Initiation Of Androgen Deprivation Therapy Research Articles

A Real World Observational Study Characterizing Patients With Advanced Prostate Cancer Treated With or Without Androgen Receptor-Pathway-Inhibitor Therapies in Alberta, Canada

BackgroundData are needed to improve the current understanding of clinical management and characteristics of patients with advanced prostate cancer (PC) treated with androgen receptor pathway inhibition (ARPI) therapy. MethodsThis retrospective cohort study using real-world, population-level data from Alberta, Canada included all individuals diagnosed in 2017-2020 with de novo metastatic castration-sensitive PC (mCSPC) or nonmetastatic castration-resistant PC (nmCRPC) who initiated androgen deprivation therapy (ADT). For mCSPC, patients were classified as ARPI-exposed if they received an ARPI within 180 days of initiating ADT, while patients with nmCRPC were classified as ARPI-exposed if they received an ARPI within 2 years of diagnosis. ResultsThis study included 976 patients with mCSPC and 233 with nmCRPC of which 33.5% and 25.3% received an ARPI, respectively. The proportion of patients with mCSPC treated with an ARPI increased considerably for patients diagnosed in 2020 compared to 2017 (56.2% vs. 6.0%). In contrast, the use of ARPI to treat nmCRPC only increased marginally from 2017 to 2019/2020 (19.7% vs. 28.9%). Patients with mHSPC who were ARPI-exposed had longer median survival than patients who were ARPI-naive (38.47 (95% CI = 32.84-NA) vs. 34.19 (95% CI = 33.33-38.83; P = .03)), with a higher proportion of patients surviving to 2-years. For nmCRPC, survival was similar between ARPI-exposed and ARPI-naive. In multivariable analyses, receiving ARPI for mCSPC was associated with younger patient age, more recent diagnoses, fewer comorbidities, a higher number of metastatic sites, referral to a medical oncologist as well as receiving surgery and radiation before ADT. Receiving ARPI for nmCRPC was associated with referral to a medical oncologist, younger age, and more recent diagnoses. ConclusionsOutcome analyses in this population suggest a continued unmet clinical need and complex clinical management pathways. Given that treatment pathways have evolved considerably, continued follow-up to understand the impact of these advancements on patient outcomes are warranted.

Population-based study of disease trajectory after radical treatment for high-risk prostate cancer.

To investigate long-term disease trajectories among men with high-risk localized or locally advanced prostate cancer (HRLPC) treated with radical radiotherapy (RT) or radical prostatectomy (RP). Men diagnosed with HRLPC in 2006-2020, who received primary RT or RP, were identified from the Prostate Cancer data Base Sweden (PCBaSe) 5.0. Follow-up ended on 30 June 2021. Treatment trajectories and risk of death from prostate cancer (PCa) or other causes were assessed by competing risk analyses using cumulative incidence for each event. In total, 8317 men received RT and 4923 men underwent RP. The median (interquartile range) follow-up was 6.2 (3.6-9.5) years. After RT, the 10-year risk of PCa-related death was 0.13 (95% confidence interval [CI] 0.12-0.14) and the risk of death from all causes was 0.32 (95% CI 0.31-0.34). After RP, the 10-year risk of PCa-related death was 0.09 (95% CI 0.08-0.10) and the risk of death from all causes was 0.19 (95% CI 0.18-0.21). The 10-year risks of androgen deprivation therapy (ADT) as secondary treatment were 0.42 (95% CI 0.41-0.44) and 0.21 (95% CI 0.20-0.23) after RT and RP, respectively. Among men who received ADT as secondary treatment, the risk of PCa-related death at 10 years after initiation of ADT was 0.33 (95% CI 030-0.36) after RT and 0.27 (95% CI 0.24-0.30) after RP. Approximately one in 10 men with HRLPC who received primary RT or RP had died from PCa 10 years after diagnosis. Approximately one in three men who received secondary ADT, an indication of PCa progression, died from PCa 10 years after the start of ADT. Early identification and aggressive treatment of men with high risk of progression after radical treatment are warranted.

Abstract CT233: Serum thymidine kinase 1 levels as a predictive marker for castration resistance in metastatic prostate cancer

Abstract Introduction Thymidine kinase 1 (TK1) is an enzyme associated with the cell division cycle; its levels increase during the S-phase of the cell cycle and decrease during the M-phase. In cancer TK1 release is increased both by increased cell proliferation and cell death. Thus, serum concentration of TK1 reflects the tumor volume, proliferation rate, and extent of cell death. Serum Thymidine Kinase 1 (sTK1) enzyme has been used as a prognostic, predictive, and monitoring biomarker in leukemia, Hodgkin's and non-Hodgkin's lymphomas. Additionally, sTK1 enzyme levels have been elevated in breast cancer and prostate cancer. This study evaluated whether sTK1 predicts the risk of castration resistance in patients with metastatic prostate cancer undergoing androgen deprivation therapy (ADT). Materials and Methods sTK1 levels was measured in men diagnosed with metastatic prostate cancer at 3 time points; before the initiation of ADT, 6 months after the start of treatment, and within 6 months before the development of castration resistance. Samples at study visits of ESTO2 trial, which compares atorvastatin to placebo in combination with ADT. The trial intervention was blinded at analysis. Cox regression modeling was used to assess whether sTK1 values predict the risk of castration resistance. sTK1 was analyzed both as continuous and categorical variable, stratified by median value 0.12 ng/ml. The time from the initiation of ADT to the formation of castration resistance, death, or a general index date (May 31, 2023) was used as the time-metric. Results The study included serum samples from 70 patients, of which 23 had developed castration resistance by May 31,2023. The median follow-up time was 13 months. The sTK1 value measured before ADT initiation did not predict the risk of castration resistance (HR 0.91, 95% CI 0.62-1.35). However, sTK1 at 6 months after the initiation of ADT or up to a maximum of 6 months before formation of castration resistance did predict the risk (HR 1.5, 95% CI 1.07-2.1 and HR 1.79, 95% CI 1.16-2.76, respectively). sTK1 predicted the risk at both measurement points also when analyzed as categorical variable. sTK1 was predictive only among men with metastatic disease; sTK1 no longer predicted the risk of castration resistance who started ADT for biochemically recurrent, non-metastatic disease. Conclusions Our findings suggest that sTK1 value can be used to predict the risk of progression to castration resistance during ADT in metastatic prostate cancer. However, these findings need validation from larger datasets. Citation Format: Aino Siltari, Paavo Raittinen, Jarno Riikonen, Juha Koskimäki, Tomi Pakarainen, Mikael Anttinen, Otto Ettala, Teuvo Tammela, Stig Linder, Teemu J. Murtola. Serum thymidine kinase 1 levels as a predictive marker for castration resistance in metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT233.

Salvage Androgen Deprivation Therapy as Potential Treatment for Recurrence after Robot-Assisted Radical Prostatectomy.

The efficacy of intermittent androgen deprivation therapy (ADT) for biochemical recurrence (BCR) after robot-assisted radical prostatectomy (RARP) is unknown, and its usefulness in Japanese practice needs to be investigated. We conducted a retrospective analysis of 85 patients who underwent RARP and were selected for intermittent ADT for postoperative recurrence at Kanazawa University Hospital between 2009 and 2019. Intermittent ADT was administered for 2 years. If prostate-specific antigen levels increased post-treatment, intermittent ADT was reinitiated. The median follow-up period was 47 months. The 73 patients had completed the initial course of ADT, and 12 were under initial ADT. The 5-year castration-resistant prostate-cancer-free survival rates, cancer-specific survival, and overall survival were 92.7%, 98.3%, and 94.7%, respectively. A subgroup analysis of 69 patients who completed intermittent ADT was conducted to evaluate the BCR rate following initial ADT. The 5-year BCR-free survival rate was 53.2%. Multivariate analysis identified testosterone ≤ 0.03 ng/mL during ADT as the sole predictor of BCR after ADT. Salvage intermittent ADT may be an effective treatment option for BCR after RARP. In addition, it would be useful to confirm strong testosterone suppression as a criterion for transition to intermittent therapy.

Salvage high-intensity focused ultrasound (S-HIFU) for recurrence after primary radiotherapy of prostate cancer

ObjectivesTo evaluate functional and oncological outcomes of salvage high-intensity focal ultrasound (S-HIFU) after external beam radiotherapy (EBRT) failure in prostate cancer (PCa) patients. MethodsThis single-center study included patients who underwent S-HIFU for local recurrence after EBRT between 2006 and 2023. Cancer-specific survival, metastasis-free survival and progression-free survival were illustrated using Kaplan–Meier curves. Disease progression was defined by one of the following criteria: increase of 2ng/mL or more above the PSA nadir, positive post-S-HIFU biopsy or initiation of androgen deprivation therapy (ADT). Multivariable Cox proportional hazards model was used to identify predictors of disease progression after S-HIFU. ResultsA total of 52 S-HIFU sessions for 48 patients were performed. Median time between EBRT and S-HIFU was 6.5 years. Median PSA before S-HIFU was 3.2ng/mL and median PSA nadir after S-HIFU was 0.58ng/mL. A total of 39 (81.3%) complications was recorded, including 3 (6.3%) high grade complications according to the Clavien-Dindo classification. After a median follow-up period of 6 years, 14 (29.2%) patients developed metastatic disease. Eighteen (37.5%) patients had no recurrence, whereas 30 (62.5%) patients received ADT for disease progression. The estimated 5-yr cancer-specific survival (CSS), metastasis-free survival (MFS) and progression-free survival rates (PFSR) were 100%, 79.9% (95% CI 67–92) and 41.2% (95% CI 74–96), respectively. The estimated 10-yr CSS, MFS and PFSR were 80% (95% CI 45–100), 50.7% (95% CI 19.4–82.1) and 14% (95% CI 10.8–45), respectively. The hazard of progression increased with the intermediate (HR 3.8; 95% CI 0.99 to 15; p=0.049) and high pre-EBRT d’Amico-s risk group (HR 4.1; 95% CI 0.98 to 16.2; p=0.050). Also, the time between EBRT and S-HIFU was significantly associated with risk of progression (HR 0.61; 95% CI 0.43 to 0.86; p=0.004). No significant difference linked to the disease progression (DP) risk was found between focal vs whole-gland treatment (p=0.70). ConclusionPhysicians should consider HIFU as a local salvage treatment after failed EBRT, thus avoiding or delaying palliative androgen deprivation therapy. Further studies are needed to improve patient selection for this therapy. Level of evidence4.

The Evaluation of Clinical and Intravoxel Incoherent Motion Parameters of Primary Lesion in Oligometastatic Prostate Cancer.

In the realm of cancer studies,the differences among the biological behavior of oligometastatic prostate cancer (OPCa), localized prostate cancer (LPCa), and widely prostate cancer (WPCa) are still unclear. The purpose of our study was to assess the clinical and intravoxel incoherent motion (IVIM) parameters of tumor burden in OPCa. In addition, the correlation between clinical and IVIM parameters and the prostate-specific antigen nadir (PSAN) and time to nadir (TTN) during initial androgen deprivation therapy (ADT) in OPCa was explored. It was found that the IVIM parameters could effectively differentiate LPCa and WPCa, as well as LPCa and OPC. Moreover, Gleason score (GS) was positively correlated with PSAN, while prostate volume was positively correlated with TTN. About 54 patients were included in this retrospective study (mean age=74±7.4 years). ADC, D, D*, and f were acquired according to the biexponential Diffusion Weighted Imaging (DWI) model. The Kruskal-Wallis test was used to test the differences in clinical and IVIM parameters among the three groups. The Receiver Operating Characteristic (ROC) curve was used to evaluate the discrimination abilities. The Area Under the Curve (AUC) was compared using the DeLong test. Furthermore, Spearman correlation analysis was performed to assess the correlation between clinical and IVIM parameters of PSAN and TTN during initial ADT with OPCa. There were significant differences among the three groups observed for age, PSA, GS, ADC, D and D* values (P&#60;0.05). Multi-parameter pairwise comparison results showed that significant differences between LPCa and WPCa were observed for the age, PSA, GS, ADC, D and D* values (P<0.05). However, D* was different between the LPCa and OPCa groups (P=0.032). GS showed a significant positive correlation with PSAN (Rho=0.594, P=0.042), and prostate volume showed a significant positive correlation with TTN (Rho=0.777, P=0.003). The IVIM parameters can effectively differentiate LPCa and WPCa, as well as LPCa and OPCa. Moreover, there was a certain trend in their distribution, which could reflect the tumor burden of PCa.

Abstract 6271: Novel insights into androgen receptor-variant 7 subnuclear localization and function in castration resistant prostate cancer

Abstract Prostate cancer (PC) stands as the most frequently diagnosed and second leading cause of cancer death among American men. PC mortality is predominantly attributed to castration-resistant prostate cancer (CRPC), often emerging within 2-3 years following the initiation of androgen deprivation therapy. This resistance primarily arises from sustained androgen receptor (AR) signaling, ultimately resulting in a compromised response to AR-directed therapies. AR splice variant expression is a key contributor to the persistent AR signaling in CRPC. AR-variant 7 (AR-V7) is the most clinically prevalent variant, expressed in about 75% of patients with CRPC and confers resistance to standard of care (SoC) treatments. AR-V7 differs from the full-length AR (AR-fl) because it lacks the ligand binding and hinge domains, rendering it resistant to SoC treatments. Currently, there are no selective inhibitors for AR-V7. Therefore, we sought to identify unique biological features of AR-V7, distinct from AR-fl, to exploit therapeutic options for targeting AR-V7. Previous studies have demonstrated high sequence homology, largely overlapping cistromes, and gene transactivation profiles between AR-V7 and AR-FL. Our published mechanistic studies revealed that AR-V7 utilizes a unique nuclear import pathway, not shared by AR-fl, allowing for constitutive import and activation of target genes in the nucleus. Herein, we report an additional novel subnuclear phenotype of AR-V7 in LNCAP95 and 22RV1 cells modeling CRPC. Staining with AR-V7- and AR-fl- specific antibodies revealed that unlike AR-fl, AR-V7 exhibited prominent nucleolar localization. To validate AR-V7 nucleolar localization, CRPC cells stained with fibrillarin (nucleolar marker), and subsequent fluorescence intensity analysis revealed that AR-V7 was predominantly localized in fibrillarin positive nucleoli, whereas AR-fl protein was solely localized in the nucleoplasm. This suggests a novel functional role of AR-V7 in the nucleus. To further confirm AR-V7 nucleolar localization, Actinomycin D (ActD) was used as a tool compound to disrupt nucleolar integrity. Treatment with ActD for 4 hours in CRPC cells significantly reduced the area of fibrillarin positive nucleoli and prompted AR-V7 re-distribution out of the nucleoli and into the nucleoplasm. Ongoing efforts to further investigate AR-V7 nucleolar function in CRPC cells include mutating the predicted nucleolar localization signal located in AR-V7 and identifying nucleolar-interacting proteins through proximity-labeling assays. In conclusion, we unveiled a novel nuclear compartmentalization of AR-V7 within the nucleolus, the primary hub for ribosomal biogenesis. These observations suggest that AR-V7 could regulate the high levels of protein synthesis occurring in CRPC cells, creating a window of a potential therapeutic opportunity for selective inhibition. Citation Format: Michelle K. Naidoo, Paraskevi Giannakakou. Novel insights into androgen receptor-variant 7 subnuclear localization and function in castration resistant 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 6271.

Abstract 7652: Plasma markers of hemostasis, fibrinolysis, and angiogenesis prior to androgen deprivation therapy (ADT) in progressive prostate cancer (PC) and associations with long-term thrombotic events and survival

Abstract Background: PC is the third most common malignancy associated with thrombosis, procoagulants may play a role in tumorigenesis and progression, and patients (pts) with PC may have activation of the hemostatic system evident in plasma. The prognostic significance of these markers and their relationship to thrombotic events and overall survival (OS) are under-explored. Methods: Patients &amp;gt;18 years were included if they had progressive PC planned to start ADT, were &amp;gt;6 months from surgery or RT, with no history of prior VTE, unexplained bleeding, current or planned anticoagulation, or an additional active malignancy. Plasma samples were obtained via peripheral venipuncture in tubes containing 3.2% sodium citrate and immediately placed on ice. Samples were analyzed for D-dimer, thrombin-antithrombin complex (TAT), IL-6, IL-8, VEGF, and tissue factor (TF) levels by ELISA. Patients had markers drawn at baseline (prior to initiation of ADT), 1 month, and 6 months after initiation. Results: 40 patients were accrued with a median age of 68 years. At baseline, 29 (73%) had presence of metastases. Baseline median PSA was 15 and median PSA doubling time was 0.32. Baseline median hemoglobin was 13.85, platelets were 218, D-dimer was 322 ng/dL, IL-6 was 0 pg/mL, IL-8 was 0 pg/mL, TAT was 3 ug/L, VEGF was 21 pg/mL, and TF was 26 pg/mL. Median follow-up was 78 months. During follow up, 35 (87.5%) had metastases. 10 (25%) had thrombotic events (6 [15%] venous, 4 [10%] arterial) at median 37 months follow up. Median baseline age of pts with subsequent thrombotic events was 74, vs 67 in those without a thrombotic event. While there was no significant difference in baseline PSA between groups with and without clotting events, pretreatment PSA doubling time was significantly lower in pts with subsequent thrombosis (0.27 vs 0.35, p=0.047). Median baseline D-dimer and TF were higher in patients with subsequent thrombosis (D-dimer: 516 vs 282, p=0.10; TF: 36 vs 24, p=0.12). In univariate analysis, baseline IL-6 and VEGF were associated with OS (IL-6: HR=1.05, 95% CI [1.01,1.09], p=0.025; VEGF: HR=1.02, 95% CI [1.00,1.03], p=0.028). When controlling for presence of metastasis, baseline TAT was associated with OS (HR=1.05, 95% CI [1.00,1.11], p=0.055). Conclusions: Plasma markers of hemostatic activation, fibrinolysis, and angiogenesis prior to initiation of ADT are associated with subsequent thrombotic events and overall survival years later. Further analysis will examine how these markers change over time with hormonal therapy. Citation Format: Jessica S. Palmer, Charlene Thomas, Nicole Jacobs, David Nanus, Scott T. Tagawa. Plasma markers of hemostasis, fibrinolysis, and angiogenesis prior to androgen deprivation therapy (ADT) in progressive prostate cancer (PC) and associations with long-term thrombotic events and survival [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 7652.

Bothersome Hot Flashes Following Neoadjuvant Androgen Deprivation Therapy and Stereotactic Body Radiotherapy for Localized Prostate Cancer.

Androgen deprivation therapy (ADT) improves local cancer control in unfavorable localized prostate cancer treated with radiotherapy. ADT is known to cause hormonally related symptoms that resolve with testosterone recovery. Hot flashes are particularly burdensome. This study sought to evaluate the timeline of hot flashes following short-course ADT and stereotactic body radiotherapy (SBRT) as well as its relationship with testosterone recovery. Institutional IRB approval was obtained for this retrospective review of prospectively collected data (IRB#: 2009-510). ADT was initiated three months prior to the start of SBRT. Hot flashes were self-reported via question 13a of the Expanded Prostate Index Composite (EPIC)-26 prior to ADT initiation, the first day of robotic SBRT, and at each follow-up (one, three, six, nine, 12, 18, 24, and 36 months). The responses were grouped into three relevant categories (no problem, very small-small problem, and moderate-big problem). Scores were transformed to a 0-100 scale with higher scores reflecting less bother. Testosterone levels were measured at each follow-up. From 2007 to 2010, 122 localized prostate cancer patients (nine low-, 64 intermediate-, and 49 high-risk according to the D'Amico classification) at a median age of 72 years (range 54.5-88.3) were treated with short course ADT (three to six months) and SBRT (35-36.25 Gy) at Georgetown University Hospital. Thirty-two percent were Black and 27% were obese. Seventy-seven percent of patients received three months of ADT. At baseline, 2% of men experienced hot flashes that were a "moderate to big problem" and that proportion peaked at the start of SBRT (45%) before returning to baseline (2%) nine months post-SBRT with a cumulative incidence of 52.4%. The median baseline EPIC-26 hot flash score of 94 declined to 50 at the start of SBRT but this returned to baseline (92) by six months post SBRT. These changes were both statistically and clinically significant (MID = 9.5083, p<0.01). Testosterone recovery (> 230 ng/dL) occurred in approximately 70% of patients by 12 months post SBRT. Resolution of hot flashes correlated with testosterone recovery. Bothersome hot flashes occur in greater than 50% of men treated with neoadjuvant ADT. Resolution of hot flashes occurs in the majority of patients within one year after treatment. Reassurance of the temporary nature of hot flashes may assist in reducing patient anxiety. Measuring testosterone levels at follow-up visits may allow for anticipatory counseling that may limit the associated bother.

Characterizing the real-world economic burden of metastatic castration-sensitive prostate cancer in the United States

Aims To describe healthcare resource utilization (HRU) and costs of patients with metastatic castration-sensitive prostate cancer (mCSPC). Methods Linked data from Flatiron Metastatic PC Core Registry and Komodo’s Healthcare Map were evaluated (01/2016-12/2021). Patients with chart-confirmed diagnoses for metastatic PC without confirmed castration resistance in Flatiron who initiated androgen deprivation therapy (ADT) monotherapy or advanced therapy for mCSPC in 2017 or later (index date) with a corresponding pharmacy or medical claim in Komodo Health were included. Advanced therapies considered were androgen-receptor signaling inhibitors, chemotherapies, estrogens, immunotherapies, poly ADP-ribose polymerase inhibitors, and radiopharmaceuticals. Patients with <12 months of continuous insurance eligibility before index were excluded. Per-patient-per-month (PPPM) all-cause and PC-related HRU and costs (medical and pharmacy; from a payer’s perspective in 2022 $USD) were described in the 12-month baseline period and follow-up period (from the index date to castration resistance, end of continuous insurance eligibility, end of data availability, or death). Results Of 871 patients included (mean age: 70.6 years), 52% initiated ADT monotherapy as their index treatment without documented advanced therapy use. During baseline, 31% of patients had a PC-related inpatient admission and 94% had a PC-related outpatient visit; mean all-cause costs were $2551 PPPM and PC-related costs were $839 PPPM with $787 PPPM attributable to medical costs. Patients had a mean follow-up of 15 months, during which 38% had a PC-related inpatient admission and 98% had a PC-related outpatient visit; mean all-cause costs were $5950 PPPM with PC-related total costs of $4363 PPPM, including medical costs of $2012 PPPM. Limitations All analyses were descriptive; statistical testing was not performed. Treatment effectiveness and clinical outcomes were not assessed. Conclusion This real-world study demonstrated a significant economic burden in mCSPC patients, and a propensity to use ADT monotherapy in clinical practice despite the availability and guideline recommendations of advanced life-prolonging therapies.

Lower baseline testosterone level is related to earlier development of castration resistance in metastatic prostate cancer: a multi-center cohort study.

In the era of concurrent combination therapy in metastatic hormone sensitive prostate cancer, the impact of the testosterone level before initiating androgen deprivation therapy on treatment outcome is still uncertain. We aimed to investigate its effect on time-to-castration-resistance in a metastatic hormone sensitive prostate cancer cohort. This is a multi-center retrospective study of 5 databases from China, Japan, Austria and Spain including 258 metastatic hormone sensitive prostate cancer patients with androgen deprivation therapy initiated between 2002 and 2021. Baseline testosterone was divided into high and low groups using 12 nmol/L as cutoff level. Primary outcome was time-to-castration-resistance. Secondary outcomes were survival functions. Kaplan-Meier method was employed to evaluate the correlation between baseline testosterone and time-to-castration-resistance. Subgroup analysis was performed to elucidate the effect of upfront combination-therapy and metastatic volume. Median age was 72 years. Median follow-up time was 31 months. Median pre-treatment prostate-specific-antigen level was 161 ng/mL. Majority of case were graded as International-Society-of-Urological-Pathology grade 5 (63.6%). 57.8% patients had high volume disease and 69.0% received upfront combination treatment. 44.6% of the cohort developed castration-resistance. The low testosterone group demonstrated shorter mean-time-to-castration-resistance (19.0 vs 22.4 months, p=0.031). The variance was more significant in patients without combination therapy (13.2 vs 26.3 months, p=0.015). Cancer-specific and overall survival were inferior in the low baseline testosterone level group without receiving combination therapy (p=0.001). Lower pre-treatment testosterone level is correlated to shorter time-to-castration resistance and worse survival in metastatic prostate cancer patients without upfront combination therapy. Those with low baseline testosterone should be encouraged to adopt combination therapy to delay progression.

Real-world analyses of mortality risk after androgen deprivation therapy initiation in Black vs. White patients with prostate cancer.

84 Background: 2 studies found significantly longer overall survival in Black vs. White patients with metastatic castration-resistant prostate cancer (PCa): a 2019 meta-analysis of 9 phase III trials and a 2020 registry study. Our real-world data study compared all-cause mortality risk for Black vs. White PCa patients. Compared to the prior studies, our study encompasses a broader scope and is not exclusive to men with castration-resistant PCa. Methods: Data were collected from the Decision Resources Group Real World Evidence repository, which links medical and prescription claims, and US Electronic Healthcare Records. The analysis set included PCa patients who received ≥1 androgen deprivation therapy (ADT) injection between 1991-2020. Cox regression was used to compare all-cause mortality rates between White and Black patients. Multivariable regression model accounted for the following variables: baseline metastasis, BMI, oncology vs. urology setting, antagonist vs. agonist, personal major adverse cardiovascular event (MACE) history, tobacco history, baseline PSA (&gt;4 vs. ≤4 ng/mL), race (White vs. Black), statin use, increasing age per year, ethnicity (non-Hispanic vs. Hispanic), increasing ADT exposure per year, diabetes, hypertension, and family MACE history. Results: 44,439 patients were included for the all-patient analyses. 34,762 patients were included in the Black vs White analyses: 5,817 and 28,945 were Black and White, respectively. Overall, mortality risk was 2.6% and 17% at 1 and 4 years after ADT initiation, respectively. Mortality risk after ADT initiation was 1.6% and 2.6% at 1 year and 11.7% and 18.1% at 4 years for Black and White patients, respectively. Both unadjusted (HR=1.66, 95% CI 1.53-1.80, p&lt;0.05) and adjusted (HR=1.24, 95% CI 1.01-1.52, p&lt;0.05) mortality risks were higher for White vs. Black patients. Conclusions: All-cause mortality incidence was higher in White vs. Black patients. Adding to the body of evidence, our research also reveals that Black race is associated with a protective effect on survival for all-cause mortality in men undergoing ADT. Potential hypotheses for higher mortality in White vs. Black patients include survival bias to MACE (i.e., Black patients may have died from PCa before having MACE), survival bias to be diagnosed with PCa (i.e., Black patients may have higher rate of CV death and kidney failure prior to PCa diagnosis), and protective effects of higher BMI in Black patients against cancer cachexia. The large size (~45,000 patients from a database with &gt;300 million patients), long follow-up (10 years for some patients), recent clinical experience (99% from 2010-2020), and diversity of the dataset give weight to the results being an accurate representation of current clinical experience. Future studies should confirm our findings that White PCa patients have higher mortality risk and investigate the above hypotheses.

Clinical and patient factors associated with treatment intensification for metastatic castration-sensitive prostate cancer.

63 Background: Intensified therapies convey a survival advantage over androgen deprivation therapy (ADT) alone in metastatic hormone sensitive prostate cancer (mHSPC). We sought to identify area- and patient-level factors that are associated with intensification of therapy among mHSPC patients treated in US health systems. Methods: Electronic health records from OPTUM were used to identify patients aged ≥18 with mHSPC who received ADT between 2020 and 2022. Treatment intensification was defined as receiving one of the following within 90 days of initiation of ADT: apalutamide, enzalutamide, abiraterone +/- prednisone +/- docetaxel, darolutamide +/- docetaxel, docetaxel +/- other systemic therapy, and external beam radiation therapy (EBRT). Multivariable logistic regression was used to determine factors associated with intensification. We used Chi-squared tests to select the model with the best statistical fit. Results: We identified 1,123 patients with mHSPC who received ≥1 ADT in the post-index period with mean age of 71.2 (9.5), 73% Caucasian, 18% African American, and 2% Asian. Overall, 640 (57%) patients received treatment intensification within 90 days of ADT initiation. The proportion of patients receiving intensification increased from 53% to 63% between 2020 and 2022. The most common intensification treatments were abiraterone acetate (46%) and enzalutamide (38%). The median time to first treatment after metastasis was 15 days for receiving intensified therapy and 34 days for non-intensified therapy. In multivariable logistic regression, younger age, presence of bone/bone marrow metastasis at baseline, region (Northeast and West), and lower modified Charlson Comorbidity Index (CCI) score (excluding cancer) were significantly associated with receiving intensified therapy (Table). PSA was not included in models due to substantial missingness (40%). Conclusions: Just over half of eligible patients received treatment intensification following ADT. There are also significant disparities in treatment by age, region, and site of metastases. Future studies examining physician and patient preferences for intensification, as well as possible misperceptions and biases, would provide evidence to address undertreatment in this setting. [Table: see text]

Racial and ethnic differences in the receipt of metabolic syndrome risk factor screening and treatment among individuals with prostate cancer treated with androgen deprivation therapy.

29 Background: Racial and ethnic health disparities in prostate cancer screening, and treatment constitute the largest of all cancer disparities. Androgen deprivation therapy (ADT) is widely used in the treatment of localized or metastatic prostate cancer. However, ADT is associated with toxic cardiovascular and metabolic adverse events that may occur as early as 6 months of therapy initiation. This study aimed to assess racial/ethnic differences and longitudinal changes in metabolic syndrome risk factor (MSRF) screening/treatment among patients with prostate cancer treated with ADT at a university-affiliated comprehensive cancer center in the southwestern U.S. between 2010-2021. We also aimed to identify patient and healthcare provider factors that influence MSRF screening among study sample. Methods: A retrospective observational cohort study of 803 patients treated with ADT for at least six months at the cancer center was conducted. Patients were followed three months pre- to 12 months post-ADT initiation to evaluate MSRF screening/treatment. Determination of MSRF screening was based on primary care provider referral for MSRF screening/treatment or receipt of blood glucose, lipid profile, and blood pressure screening within six months post-treatment with ADT. Patients were considered treated for MSRF if they were started or continued therapy (within six months of ADT initiation) with science advisory guideline recommended treatments. Results: Guideline-concordant MSRF screening rate approached 23.5%; MSRF treatment rate was 76.9%. A higher treatment rate in MSRF treatment was found for NHW compared to Hispanic men ( p=0.02). We found a significant difference in the proportion of patients receiving MSRF screening across all racial/ethnic groups ( p=0.03). MSRF screening rates from 13.9% to 35.6% were observed over the 10-year data collection period. Patients with dyslipidemia at baseline had higher odds of having MSRF screening than patients without dyslipidemia ( p&lt;0.0001). Oncologists with &gt;20 years of experience had higher odds of providing MSRF screening compared with &lt;10 years of experience ( p=0.006). Conclusions: Minority populations had significantly lower odds of having MSRF screening than NHW patients after adjusting for clinical and socio-economic variables. Closer clinical attention and education, as well as the development and implementation of innovative practice tools and interventions to optimize MSRF screening and treatment are warranted to mitigate the harmful adverse effects of ADT in patients with prostate cancer.

Addressing the risk and management of cardiometabolic complications in prostate cancer patients on androgen deprivation therapy and androgen receptor axis-targeted therapy: consensus statements from the Hong Kong Urological Association and the Hong Kong Society of Uro-Oncology.

Androgen deprivation therapy (ADT) is the foundational treatment for metastatic prostate cancer (PCa). Androgen receptor (AR) axis-targeted therapies are a new standard of care for advanced PCa. Although these agents have significantly improved patient survival, the suppression of testosterone is associated with an increased risk of cardiometabolic syndrome. This highlights the urgency of multidisciplinary efforts to address the cardiometabolic risk of anticancer treatment in men with PCa. Two professional organizations invited five urologists, five clinical oncologists, and two cardiologists to form a consensus panel. They reviewed the relevant literature obtained by searching PubMed for the publication period from April 2013 to April 2023, to address three discussion areas: (i) baseline assessment and screening for risk factors in PCa patients before the initiation of ADT and AR axis-targeted therapies; (ii) follow-up and management of cardiometabolic complications; and (iii) selection of ADT agents among high-risk patients. The panel convened four meetings to discuss and draft consensus statements using a modified Delphi method. Each drafted statement was anonymously voted on by every panelist. The panel reached a consensus on 18 statements based on recent evidence and expert insights. These consensus statements serve as a practical recommendation for clinicians in Hong Kong, and possibly the Asia-Pacific region, in the management of cardiometabolic toxicities of ADT or AR axis-targeted therapies in men with PCa.

Diagnosis and management of neuroendocrine prostate cancer.

Although most patients with prostate cancer (PC) respond to initial androgen deprivation therapy (ADT), castration-resistant disease invariably develops. Progression to treatment-emergent neuroendocrine PC (t-NEPC) represents a unique mechanism of resistance to androgen receptor (AR)-targeted therapy in which lineage plasticity and neuroendocrine differentiation induce a phenotypic switch from an AR-driven adenocarcinoma to an AR-independent NEPC. t-NEPC is characterized by an aggressive clinical course, increased resistance to AR-targeted therapies, and a poor overall prognosis. This review provides an overview of our current knowledge of NEPC, with a focus on the unmet needs, diagnosis, and clinical management of t-NEPC. Evidence extrapolated from the literature on small cell lung cancer or data from metastatic castration-resistant PC (mCRPC) cohorts enriched for t-NEPC suggests an increased sensitivity to platinum-based chemotherapy. However, optimal strategies for managing t-NEPC have not been established, and prospective clinical trial data are limited. Intertumoral heterogeneity within a given patient, as well as the lack of robust molecular or clinical biomarkers for early detection, often lead to delays in diagnosis and prolonged treatment with suboptimal strategies (i.e., conventional chemohormonal therapies for mCRPC), which may further contribute to poor outcomes. Recent advances in genomic and molecular classification of NEPC and the development of novel biomarkers may facilitate an early diagnosis, help to identify promising therapeutic targets, and improve the selection of patients most likely to benefit from NEPC-targeted therapies.

Health-Related Quality of Life Assessment in Prostate Cancer Patient Undergoing Androgen Deprivation Therapy: Real-World Experience in the READT Study.

To investigate the effect of androgen deprivation therapy (ADT) on health-related quality of life (HRQOL) in Asian men with all stages of prostate cancer. READT (real-life evaluation of the effect of ADT in prostate cancer patients in Asia) was a multi-center, prospective observational study involving six sites across four Asian populations. We enrolled eligible prostate cancer patients, who opted for ADT alone or in combination without prior neoadjuvant or adjuvant ADT within 12 months. The EuroQoL-5 dimensions, 5 level scale (EQ-5D-5L) utility index scores and visual analog scale (VAS) were evaluated at baseline, month 6 and month 12. A total of 504 patients were recruited into READT between September 2016 and May 2020 with 52.9% diagnosed with metastatic prostate cancer. The EQ-5D-5L was evaluable in 442/504 (87.7%) of patients. Overall baseline EQ-5D-5L utility index score was 0.924 (interquartile range [IQR] 0.876-1.000). We observed a statistically significant difference in baseline EQ-5D-5L utility index score among different populations with a median EQ-5D-5L utility index score of 1 for Taiwan &amp; Hong Kong, 0.897 for China and 0.838 for Malaysia. Similar trend was observed throughout multiple treatment time-points. Stage IV prostate cancer were significantly associated with a lower baseline EQ-5D-5L utility index score compared to stage I-III prostate cancer, producing a median disutility value of -0.080. Participants had a high median VAS (80, IQR 70-90), indicating good overall health on average during ADT initiation. The study highlights the differences in health state utility index scores among various Asian prostate cancer patients receiving ADT at real-world setting. Our findings will be informative and useful in cost-effectiveness evaluation and policy decision making.

Biochemical progression free and overall survival among Black men with stage IV prostate cancer in South Africa: Results from a prospective cohort study.

Men of African descent are disproportionately affected by prostate cancer (PCa), and many have metastatic disease at presentation. In South Africa (SA), androgen deprivation therapy (ADT) is the first-line treatment for stage IV PCa. To identify predictors of overall survival (OS) in Black South African men with stage IV PCa treated with ADT. Men diagnosed with prostate cancer (3/22/2016-10/30/2020) at Chris Hani Baragwanath Academic Hospital in Soweto, Johannesburg, were recruited for the Men of African Descent with Cancer of the Prostate study. We included men with newly diagnosed stage IV PCa treated with ADT who had a prostate-specific antigen (PSA) level drawn prior to initiation of ADT and had ≥1 PSA drawn ≥12 weeks after ADT start. We used Kaplan-Meier statistics to estimate OS and Cox regression models to identify predictors of OS. Of the 1097 men diagnosed with prostate cancer, we included 153 men with stage IV PCa who received ADT and met PSA requirements. The median age was 68.0 years (interquartile range 64-73 years). Median OS from time of ADT initiation was 3.39 years (95% confidence interval (CI): 3.14%-noncalculable), while biochemical progression-free survival was 2.36 years (95% CI: 2.03%-3.73%). Biochemical progression (HR 3.52, 95% CI: 1.85%-6.70%), PSA nadir level >4 ng/mL (HR 3.77, 95% CI: 1.86%-7.62%), alkaline phosphatase level at diagnosis >150 IU/dL (HR 3.09, 95% CI: 1.64%-5.83%), and hemoglobin at diagnosis <13.5 g/dL (HR 2.90, 95% CI: 1.28%-6.56%) were associated with worse OS. In this study, we identified factors associated with poor OS among Black South African men with stage IV PCa treated with ADT. These factors may be useful in identifying patients for upfront treatment escalation, including the use of docetaxel chemotherapy or escalation of therapy at the time of biochemical progression. In this study, we found that high alkaline phosphatase level, anemia at diagnosis, and high PSA nadir after initiation of androgen deprivation therapy are associated with worse overall survival among Black South African men treated with androgen deprivation therapy for metastatic prostate cancer.

Follicle-Stimulating Hormone Exacerbates Cardiovascular Disease in the Presence of Low or Castrate Testosterone Levels

Low testosterone (T), common in aging men, associates with cardiovascular disease. We investigated whether follicle-stimulating hormone (FSH), which is affected by T, modulates the cardiovascular effects associated withlow T or castration. FSHβ-/-:low-density lipoprotein receptor (LDLR)-/- mice, untreated or castrated (orchiectomy, gonadotropin-releasing hormone agonist or antagonist), demonstrated significantly less atherogenesis compared with similarly treated LDLR-/- mice, but not following FSH delivery. Smaller plaque burden in LDLR-/- mice receiving gonadotropin-releasing hormone antagonists vs agonists were nullified in FSHβ-/-:LDLR-/- mice. Atherosclerotic and necrotic plaque size and macrophage infiltration correlated with serum FSH/T. In patients with prostate cancer, FSH/T following androgen-deprivation therapy initiation predicted cardiovascular events. FSH facilitates cardiovascular disease when T is low or eliminated.

Auto-recruit path for bone health screening of outpatient management system for patient with prostate cancer initiating androgen deprivation therapy

Auto-recruit path for bone health screening of outpatient management system for patient with prostate cancer initiating androgen deprivation therapy