted. ResultsA total of 15 double-blind placebo-controlled phase 3 trials comprising 15,842 patients were included. In addition to hot flush and hypertension of any degree of severity, inclusion of ARAT agents was associated with a significantly higher risk of acute myocardial infarction (OR: 1.96, 95% CI: 1.05-3.68, P = .04), myocardial infarction (OR: 2.44, 95% CI: 1.27-4.66, P = .007) and angina pectoris (OR: 2.00, 95% CI: 1.00-4.02, P = .05). With regard to individual ARAT agents, enzalutamide was associated with a significantly higher risk of acute myocardial infarction (OR: 3.11, 95% CI: 1.17-8.28, P = .02), coronary artery disease (OR: 8.33, 95% CI: 1.54-44.95, P = .01), and high-grade hypertension (OR: 4.94, 95% CI: 1.11-22.06, P = .04), while abiraterone and apalutamide were associated with a significantly higher risk of angina pectoris (OR: 5.48, 95% CI: 1.23-24.33, P = .03) and myocardial infarction (OR: 7.00, 95% CI: 1.60-30.62, P = .01), respectively. ConclusionThe inclusion of ARAT agents was associated with a significantly higher risk of several CVAEs. Clinicians should remain vigilant, both in pre-treatment screening and monitoring for clinical symptoms and signs, when considering ARAT agent particularly for patients with pre-existing risk factors.

Trends in local therapy utilization and survival of patients with de-novo metastatic prostate cancer treated by hormone therapy with or without systemic therapy intensification with chemotherapy.

90 Background: Guideline-recommended treatment for de novo metastatic prostate cancer (mPCa) includes hormone therapy (HT) and androgen receptor axis-targeted (ARAT) therapy with or without chemotherapy. While retrospective data have implicated the potential survival benefit of treating the primary tumor with radical prostatectomy, prospective clinical trials have demonstrated a benefit of definitive local radiotherapy in the context of low-volume mPCa. Given this emerging data, we sought to assess population-based treatment trends in the utilization of local therapy (LT) for mPCa and the association between the receipt of contemporary LT and overall survival in patients with mPCa. Methods: Using the National Cancer Database from 2004 to 2020, we identified men aged 18-90+ who were diagnosed with de-novo mPCa. To mitigate potential confounding, propensity score matching (PSM) was employed to balance patient characteristics between the two groups, including metastatic volume. High-volume mPCa was defined as the presence of any visceral metastases or bone metastases with at least 1 distant invasion. Cox proportional hazard models with clustering were utilized to estimate hazard ratios (HRs) for the risk of all-cause mortality to account for the inherent correlation created by PSM. Results: Among 30,713 patients, 2,569 (8.36%) received both LT and systemic therapy, while 26,038 (84.78%) received systemic therapy alone. Of these, 5,453 (19.06%) had high-volume PCa, and 23,154 (80.94%) had low-volume PCa. No upward trend in LT utilization was observed from 2004 to 2020, with fluctuations in rates observed over time. After PSM, LT was associated with lower all-cause mortality risk (HR=0.87, 95% CI: 0.81-0.93, p<0.001). In patients without chemotherapy intensification, LT was correlated with an 18% lower all-cause mortality risk (HR=0.82, 95% CI: 0.26-0.70, p<0.001), specifically, radical prostatectomy with a 72% lower risk (HR=0.28, 95% CI: 0.20-0.38, p<0.001). For patients receiving chemotherapy intensification, definitive radiotherapy was related to an 18% increased all-cause mortality risk (HR=1.18, 95% CI: 1.01-1.39, p=0.04), while radical prostatectomy showed a 54% decreased risk (HR=0.46, 95% CI: 0.29-0.74, p=0.001). Conclusions: We did not observe an increasing population-based utilization of LT. This contemporary analysis showed that LT was associated with a 13% reduction in the risk of all-cause mortality. Importantly, this observation was also seen in patients receiving systemic therapy intensification with chemotherapy. The retrospective nature of this data, as well as residual confounding despite PSM (including metastatic volume), remain important limitations in this study. Ongoing Phase 3 trials (S1802) will be critical for informing future widespread uptake of LT in mPCa.

Survival outcome of chemotherapy-naïve castration-resistant prostate cancer treated with new-generation androgen receptor axis-targeted agents in real-world analysis.

The androgen receptor axis-targeted (ARAT) agents abiraterone and enzalutamide have been introduced against castration-resistant prostate cancer (CRPC). However, determining which of these agents should be used first is a clinical challenge. Therefore, in this study, we compared the efficacy of first-line abiraterone and enzalutamide treatments in chemotherapy-naïve patients with CRPC. A total of 242 chemotherapy-naïve CRPC cases treated with first-line ARAT were analyzed. Outcome measures were PSA response, PSA progression-free survival (PSA-PFS), time to treatment failure (TTF), cancer specific survival (CSS), and overall survival (OS). Abiraterone (A) and enzalutamide (E) were administered to 61 and 181 patients, respectively. The median PSA response rate (- 65.4% [A] and - 78.8% [E], p = 0.0341), PSA decline ≥ 30% (55.7% [A] and 72.9% [E], p = 0.0183), PSA-PFS (median 4months [A] and 8months [E], p = 0.0126), TTF (median 6months [A] and 14months [E], p < 0.0001), CSS (median 45months [A] and not reached [E], p < 0.0001), and OS (median 28months [A] and 80months [E], p < 0.001) were significantly better in the enzalutamide group. In the multivariate analyses for CSS and OS, ALP (p = 0.00376) and ARAT (p < 0.001) (CSS), evidence of metastasis (p = 0.0467), Hb (p = 0.00205), and ARAT (p = 0.00514) (OS) were significant factors, respectively. This study showed that PSA response, PSA-PFS, TTF, CSS, and OS were better with first-line enzalutamide administration. Direct inhibition of androgen receptor signaling by enzalutamide is associated with better clinical outcomes.

Understanding treatment toxicity patterns through remote symptom monitoring and examining the effect of frailty in older men with metastatic prostate cancer.

12054 Background: Advancements in metastatic prostate cancer (mPC) treatments have increased survival, but using multiple lines of therapy has increased the prevalence and severity of toxicities. Older men and those living with frailty experience higher symptom burden associated with treatment. Although toxicities have been described in previous trials, much of the focus has been on pain and fatigue among fit and younger men, and only a few trials have examined the effects of frailty on toxicity. Thus, the aims of this study were to (1) understand the prevalence, duration, and changes in symptom severity among older men receiving mPC treatments; and (2) examine differences among frail and non-frail men. Methods: Men aged 65+ with mPC starting chemotherapy (chemo), androgen receptor-axis-targeted (ARAT) therapies, or radium-223 (Rad223) from two academic Canadian cancer centres were enrolled in a prospective cohort study. Participants self-reported symptoms daily using the Edmonton Symptom Assessment Scale (ESAS) for the first treatment cycle via internet or telephone. Frailty status was determined using the Vulnerable Elders Survey (VES-13). Study outcomes were the development of moderate-to-severe symptoms (ESAS≥4), their duration, and the proportion of participants who had improvements in symptom severity (ESAS&lt;4) after reporting moderate-to-severe symptoms at baseline. Outcomes were determined using descriptive statistics. Associations between symptom prevalence, duration, and frailty were assessed using t-tests and chi-square tests. Results: 90 men (mean age=77 +/- 6.1 years, 58% frail (VES-13≥3)) starting chemo (n=34), an ARAT (n=43), or Rad223 (n=13) were included. The most common moderate-to-severe symptoms across cohorts were fatigue (46.8%), insomnia (42.9%), poor wellbeing (41.2%), decreased appetite (37.1%), and pain (35.9%). These symptoms were numerically higher in frail men, but differences between frail and non-frail were only statistically significant for poor wellbeing (62.5% in frail vs. 31.4% in non-frail, p=0.039). On average, poor wellbeing lasted 6.5 days (SD=7.6) days, decreased appetite lasted 5.5 days (SD=4.9), fatigue lasted 5.1 days (SD=7.3), pain lasted 4.7 days (SD=5.6), and insomnia lasted 4.6 days (SD=6.2) across cohorts. Fatigue and pain lasted numerically longer in frail men whereas insomnia, poor wellbeing, and decreased appetite lasted numerically longer in non-frail men, but these differences were not statistically significant. Among participants who reported moderate-to-severe symptoms at baseline, 15.4%, 10.7%, 7.7%, 5.3% and 3.6% had improvements in pain, appetite, wellbeing, insomnia, and fatigue, respectively. Conclusions: Understanding temporal patterns of symptoms and the impact of frailty in older men receiving mPC treatments may help inform supportive care approaches. Clinical trial information: NCT04193657 .

A comparison of the sarcopenic effect of androgen receptor-axis-targeted agents vs. androgen deprivation alone in patients with metastatic prostate cancer.

Androgen deprivation therapy (ADT) with androgen receptor axis-targeted (ARAT) therapy is the standard of care provided to patients with metastatic prostate cancer. While effective, it results in sequelae, such as loss of skeletal muscle mass. In this study, we compared the sarcopenic effects of abiraterone and enzalutamide, two ARATs used to treat metastatic prostate cancer. Our cohort was comprised of 55 patients diagnosed with metastatic hormonenaive prostate cancer from 2014-2019. Patients were divided into three treatment groups: gonadotropin-releasing hormone (GnRH ) agonist alone; GnRH agonist combined with abiraterone acetate; and GnRH agonist combined with enzalutamide. We then compared axial computed tomographic (CT) scans at the L3 level before and after the initiation of hormone therapy for each patient. A skeletal muscle index (SMI) was calculated for each patient, and alongside clinical data, was compared between the three groups. One-way analysis of variance (ANOVA) and Fisher's exact test were used to compare means and proportions, respectively. Baseline clinical characteristics were not significantly different between the three groups. The percent SMI change and number of newly sarcopenic patients were not found to be significantly different between the groups. The only variable that was significantly different across the three groups was time between CT scans. Although we found no significant difference in the sarcopenic effects of GnRH alone, GnRH with abiraterone, or GnRH with enzalutamide in our cohort of 55 hormone-naive metastatic prostate cancer patients, overall decreases in muscle mass were observed for all three groups. This highlights the importance of muscle-retaining strategies for patients undergoing ADT for metastatic prostate cancer, regardless of therapeutic regimen.

Plasmatic MicroRNAs and Treatment Outcomes of Patients with Metastatic Castration-Resistant Prostate Cancer: A Hospital-Based Cohort Study and In Silico Analysis.

Prostate cancer (PCa) is one of the most common malignancies among men worldwide. Inevitably, all advanced PCa patients develop metastatic castration-resistant prostate cancer (mCRPC), an aggressive phase of the disease. Treating mCRPC is challenging, and prognostic tools are needed for disease management. MicroRNA (miRNA) deregulation has been reported in PCa, constituting potential non-invasive prognostic biomarkers. As such, this study aimed to evaluate the prognostic potential of nine miRNAs in the liquid biopsies (plasma) of mCRPC patients treated with second-generation androgen receptor axis-targeted (ARAT) agents, abiraterone acetate (AbA) and enzalutamide (ENZ). Low expression levels of miR-16-5p and miR-145-5p in mCRPC patients treated with AbA were significantly associated with lower progression-free survival (PFS). The two miRNAs were the only predictors of the risk of disease progression in AbA-stratified analyses. Low miR-20a-5p levels in mCRPC patients with Gleason scores of <8 were associated with worse overall survival (OS). The transcript seems to predict the risk of death regardless of the ARAT agent. According to the in silico analyses, miR-16-5p, miR-145-5p, and miR-20a-5p seem to be implicated in several processes, namely, cell cycle, proliferation, migration, survival, metabolism, and angiogenesis, suggesting an epigenetic mechanism related to treatment outcome. These miRNAs may represent attractive prognostic tools to be used in mCRPC management, as well as a step further in the identification of new potential therapeutic targets, to use in combination with ARAT for an improved treatment outcome. Despite the promising results, real-world validation is necessary.

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&lt;.0001), respectively. ARAT(DOC) significantly prolonged PFS (HR 3.15, p&lt;.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&lt;.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&lt;.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]

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.

Plasma progastrin-releasing peptide level shows different predictive profiles for treatment response by androgen receptor axis-targeted agents in patients with metastatic castration-resistant prostate cancer.

The neuroendocrine (NE) pathway cannot be ignored as a mechanism for castration-resistant prostate cancer (CRPC) progression. The neuromediator, gastrin-releasing peptide (GRP) may be involved in the aberrant activation of the normal androgen receptor (AR) and increased AR variants. This study focused on plasma levels of progastrin-releasing peptide (ProGRP) and examined the treatment outcomes with androgen receptor axis-targeted (ARAT) agents. One hundred patients with metastatic CRPC were enrolled. Enzalutamide (ENZ) or abiraterone acetate/prednisone (AA/P) were administered to 50 patients each in a nonrandomized manner as a first-line or later choice. Plasma ProGRP levels were determined using a chemiluminescent enzyme immunoassay, and data were collected prospectively. The study endpoints were prostate-specific antigen (PSA) response and survival estimates. In the ENZ series, ProGRP levels correlated with the maximum PSA change from baseline (high ProGRP: -34.5% vs. low ProGRP: -85.7% p= .033). PSA progression-free survival (PFS), radiographic/symptomatic (r/s) PFS, and overall survival (OS) in patients with high ProGRP were significantly worse than those in patients with low ProGRP (median PSA-PFS: 3.3 vs. 10.0months, p =.001, r/s PFS: 5.0 vs. 15.0months, p< 0.001, and OS 17.5 vs. 49.0months, p< .001, respectively). In addition, ProGRP showed an independent predictive value for all survival estimates in multivariate analyses. In the AA/P series, ProGRP levels did not correlate with the PSA change or predict PSA-PFS and r/s PFS, but they maintained a significant difference in OS (19.0 vs. 48.0months, p= .003). Plasma ProGRP provides a consistent predictive value for OS in metastatic CRPC patients who underwent therapy with ARAT agents. Meanwhile, ProGRP showed different predictive profiles for PSA- and r/s PFS between ENZ and AA/P. These findings clinically suggest a mechanism for CRPC progression involving the NE pathway via the GRP. The underlying mechanism of different predictive profiles by the ARAT agent should be explored in future research.

Androgen receptor axis-targeted agents are not superior to conventional hormonal therapy for treatment of metastatic prostate cancer.

The present study aimed to use real-world Japanese data to compare the treatment outcome of conventional hormonal therapy to that of using androgen receptor axis-targeted (ARAT) agents for patients with metastatic castration-resistant prostate cancer. The overall survival between the conventional hormonal therapy group and the ARAT agent therapy group was compared using a group of 75 Japanese patients who were treated for metastatic castration-resistant prostate cancer. A subgroup analysis was carried out and the risk factors that affected overall survival (OS) were determined. The median OS from the time of prostate-specific antigen recurrence was 73.1 months in the ARAT group and 45.2 months in the conventional treatment group (P=0.414). Although OS tended to be slightly longer in the ARAT group, the difference between the groups was not significant. Subgroup analysis suggested that the therapeutic outcome of using ARAT agents tended to be less beneficial in patients who were older, and in those with a higher tumor volume or low Gleason grade. In conclusion, use of ARAT agents did not impart a significant survival benefit to patients with metastatic castration-resistant prostate cancer when compared with survival rates in response to conventional therapy. However, there was some clinical benefit when ARAT agents were used after patients developed castration-resistant prostate cancer. These findings suggest that up-front therapy using ARAT agents at the time of the initial hormone therapy can impart clinical benefit in Japanese patients with metastatic prostate cancer.

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.

¿Es el intervalo libre de docetaxel un factor predictivo para el cáncer de próstata resistente a la castración?

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<.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.

Impact of Progressive Site-Directed Therapy in Oligometastatic Castration-Resistant Prostate Cancer on Subsequent Treatment Response.

Simple SummaryLocal treatment for oligometastatic hormone-naive prostate cancer has been shown to be effective in phase II trials. As for the efficacy of targeted therapy for oligometastatic castration-resistant prostate cancer, the results of the phase trial are not yet available, but the number of reports showing efficacy by retrospective analysis is increasing. Progressive site-directed therapy has been shown to delay the next intervention and prolong progression-free survival, but its impact on subsequent treatment efficacy and contribution to overall survival has not been reported. The purpose of this retrospective study is to evaluate the impact of progressive site-directed therapy for oligometastatic castration-resistant prostate cancer on the subsequent treatment outcomes. We found that progressive site-directed therapy was associated with better response to subsequent androgen receptor axis-targeted drugs and better overall survival. Progressive site-directed therapy for oligometastatic castration-resistant prostate cancer may improve subsequent oncological outcomes.The purpose of this study was to evaluate the impact of progressive site-directed therapy (PSDT) for oligometastatic castration-resistant prostate cancer (OM-CRPC) on the efficacy of subsequent androgen receptor axis-targeted (ARAT) drugs, and to demonstrate the possibility of prolonging overall survival (OS). We performed a retrospective analysis of 15 OM-CRPC patients who underwent PSDT and subsequently received first-line ARAT drugs (PSDT group) and 13 OM-CRPC patients who were treated with first-line ARAT drugs without PSDT (non-PSDT group). PSDT was performed with the intention of treating all progressing sites detected by whole-body diffusion-weighted MRI with radiotherapy. Thirteen patients (86.7%) treated with PSDT had a decrease in PSA levels, which was at least 50% in 10 (66.7%) patients. The median PSA progression-free survival (PFS) for PSDT was 7.4 months. The median PSA-PFS for ARAT was 27.2 months in patients in the PSDT group and 11.7 months in the non-PSDT group, with a significant difference between the two groups (hazard ratio [HR], 0.28; p = 0.010). The median OS was not reached in the PSDT group and was significantly longer than 44.5 months in the non-PSDT group (HR, 0.11; p = 0.014). In OM-CRPC, PSDT may improve the efficacy of subsequent ARAT and OS.

Androgen receptor axis-targeted agents for non-metastatic castration-resistant prostate cancer impact on overall survival and safety profile.

The management of non-metastatic castration-resistant prostate cancer (nmCRPC) has undergone a paradigm shift with the development of androgen receptor axis-targeted (ARAT) agents. The updated results with final overall survival (OS) data of the phase III PROSPER, SPARTAN, and ARAMIS trials have recently been reported. Therefore, we performed an updated meta-analysis and network meta-analysis to indirectly compare the efficacy and safety of currently available treatments. Multiple databases were searched for articles published before January 2021. Studies that compared OS and adverse events (AEs) in patients with nmCRPC were considered eligible. Three studies (N.=4117) met our eligibility criteria. Formal network meta-analyses were conducted. ARAT agent is associated with significantly longer OS compared to placebo (pooled hazard ratio [HR]: 0.74, 95% confidence interval [CI]: 0.65-0.83, P<0.001), with similar results shown for patients with both N1 and N0 disease (pooled HR 0.61 and pooled HR 0.76, respectively). In the network meta-analysis, apalutamide, darolutamide, and enzalutamide were more effective than placebo, with similar efficacies in terms of OS. For AEs (including any AEs, grade 3 or grade 4 AEs, grade 5 AEs, serious AEs, and AEs leading to treatment discontinuation), darolutamide was shown to be likely well tolerated. Quality of Life was preserved in treatment arms irrespective of the drug. All three ARAT agents are efficacious options for the treatment of nmCRPC, whereas darolutamide appears to have the most favorable tolerability profile. These findings may facilitate individualized treatment strategies and inform future direct comparative trials.

Metformin and Androgen Receptor-Axis-Targeted (ARAT) Agents Induce Two PARP-1-Dependent Cell Death Pathways in Androgen-Sensitive Human Prostate Cancer Cells.

Simple SummaryIn the present study, we sought to determine whether a commonly used oral drug to treat adult-onset diabetes, metformin, which has a longstanding clinical history and known safety and tolerability profile, can improve the anti-cancer effects of two well-established oral agents currently in use to treat advanced prostate cancer, abiraterone and enzalutamide. We used androgen-sensitive cell culture models of human prostate cancer to test our hypothesis. We found that metformin and the oral anti-prostate cancer agents together are more effective in inhibiting prostate cancer cell growth and inducing prostate cancer cell death than when used alone. We identified new pathways by which the enhanced anti-cancer effects occur with the combination treatments. The present work suggests that incorporating metformin with abiraterone or enzalutamide may improve treatment outcomes in hormone sensitive prostate cancer.We explored whether the anti-prostate cancer (PC) activity of the androgen receptor-axis-targeted agents (ARATs) abiraterone and enzalutamide is enhanced by metformin. Using complementary biological and molecular approaches, we determined the associated underlying mechanisms in pre-clinical androgen-sensitive PC models. ARATs increased androgren receptors (ARs) in LNCaP and AR/ARv7 (AR variant) in VCaP cells, inhibited cell proliferation in both, and induced poly(ADP-ribose) polymerase-1 (PARP-1) cleavage and death in VCaP but not LNCaP cells. Metformin decreased AR and ARv7 expression and induced cleaved PARP-1-associated death in both cell lines. Metformin with abiraterone or enzalutamide decreased AR and ARv7 expression showed greater inhibition of cell proliferation and greater induction of cell death than single agent treatments. Combination treatments led to increased cleaved PARP-1 and enhanced PARP-1 activity manifested by increases in poly(ADP-ribose) (PAR) and nuclear accumulation of apoptosis inducing factor (AIF). Enhanced annexin V staining occurred in LNCaP cells only with metformin/ARAT combinations, but no caspase 3 recruitment occurred in either cell line. Finally, metformin and metformin/ARAT combinations increased lysosomal permeability resulting in cathepsin G-mediated PARP-1 cleavage and cell death. In conclusion, metformin enhances the efficacy of abiraterone and enzalutamide via two PARP-1-dependent, caspase 3-independent pathways, providing a rationale to evaluate these combinations in castration-sensitive PC.

Chimeric Antigen Receptor-Engineered T Cell Therapy for the Management of Patients with Metastatic Prostate Cancer: A Comprehensive Review.

Prostate cancer (PCa) has a vast clinical spectrum from the hormone-sensitive setting to castration-resistant metastatic disease. Thus, chemotherapy regimens and the administration of androgen receptor axis-targeted (ARAT) agents for advanced PCa have shown limited therapeutic efficacy. Scientific advances in the field of molecular medicine and technological developments over the last decade have paved the path for immunotherapy to become an essential clinical modality for the treatment of patients with metastatic PCa. However, several immunotherapeutic agents have shown poor outcomes in patients with advanced disease, possibly due to the low PCa mutational burden. Adoptive cellular approaches utilizing chimeric antigen receptor T cells (CAR-T) targeting cancer-specific antigens would be a solution for circumventing the immune tolerance mechanisms. The immunotherapeutic regimen of CAR-T cell therapy has shown potential in the eradication of hematologic malignancies, and current clinical objectives maintain the equivalent efficacy in the treatment of solid tumors, including PCa. This review will explore the current modalities of CAR-T therapy in the disease spectrum of PCa while describing key limitations of this immunotherapeutic approach and discuss future directions in the application of immunotherapy for the treatment of metastatic PCa and patients with advanced disease.

Endocrine consequences of treatment with the new androgen receptor axis-targeted agents for advanced prostate cancer.

Prostate cancer (PCa) is the commonest non-cutaneous malignancy worldwide and the second cause of cancer death among males in the USA. Approval of the new androgen receptor axis-targeted (ARAT) agents (abiraterone acetate, enzalutamide, apalutamide, and darolutamide) has altered the course of advanced PCa. We aimed to assess the endocrine and metabolic adverse events associated with treatment using ARAT compounds. We searched the PubMed, Cochrane Library, and Scopus databases from database inception to August 2020. We included randomized controlled trials reporting the endocrine and metabolic side effects of ARAT agents compared to each other or to placebo. Although metastatic PCa remains incurable, ARAT medications combined with androgen deprivation therapy improve overall metastasis-free and progression-free survival in metastatic hormone-sensitive PCa, non-metastatic castration-resistant PCa, and metastatic castration-resistant PCa patients. This benefit comes at the cost of certain endocrine and metabolic consequences. Treatment with abiraterone acetate induces mineralocorticoid excess, hypokalemia, hypertension, elevated liver function tests, insulin resistance, and hyperglycemia. Enzalutamide may induce or worsen hypertension and increase the risk of falls and fractures in elderly patients, while common endocrine adverse events of apalutamide include hypothyroidism, hypertension, and skin rash. On the other hand, darolutamide seems to have a somewhat safer endocrine and metabolic profile. Treatment of advanced PCa should be personalized, with administration of a combination of androgen deprivation therapy, ARAT agents, and chemotherapy being based on the patient's safety profile and the risk of side effects.

Corticosteroids alleviate adverse events associated with enzalutamide in patients with metastatic castration-resistant prostate cancer.

The aim of the present study was to investigate the impact of the combined use of corticosteroid on adverse events (AEs) induced by enzalutamide (Enz) in patients with metastatic castration-resistant prostate cancer (mCRPC). The cohort of the present study included 121 consecutive patients with mCRPC who sequentially received androgen receptor-axis-targeted (ARAT) agents, abiraterone acetate (AA) and Enz, in any order, without prior docetaxel therapy. Detailed assessments of AEs during treatment with Enz were conducted according to whether or not corticosteroid was administered. Of these patients, 63 and 58 received ARAT therapy with the Enz-to-AA sequence (group 1) and the AA-to-Enz sequence (group 2), respectively. No patient in group 1 received corticosteroid during treatment with Enz, while corticosteroid was continuously administered in combination with Enz to all patients in group 2 following AA failure. When ARAT therapy was initiated, no significant differences in the major baseline characteristics were observed between the two groups. During Enz therapy, there were no significant differences in the incidence of any AEs or AEs ≥ grade 3 between the two groups. However, the incidences of fatigue and appetite loss in group 1 were significantly higher when compared with those in group 2. Furthermore, the combined use of corticosteroid was revealed to be independently associated with the prevention of fatigue and appetite loss during Enz therapy. The results of the present study suggested that the combined use of corticosteroids could reduce the incidence of certain types of AE, particularly fatigue and appetite loss, in mCRPC patients treated with Enz.