Continuous Androgen Deprivation Research Articles

Clinical efficacy of different androgen deprivation therapies for prostate cancer and evaluation based on dynamic-contrast enhanced magnetic resonance imaging

ObjectiveTo evaluate the clinical efficacy of different androgen deprivation therapies for prostate cancer (PCa) based on dynamic-contrast enhanced magnetic resonance imaging (DCE-MRI).Methods104 patients with PCa were studied, all of whom were treated with androgen deprivation therapy. The patients were divided into a continuous group (continuous androgen deprivation therapy) and an intermittent group (intermittent androgen deprivation therapy) by random number table method, 52 cases/group. The therapeutic effect and DCE-MRI indices were compared and the relationship between DCE-MRI indices and clinical efficacy and the evaluation value of therapeutic efficacy were analyzed.ResultsThe objective response rate (ORR) of the intermittent group was higher than that of the continuous group (p < 0.05), and there was no significant difference in disease control rate (DCR) between the two groups (p > 0.05). After treatment, volume transfer coefficient (Ktrans), reverse transfer constant (Kep), volume fraction (Ve), blood volume (BV), and blood flow (BF) in both groups were lowered, and those in the intermittent group were lower than the continuous group (p < 0.05). Ktrans, Kep, Ve, BF, and BV in the ORR group were lower than those in the non-ORR group (p < 0.05). Ktrans, Kep, Ve, BF, and BV were correlated with the therapeutic effect of PCa (p < 0.05). The AUC value of the combined detection of DCE-MRI indices in evaluating the therapeutic effect of PCa was greater than that of each index alone (p < 0.05).ConclusionCompared with continuous androgen deprivation therapy, intermittent androgen deprivation therapy has better clinical efficacy in the treatment of PCa, and DCE-MRI indices are related to the treatment efficacy of PCa and have an evaluation value.

Real-World Evaluation of Primary Versus Secondary Prevention of Skeletal-Related Events in Metastatic Castration-Resistant Prostate Cancer.

Anti-osteoclast treatment with denosumab or zoledronate is known to effectively reduce the need for radiotherapy to bone and other skeletal-related events (SREs) in patients with metastatic castration-resistant prostate cancer (mCRPC). In this study, we analyze primary versus secondary initiation of bone-targeting agents (BTAs) relative to first palliative bone radiotherapy in patients dying of mCRPC. Provincial administrative databases from Ontario, Canada identified patients with prostate cancer (2007-2018, n = 98646) who received continuous androgen deprivation therapy (n = 29453), died of prostate cancer (2013-2018, n = 3864), and received life-prolonging therapy for mCRPC (n = 1850). Variables were collected looking back 3 years from death. Multivariable analysis explored the relationship between clinical variables and BTAs. Of the 58% (1066/1850) patients with mCRPC who received BTA, only 289 (25.4%) started BTA prior to first palliative bone radiotherapy as primary prevention. Eight hundred and forty-eight (74.6%) patients either never received BTA before death (n = 447) or started BTA only after first bone radiotherapy (n = 401). More patients received denosumab (n = 825, 77%) than zoledronic acid (n = 241, 23%). 51.2% (582/1137) of palliative bone radiotherapy was initiated in the last 12 months of life. Factors associated with the use of BTA included elevated alkaline phosphatase (OR = 1.0, P = .023), de novo metastases (OR = 1.4, P = .005), medical oncologist involvement (OR = 2.0, P = .007), diagnosis 2012-2017 versus 2007-2011 (OR = 0.75, P = .034), and academic center (OR = 0.061, P = .007). A majority of patients with mCRPC never receive BTAs prior to first SRE, despite universal access and availability of these agents in Ontario. These results highlight an opportunity to improve outcomes by emphasizing early introduction of BTA in patients with mCRPC being started on systemic therapy.

How the Management of Biochemical Recurrence in Prostate Cancer Will Be Modified by the Concept of Anticipation and Incrementation of Therapy.

Biochemical recurrence (BCR) after primary treatments for prostate cancer (PC) is an extremely heterogeneous phase and at least a stratification into low- and high-risk cases for early progression in metastatic disease is necessary. At present, PSA-DT represents the best parameter to define low- and high-risk BCR PC, but real precision medicine is strongly suggested to define tailored management for patients with BCR. Before defining management, it is necessary to exclude the presence of low-volume metastasis associated with PSA progression using new-generation imaging, preferably with PSMA PET/CT. Low-risk BCR cases should be actively observed without early systemic therapies. Early treatment of low-risk BCR with continuous androgen deprivation therapy (ADT) can produce disadvantages such as the development of castration resistance before the appearance of metastases (non-metastatic castration-resistant PC). Patients with high-risk BCR benefit from early systemic therapy. Even with overall survival (OS) as the primary treatment endpoint, metastasis-free survival (MFS) should be used as a surrogate endpoint in clinical trials, especially in long survival stages of the disease. The EMBARK study has greatly influenced the management of high-risk BCR, by introducing the concept of anticipation and intensification through the use of androgen receptor signaling inhibitors (ARSIs) and ADT combination therapy. In high-risk (PSA-DT ≤ 9 months) BCR cases, the combination of enzalutamide with leuprolide significantly improves MFS when compared to leuprolide alone, maintaining an unchanged quality of life in the asymptomatic phase of the disease. The possibility of using ARSIs alone in this early disease setting is suggested by the EMBARK study (arm with enzalutamide alone) with less evidence than with the intensification of the combination therapy. Continued use versus discontinuation of enzalutamide plus leuprolide intensified therapy upon reaching undetectable PSA levels needs to be better defined with further analysis. Real-world analysis must verify the significant results obtained in the context of a phase 3 study.

Testosterone suppression and recovery in patients with advanced prostate cancer treated with intermittent androgen deprivation therapy (iADT) with relugolix.

70 Background: Many patients with advanced prostate cancer do not want to pursue continuous androgen deprivation therapy (cADT) because of concerns about side effects, and pursue iADT. However, even intermittent treatment with GNRH agonist therapy may not lead to rapid recovery of testosterone during the off-treatment period. In the pivotal HERO trial of relugolix (GNRH antagonist) the testosterone recovery time was in weeks [PMID 32469183]. The objective of the study was to measure the time to testosterone suppression to castrate level and time to recovery of serum testosterone to non-castrate level in real-world patients with advanced prostate cancer undergoing intermittent relugolix therapy. Methods: In this IRB-approved retrospective study, the eligibility was: patients with advanced prostate cancer undergoing iADT with relugolix. iADT with relugolix was defined as initiating relugolix at PSA ≥ 10 ng/ml and holding relugolix when PSA ≤ 4 ng/ml. The primary endpoints were: 1) time to serum castrate level of testosterone after relugolix initiation and 2) time to recovery to non-castrate level after discontinuation of relugolix. Castrate level of serum testosterone was defined as serum testosterone level ≤ 50 ng/dL. Results: Overall 25 consecutive patients with advanced prostate cancer treated with iADT with relugolix were eligible and included. The median age was 75 [range 68-88]. Patients with a Gleason score of ≥ 8 comprised 44% of the cohort. The median PSA at the start of therapy was 18.2 ng/ml [5.1 – 99.1 ng/ml]. Median time to testosterone ≤ 50 ng/dl after relugolix initiation was 1.13 months [0.67 – 2.5 months], and median time to testosterone recovery after relugolix discontinuation was 1.4 months [0.83 – 6.57 months]. The median PSA nadir achieved with relugolix was 2.02 ng/ml [0.1 – 4.8], and median time to PSA nadir was 1.35 months from initiation of therapy (0.67 – 4.8 months). Median time to PSA relapse ≥ 10 ng/dl after holding relugolix was 3.4 months (0.9 – 8.23 months). Conclusions: This is the first real-world study to show that iADT with relugolix is associated with a rapid time to testosterone suppression and recovery. These results may guide patients’ counseling, monitoring of serum testosterone and PSA levels in patients wishing to pursue iADT for advanced prostate cancer. These hypothesis-generating data need external validation.

Apalutamide (APA) plus intermittent versus continuous androgen-deprivation therapy (ADT) in participants (pts) with metastatic castration-sensitive prostate cancer (mCSPC): LIBERTAS phase 3 study design.

Apalutamide (APA) plus intermittent versus continuous androgen-deprivation therapy (ADT) in participants (pts) with metastatic castration-sensitive prostate cancer (mCSPC): LIBERTAS phase 3 study design.

Testosterone Recovery for Relugolix Versus Leuprolide in Men with Advanced Prostate Cancer: Results from the Phase 3 HERO Study

BackgroundIn the HERO study, relugolix demonstrated sustained testosterone suppression superior to that of leuprolide acetate (97% vs 89%; difference 7.9% [95% confidence interval, 4.1–12%; p < 0.001]). ObjectiveTo analyze testosterone recovery in a prespecified subset of men from the HERO study not indicated to continue androgen deprivation therapy. Design, setting, and participantsMen (N = 934) were randomized (2:1) to receive relugolix 120 mg orally daily or leuprolide acetate injections every 12 wk for 48 wk. Outcome measurements and statistical analysisTestosterone recovery was assessed in 184 men who completed 48 wk of treatment. During the 90-d recovery period, assessments included time to testosterone recovery (>280 ng/dl; ≥80% of baseline testosterone), serum levels of prostate-specific antigen and pituitary hormones, and adverse events. Results and limitationsThe cumulative incidence rate of testosterone recovery to >280 ng/dl at 90 d following drug discontinuation was significantly higher in the relugolix cohort (n = 137) than in the leuprolide acetate cohort (n = 47; 54% vs 3.2%; nominal p = 0.002). The median time to testosterone recovery was faster following relugolix treatment than with leuprolide acetate treatment (86.0 vs 112.0 d). Compared with leuprolide acetate, more men treated with relugolix achieved ≥80% of baseline testosterone levels (39% vs 2.1%). Men ≤65 yr and those with baseline testosterone greater than the median had a higher incident rate of testosterone recovery. Adverse events were generally similar between treatment groups. One limitation is the short testosterone recovery follow-up period. ConclusionsOral relugolix had faster and more complete recovery of testosterone to normal levels after treatment discontinuation than leuprolide acetate in a subset of men from the HERO study. The clinical implications of a faster testosterone recovery with relugolix may be significant for men being treated with androgen deprivation therapy and influence treatment decisions. Patient summaryThe male hormone testosterone is reduced during androgen deprivation therapy for prostate cancer. Reduced testosterone levels cause side effects, impacting patient quality of life. When treatment is stopped, the side effects lessen over time as the levels of testosterone come back to pretreatment range (testosterone recovery). In this study, we found that the time to testosterone recovery was faster with relugolix than with leuprolide acetate.

Abstract C017: Comparing prostate specific antigen dynamics between Black patients and White patients

Abstract Black men have the highest prostate cancer (PCa) mortality across all US population groups. We hypothesize that this may be the result of low participation from black men in clinical trials and socioeconomic facotrs. We use a simple mathematical model to investigate differences in PSA dynamics between black and white men undergoing androgen deprivation therapy (ADT). The model was calibrated to longitudinal PSA data from 57 PCa patients (N = 47 white, N = 10 black) receiving continuous androgen deprivation therapy (ADT). To compensate for the lack of data for black patients, propensity score matching was used to select 15 white patients that were most alike to the 10 black patients based on their Eastern Cooperative Oncology Group (ECOG) score, age, and tumor burden. Using a previously developed model of stem cell, non-stem, and prostate-specific antigen (PSA) dynamics, parameter analysis and leave-one-out process were used to determine which parameters should be uniform among all patients and which should be patient-specific to determine if any parameters showed a significant difference. Each patient’s parameter values were used to see if intermittent ADT (IADT) or adaptive ADT could extend the time to progression and narrow disparity gaps. We then sampled from the parameter distributions to create 50 black and 50 white in-silico patients to simulate continuous and intermittent ADT to further validate our results. The leave-one-out analysis found that a uniform ADT cytotoxicity resulted in the best Akaike Information Criteria score for black and white patients. A nested optimization was subsequently used to determine race-specific uniform cytotoxicity rates, while the remaining patient-specific parameters were determined. Statistical analysis found that black patients had a significantly higher stem cell self-renewal rate than the white patients. We hypothesize that this is primarily responsible for earlier progression in black patients. Simulations of continuous and intermittent ADT for real and in-silico patients showed that IADT and adaptive ADT can extend the time to progression (TTP) for both black and white patients. The TTP was extended by 50% for the black patients, and 25% for the white patients, thus the black patients had a greater benefit. However, the median TTP for black patients on IADT was less than that for white patients on continuous ADT. This suggests that further investigation of different treatments needs to be done to close disparity gaps. Our results show that stem cell self-renewal is driving differences in PSA dynamics between white and black patients. Intermittent Androgen Deprivation Therapy could potentially be a step in addressing the higher stem-cell self-renewal rate in black patients and narrowing the health disparity gap between black and white Pca patients. This valuable information can be used in the future to design race-specific treatment modalities to maximally delay time to progression. Citation Format: Alexandria Johnson, Renee Brady. Comparing prostate specific antigen dynamics between Black patients and White patients [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C017.

Intermittent Versus Continuous Androgen Deprivation Therapy for Biochemical Progression After Primary Therapy in Hormone-Sensitive Nonmetastatic Prostate Cancer: Comparative Analysis in Terms of CRPC-M0 Progression

IntroductionTo analyze whether the use of an intermittent (IAD) versus continuous (CAD) androgen deprivation therapy for the treatment of biochemical progression after primary treatments in prostate cancer can influence the development of nonmetastatic castration resistant prostate cancer (CRPC-M0). Patients170 male patients with an histologically confirmed diagnosis of PC, presenting a biochemical progression after primary treatments (82 after radical prostatectomy and 88 after external radiation therapy), nonmetastatic at imaging were considered for continuous (85 cases) or intermittent (85 cases) administration of androgen deprivation therapy. Methodswe retrospectively collect all data regarding histological diagnosis, primary treatment, imaging for M0-M1 staging, PSA at progression, time to biochemical progression from primary therapy, ADT used, IAD cycles, so to compare in 2 groups (IAD vs. CAD) time for progression from the beginning of ADT treatment and type of progression in terms of CRPC-M0 versus CRPC-M1 cases. Resultsno significant (P= .4955) difference in the whole CRPC progression was found between IAD (25.8%) and CAD (30.5%) treatment at a mean of 32.7 ± 7.02 months and 35.6 ± 13.1 months respectively (P= .0738). Mean PSA at CRPC development was significantly higher in the IAD group (5.16 ± 0.68 ng/mL) than in the CAD group (3.1 ± 0.7 ng/mL) (P < .001). In all cases, imaging to detect M status at CRPC development was PET TC scan. At univariate analysis CAD administration significantly increases the RR for CRPC-M0 progression (RR 3.48; 95%CI 1.66-7.29; P = .01) when compared to the IAD administration, and this effect at multivariate analysis remained significant and independent to the other variables (RR 2.34, 95%CI 1.52-5.33; P = .03). Conclusionsin our population with biochemical progression after primary treatment for PC, the intermittent administration of ADT significantly reduces the risk to develop CRPC-M0 disease when compared to a continuous administration of ADT, whereas no difference between the 2 strategies in terms of CRPC-M1 progression exists.

Comparison of Intermittent and Continuous Androgen Deprivation Therapy in Prostate Cancer Patients: An Up-to-Date Meta-analysis for Urologists and Medical Providers.

Androgen deprivation therapy first became the treatment of choice for advanced prostate cancer in the 1940s with Charles Huggins' discoveries. Eight decades later, androgen deprivation therapy has significantly evolved, and yet is still utilized in various ways to treat certain forms of prostate cancer. For local recurrence after failed primary treatment and for locally advanced and metastatic disease, continuous androgen deprivation therapy has been standard of treatment. However, intermittent androgen deprivation therapy has emerged as a therapeutic alternative to continuous androgen deprivation therapy. The purpose of this meta-analysis is to provide an update on mortality, specifically prostate cancer-specific and nonprostate cancer causes, in order to offer some guidance when selecting the appropriate form of systemic androgen deprivation therapy. The PubMed database was searched for prospective randomized clinical trials. Inclusion and exclusion criteria were defined. Using statistical software, we analyzed random-effects models with the assumption that the data were randomly sampled, estimated the pooled log risk ratio, assessed heterogeneity, and created funnel plots to evaluate publication bias. A total of 12 randomized clinical trials met all inclusion criteria for final analysis. There was no statistically significant difference in prostate cancer-specific mortality between intermittent androgen deprivation therapy and continuous androgen deprivation therapy (RR=1.10 [0.85-1.42]). The analysis of nonprostate cancer mortality favored intermittent androgen deprivation therapy over continuous androgen deprivation therapy, but the difference was statistically insignificant (RR=0.94 [0.76-1.17]). These 2 treatment modalities can be considered as equivalent in long-term treatment outcomes. As intermittent androgen deprivation therapy is more cost-efficient and less likely to yield adverse side effects, future treatment guidelines should consider these advantages over continuous androgen deprivation therapy.

Clinical characteristics of patients with metastatic castration-resistant prostate cancer after treatment with combined androgen blockade

BackgroundAlthough the second-generation androgen receptor inhibitors and taxanes have recently been recommended for the initial treatment of metastatic prostate cancer, bicalutamide and flutamide are still used in a large number of cases. Therefore, it is important to elucidate the clinical characteristics of these treated CRPC cases and their sensitivity to the currently used therapeutic agents. We aimed to examine the outcomes of metastatic castration-resistant prostate cancer following combined androgen blockade as initial therapy at our institution.MethodsNinety-four patients who developed metastatic castration-resistant prostate cancer after hormonal treatment with combined nonsteroidal androgen receptor antagonists and continuous androgen deprivation therapy between January 2015 and December 2020 were included. The presence of visceral metastases, duration of efficacy of each treatment, and overall survival after castration-resistant prostate cancer were evaluated.ResultsPatients with a longer duration of castration-resistant prostate cancer tended to have a longer response duration to subsequent enzalutamide administration (p = 0.003). Patients who achieved a 90% reduction in prostate-specific antigen levels with enzalutamide had a significantly better castration-resistant prostate cancer prognosis (p = 0.002). Meanwhile, those with visceral metastases at the time of castration-resistant prostate cancer diagnosis had a significantly poorer prognosis (p < 0.001). A positive correlation was observed between the treatment efficacy of abiraterone and taxanes for castration-resistant prostate cancer.ConclusionThe study provides scientific evidence to support that patients with longer time to castration-resistant prostate cancer are more sensitive to enzalutamide, and the use of abiraterone between docetaxel and cabazitaxel has favorable prognostic impact. These findings provide instrumental evidence that can enable better treatment selection for prostate cancer patients.

Real-World Treatment Trends Among Patients with Metastatic Castration-Sensitive Prostate Cancer: Results from an International Study.

Continuous androgen deprivation therapy ± first-generation non-steroidal antiandrogen was previously the standard-of-care for patients with metastatic castration-sensitive prostate cancer (mCSPC). Treatment intensification with novel hormonal therapy (NHT) or taxane chemotherapy is now approved and guideline-recommended for these patients. Physician-reported data on adult patients with mCSPC from the Adelphi Prostate Cancer Disease Specific Programme were analyzed descriptively. We evaluated real-world treatment trends for patients with mCSPC in 5 European countries (United Kingdom, France, Germany, Spain, and Italy) and the United States (US), looking at differences between patients initiating treatment in 2016-2018 and in 2019-2020. We also investigated treatment trends by ethnicity and insurance status in the US. This study found that most patients with mCSPC do not receive treatment intensification. However, greater use of treatment intensification with NHT and taxane chemotherapy was observed in 2019-2020 than in 2016-2018 across 5 European countries. In the US, greater use of treatment intensification with NHT in 2019-2020 than in 2016-2018 was observed for all ethnicity groups and those with Medicare and commercial insurance status. As the number of patients with mCSPC who receive treatment intensification increases, more patients who progress to metastatic castration-resistant prostate cancer (mCRPC) will have been exposed to intensified treatments. Treatment options for patients with mCSPC and mCRPC overlap, suggesting that an unmet need will emerge for new therapies. Further studies are needed to understand optimal treatment sequencing in mCSPC and mCRPC.

Role of apalutamide in the treatment landscape for patients with advanced prostate cancer: an expert opinion statement of European clinical practice

BackgroundPatients with advanced prostate cancer have a poor prognosis, and well-tolerated new treatment strategies are required to improve survival outcomes. Apalutamide is a novel androgen signalling inhibitor developed to be used in combination with continuous androgen deprivation therapy (ADT) for the treatment of patients with advanced prostate cancer. Based on evidence from two phase 3 pivotal clinical trials in non-metastatic castration-resistant (nmCRPC; SPARTAN) and metastatic hormone-sensitive prostate cancer (mHSPC; TITAN), ADT plus apalutamide significantly extends overall survival compared with the standard of care.AimsTo provide practical recommendations to guide optimal use in the real-world setting as the use of apalutamide in clinical practice increases.MethodsExpert opinion from a group of European physicians is presented here to educate on the use of apalutamide in combination with ADT in patients with mHSPC and patients with nmCRPC who are at risk of developing metastatic disease, focusing on practical considerations such as patient selection, monitoring, and management of side effects.ResultsIn clinical practice, apalutamide in combination with ADT can be used in a broad patient population including patients with high and low volume/risk mHSPC, patients with de novo metastatic disease or metastases following treatment for localised disease, as well as older patients. Apalutamide in combination with ADT is well tolerated, with manageable side effects which do not impact health-related quality of life compared to ADT alone.ConclusionsReal-world experience with apalutamide supports the efficacy and safety findings reported by the SPARTAN and TITAN clinical trials.

CAPItello-280: A phase III study of capivasertib and docetaxel versus placebo and docetaxel in metastatic castration-resistant prostate cancer.

TPS287 Background: Docetaxel is the standard first-line chemotherapy for patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease progressed on an androgen receptor-targeted agent (ARTA; typically, abiraterone, enzalutamide, apalutamide, or darolutamide). However, most patients develop chemotherapy resistance, and median overall survival (OS) remains under 3 years. Preclinical studies have associated phosphoinositide 3-kinase (PI3K)/protein kinase (AKT)/phosphatase and tensin homolog (PTEN) pathway signaling with the development of mCRPC and with resistance to taxane chemotherapy. The ProCAID Phase II trial (NCT02121639) examined whether adding capivasertib, a potent, selective inhibitor of all three AKT isoforms (AKT1/2/3), to docetaxel chemotherapy improved clinical outcomes. Although no difference in the primary endpoint (composite progression-free survival [PFS]) was detected, OS, a secondary endpoint, was extended in the capivasertib plus docetaxel treatment group. A subsequent follow-up analysis at advanced maturity suggested that the OS benefit in ProCAID was restricted to patients who had received prior treatment with an ARTA. Methods: CAPItello-280 is a Phase III study to confirm the efficacy and safety of capivasertib in combination with docetaxel compared with placebo and docetaxel in patients with mCRPC who have not previously received chemotherapy for mCRPC, but whose disease has progressed despite treatment with an ARTA in any setting. Approximately 790 patients will be randomized 1:1 to receive either capivasertib or matching placebo (320 mg orally, twice daily [BD], 4 days on, 3 days off) plus docetaxel (75 mg/m2 on day 1 of each 21-day cycle for 6–10 cycles, with prednisone or prednisolone 5 mg BD or 10 mg once daily) with a background of continued androgen deprivation therapy until disease progression, unacceptable toxicity, death, or withdrawal of consent. The primary endpoint is OS; secondary endpoints include radiographic PFS, time to pain progression, symptomatic skeletal events, safety, and tolerability. Recruitment began in March 2022 and is planned at 207 study sites in 20 countries, including the USA, Canada, Europe, South America, and Asia-Pacific. Clinical trial information: NCT05348577 .

Association of intermittent or continuous androgen deprivation therapy with cardiovascular disease and endocrine/metabolic disorders in patients with nonmetastatic prostate cancer.

83 Background: Evidence on risks of cardiovascular disease (CVD) and endocrine/metabolic disorders associated with long-term intermittent and continuous androgen deprivation therapy (iADT and cADT, respectively) in patients (pts) with nonmetastatic prostate cancer (nmPC) is mixed. This real-world study examined these risks in pts with nmPC receiving iADT or cADT in the US. Methods: This was a retrospective cohort study of SEER-Medicare pts with nmPC initiating ADT (2010–2017), with ≥36 months of continuous insurance coverage, unless death occurred, and who did not receive chemotherapy or a second-generation anti-androgen during follow-up. iADT and cADT cohorts were defined by treatment patterns and gaps in therapy. Comorbidities and clinical events were identified using ICD-9/10-CM codes. Outcomes examined were major adverse cardiovascular events (MACE [myocardial infarction (MI), stroke, cardiomyopathy/heart failure (HF), pulmonary embolism (PE), ischemic heart disease (IHD), or all-cause mortality]) and endocrine/metabolic events (diabetes, hypercholesterolemia, bone fractures, or osteoporosis). Inverse probability of treatment-weighted Cox regression models estimated the adjusted hazard ratio (aHR) of the outcomes. Subgroup analyses examined pts by CVD history. A sensitivity analysis restricted the definition of MACE to include CVD-related mortality as a component, i.e., MACESA (MI, stroke, cardiomyopathy/HF, PE, IHD, or CVD-related mortality). Results: 10,655 pts were included; 2095 (20%) received iADT and 8560 (80%) cADT; 63% of iADT pts and 66% of cADT pts had baseline CVD history. Median follow-up was 44 and 48 months and time on ADT (excluding gaps for iADT pts) was 23 and 17 months for the iADT and cADT cohorts, respectively. In adjusted analyses, pts receiving cADT had a lower risk of MACE vs iADT. No difference in risk of endocrine/metabolic events was observed. Results for MACE were similar in pts with prior CVD history; however, there was no difference in risk of MACE in those without CVD history. Sensitivity analysis results for MACESA were similar to the main results. Conclusions: Pts with nmPC receiving cADT had a lower risk of MACE, and no difference in risk of endocrine/metabolic events, compared with iADT. There was no difference in risk of MACE in pts without a prior history of CVD. [Table: see text]

Association of intermittent vs continuous androgen deprivation therapy with cardiovascular disease and endocrine/metabolic disorders in patients with metastatic prostate cancer.

82 Background: There is mixed evidence on the risks of cardiovascular disease (CVD) and endocrine/metabolic disorders associated with long-term intermittent and continuous androgen deprivation therapy (iADT and cADT, respectively) for metastatic prostate cancer (mPC). This study examined these risks in patients (pts) with mPC receiving iADT vs cADT in the US. Methods: This was a retrospective cohort study of SEER-Medicare pts with mPC initiating ADT (2010–2017), with ≥36 months of continuous insurance coverage, unless death occurred, who did not receive chemotherapy or a second-generation anti-androgen during follow-up. iADT and cADT cohorts were defined by treatment patterns and gaps in therapy. Comorbidities and clinical events were identified using ICD-9/10-CM codes. Outcomes examined were major adverse cardiovascular events (MACE [myocardial infarction (MI), stroke, cardiomyopathy/heart failure (HF), pulmonary embolism (PE), ischemic heart disease (IHD), or all-cause mortality]) and endocrine/metabolic events (diabetes, hypercholesterolemia, bone fractures, or osteoporosis). Inverse probability of treatment weighting (IPTW) was used to adjust for differences between cohorts; weighted Cox models were used to estimate the hazard ratio (HR) of the outcomes. Subgroup analyses examined pts by CVD history; a sensitivity analysis was performed restricting the definition of MACE to include CVD-related mortality as a component, i.e., MACESA (MI, stroke, cardiomyopathy/HF, PE, IHD, or CVD-related mortality). Results: 2234 pts with mPC were included; 478 (21%) received iADT and 1756 (79%) cADT. Median follow-up time was 27 and 13 months, and time on ADT (excluding gaps for iADT pts) was 24 and 19 months for the iADT and cADT cohorts, respectively. Deaths occurred in 39% of iADT pts vs 55% of cADT pts; PC was the most common cause of death in both cohorts. In adjusted analyses, pts receiving cADT had a higher risk of MACE vs iADT. No differences in risk of endocrine/metabolic events were observed. Subgroup analysis showed that baseline history of CVD did not alter the results for MACE. Sensitivity analysis results showed no difference in risk of MACESA between pts receiving cADT vs iADT. Conclusions: Pts with mPC receiving cADT had a higher risk of MACE (including all-cause mortality), and no difference in risk of endocrine/metabolic events, compared with those receiving iADT. When MACE was restricted to include CVD-related mortality, there was no difference in risk between cohorts. [Table: see text]

A pilot trial of neoantigen DNA vaccine in combination with nivolumab/ipilimumab and prostvac in metastatic hormone-sensitive prostate cancer (mHSPC).

5068 Background: Treatment with immune checkpoint blockade (ICB) alone results in suboptimal response rates in prostate cancer. Prostvac-VF Tricom is a therapeutic vaccine that incorporates DNA for the shared self-antigen PSA. Personalized neoantigen vaccines based on specific mutated epitopes may have the ability to overcome immunoresistance seen with self-antigens. Even in low mutational burden tumors like prostate cancer, T cell responses against neoantigens have been correlated with favorable clinical outcomes. Thus, we hypothesized that the combination of shared antigen and neoantigen vaccines with dual ICB will induce robust immune responses and improve clinical outcomes. Methods: This Phase I clinical trial (NCT03532217) enrolled patients from 2018-2021. Eligible patients had histologically confirmed high risk mHSPC, must have completed a course of docetaxel and received continuous androgen deprivation therapy. Patients were treated with Prostvac-VF in combination with ipilimumab/nivolumab within 60 days of the last docetaxel dose. Then, patients were continued on monthly nivolumab with their personalized neoantigen vaccine administered via intramuscular electroporation. The primary objectives of this study were to assess the feasibility, safety/tolerability, and immune responses of this combination strategy. Key secondary objectives include failure free survival, milestone overall survival (OS), PSA responses, and radiographic progression free survival. Results: Nineteen patients were enrolled and treated on trial, and feasibility was shown with 15 (79%) receiving neoantigen vaccines. Four patients did not receive neoantigen vaccines (2 for progressive disease, 2 for ICB toxicity). Treatment was well-tolerated with only 2 (2.4%) grade 3 treatment related adverse events (TRAEs) of colitis, and no grade 4+ TRAEs. The common grade 1-2 TRAEs were diarrhea (10%), injection site reactions (10%), rash (7.4%), and fatigue (6%). Median follow-up to date is 22.6 (11.3-39.6) months, with median OS not yet reached and 2 year milestone OS of 75%. Six (31.5%) patients had PSA progression per PCWG2 criteria while on treatment, with the median time to PSA progression not yet reached for the total population. Increases in activation/co-stimulatory/co-inhibitory seen after treatment with Prostvac/ICB, suggest immune priming. Sample collection is complete and immune correlative analyses are ongoing. Final safety/tolerability and preliminary correlative and clinical outcomes will be reported. Conclusions: This is the first clinical trial evaluating the use of personalized neoantigen vaccines in a combination immunotherapeutic approach in mHSPC patients. Clinical trial information: NCT03532217.

Real-world associations between bone-targeted agents and palliative bone radiotherapy in prostate cancer decedents: A province-wide population study.

e17043 Background: Palliative bone radiation is the predominant skeletal-related event (SRE) reported in advanced prostate cancer. Bone targeted agents (BTA), such as denosumab and zoledronic acid, are shown to both prevent and delay SREs including bone radiation. This study evaluated real-world use of BTA in a large provincial database in relation to palliative bone radiotherapy prior to prostate-cancer related death. Methods: Linked, province-wide administrative databases from Ontario, Canada identified patients with prostate cancer (2007-2018, n = 98646), who received continuous androgen deprivation therapy (n = 29453), died between 2013-2018 (n = 4184), and qualified for Ontario Drug Benefits (OBD; 65 years or older, n = 3788). Patients receiving novel life prolonging therapy (LPT) for metastatic castration-resistant prostate cancer (mCRPC; abiraterone, enzalutamide, docetaxel, cabazitaxel and radium-223) were selected, and use of BTA (denosumab, zoledronic acid) was identified. Demographic, health, and treatment characteristics were collected over a 2-year observation window looking back from the date of death. Multivariable analyses were conducted to identify factors important in use of palliative bone radiation. Results: 1769 patients received LPT for mCRPC, including abiraterone (n = 1094, 62%), docetaxel (n = 881, 60%), enzalutamide (n = 480, 27%), radium-223 (n = 250, 14%) and cabazitaxel (n = 108, 6%). Amongst patients receiving LPT, 57% received BTA and 60% received palliative radiation to bone. Factors associated with palliative bone radiation were receipt of BTA (OR 1.46; 95% confidence interval [CI] 1.13-1.91), metastatic disease at diagnosis (OR 1.48; CI: 1.11-1.97), radiation oncologist involvement (OR 103.11; CI: 47.03-226.25), whereas patients with fewer chronic diseases (OR 0.73; CI: 0.54-0.98) and who had prior prostatectomy (OR 0.54; CI: 0.36-0.84) were less likely to receive radiation. This relationship was maintained for both zoledronic acid (OR 1.68; CI: 1.09-2.58) and denosumab (OR 1.35, CI: 1.03-1.77). No specific LPT was associated with use of palliative bone radiation. Conclusions: Despite clinicians prescribing BTAs to prevent SREs, in this cohort, radiotherapy to bone was more likely in patients receiving BTAs. This suggests that clinicians are prescribing BTAs to patients at greater risk of SREs, but that patients dying of prostate cancer continue to have significant bone-related morbidity despite contemporary prostate cancer treatment. An analysis of primary (before bone radiotherapy) versus secondary (after bone radiotherapy) BTA prescriptions will be presented, as well as timing of BTA initiation in relation to death.

Epidemiology and racial differences of prostate cancer clinical states.

5062 Background: There is a lack of data on the incidence rates (IRs) and racial differences in advanced prostate cancer (PC) clinical states. This is the first study to evaluate PC IRs among Black and White men in the Veterans Affairs Healthcare System (VAHCS) in the following clinical states: non-metastatic hormone-sensitive PC (nmHSPC); de novo metastatic HSPC (mHSPC); non-metastatic castration-resistant PC (nmCRPC); metastatic CRPC (mCRPC). Methods: This retrospective cohort study included adult Black and White men who were active users of the VAHCS, having ≥ two visits at VA centers over any 18-month interval during the study period (2012-2019). PC was identified by ≥ two ICD codes for PC on separate dates. Metastatic status was identified by an algorithm of ICD codes and common treatments for metastatic PC. Castrate resistant status was determined based on rising PSA during periods of continuous androgen deprivation therapy. Annual IRs for each clinical state and rate ratios (RR) for race were standardized using age and race-specific population estimates from the U.S. Census. The joinpoint regression software 4.9.0.0 was used to evaluate trends and identify change points in IRs over time. Results: 2019 IRs (per 100K person-years) and 95% confidence intervals among Black and White men respectively by clinical state were 453.0 (441.2, 464.7) and 205.3 (201.5, 209.1) (nmHSPC); 33.7 (30.4, 37.0) and 15.1 (14.1, 16.0) (mHSPC); 23.4 (21.0, 25.9) and 8.5 (7.8, 9.1) (nmCRPC); and 49.1 (45.5, 52.8) and 19.4 (18.4, 20.3) (mCRPC). The RR for all clinical states was significantly higher for Black vs. White men (all p &lt; 0.0001): 2.2 (nmHSPC and mHSPC), 2.8 (nmCRPC), and 2.5 (mCRPC). Although IRs varied over time, these RRs were consistent across time. Trends in IRs over time were also consistent by race. From 2012, the IRs for nmHSPC declined to a nadir in 2016 (annual percent change (APC) -9.1%) and then increased through 2019 (APC = 3.1%). IRs for mHSPC increased throughout the study period (APC = 10.6%). IRs for nmCRPC decreased from 2012 to a nadir in 2014 (APC = -9.3%) and then increased through 2019 (APC = 3.8%). IRs for mCRPC increased from 2012 to 2016 (APC = 7.7%) and then leveled off through 2019 (APC = -0.2%). Conclusions: Our findings provide novel and comprehensive data on IRs across prostate cancer clinical states by race and over time within the VAHCS. Despite the VAHCS providing an environment of relatively equal access to care, Black men experience a disproportionate burden of PC with IRs over 2-fold higher for all clinical states relative to White men. This highlights that resolving access to care alone is unlikely to fully eliminate PC racial differences and that there are other multifactorial issues to address. The temporal trends for nmHSPC observed in our study, including the nadir in 2016, are consistent with the timing of the 2012 US Preventive Services Task Force guidelines advising against PSA screening and the subsequent draft reversal in 2017.

Patterns of care for non-metastatic castration-resistant prostate cancer: A population-based study.

ObjectivesTo describe patterns of practice of PSA testing and imaging for Ontario men receiving continuous ADT for the treatment of non‐metastatic castration‐resistant prostate cancer (nmCRPC).Patients and MethodsThis was a retrospective, longitudinal, population‐based study of administrative health data from 2008 to 2019. Men 65 years and older receiving continuous androgen deprivation therapy (ADT) with documented CRPC were included. An administrative proxy definition was applied to capture patients with nmCRPC and excluded those with metastatic disease. Patients were indexed upon progression to CRPC and were followed until death or end of study period to assess frequency of monitoring with PSA tests and conventional imaging. A 2‐year look‐back window was used to assess patterns of care leading up to CRPC as well as baseline covariates.ResultsAt a median follow‐up of 40.1 months, 944 patients with nmCRPC were identified. Their median time from initiation of continuous ADT to CRPC was 26.0 months. 60.7% of patients had their PSA measured twice or fewer in the year prior to index, and 70.7% patients did not receive any imaging in the year following progression to CRPC. Throughout the study period, 921/944 (97.6%) patients with CRPC progressed to high‐risk (HR‐CRPC) with PSA doubling time ≤ 10 months, of which more than half received fewer than three PSA tests in the year prior to developing HR‐CRPC, and 30.9% received no imaging in the subsequent year.ConclusionPSA testing and imaging studies are underutilized in a real‐world setting for the management of nmCRPC, including those at high risk of developing metastatic disease. Infrequent monitoring impedes proper risk stratification, disease staging and detection of treatment failure and/or metastases, thereby delaying the necessary treatment intensification with life‐prolonging therapies. Adherence to guideline recommendations and the importance of timely staging should be reinforced to optimize patient outcomes.

Testosterone recovery for relugolix versus leuprolide in men with advanced prostate cancer: Results from the phase 3 HERO study.

104 Background: In the phase 3 HERO study, the oral GnRH receptor antagonist, relugolix, showed sustained testosterone suppression superior to that of leuprolide (96.7% vs 88.8%; difference: 7.9% [95% CI, 4.1 to 11.8; P &lt; 0.001]). Herein, we provide an analysis of the testosterone recovery data in a subgroup of 184 men from the HERO study who were not indicated to continue androgen deprivation therapy. Methods: The phase 3 HERO study was designed to evaluate relugolix in men with advanced prostate cancer. Overall, 934 men were randomized 2:1 to receive relugolix 120 mg orally once daily after a single oral loading dose of relugolix 360 mg on Day 1 or leuprolide injections every 12 weeks for 48 weeks. Testosterone recovery was assessed in 184 patients who completed 48 weeks of treatment and who did not plan to start alternative androgen deprivation therapy within the following 12 weeks (or within 24 weeks following the last injection of leuprolide 3-month depot). During the 90-day recovery period, assessments included time to testosterone recovery (≥ 280 ng/dL, the lower limit of the normal range) using the Kaplan-Meier method, PSA concentrations in testosterone recovery phase, and adverse events during the recovery phase. All analyses were conducted in a modified intent to treat population. Results: Overall, 137 men in the relugolix group and 47 men in the leuprolide group were included in these analyses. Mean (standard deviation) testosterone levels for men entering the recovery assessment were 427±142 ng/dL and 404±127 ng/dL in the relugolix and leuprolide groups, respectively. The cumulative incidence rate of testosterone recovery to ≥280 ng/dL at 90 days after drug discontinuation was 53.9% in the relugolix group compared with 3.2% in the leuprolide group (nominal p = 0.0017). Overall, 74 of the 137 men in relugolix group recovered testosterone with a median time to recovery of 86.0 days (95% CI: 65.0, 92.0), versus 2 of the 47 men in leuprolide group with a median time to recovery of 112.0 days (95% CI: 112.0, not estimable). At the 90-day follow-up visit, the median PSA values were 0.39 ng/mL (range: 0 to 233.1) and 0.06 ng/mL (0 to 14.0) in the relugolix and leuprolide groups, respectively. Incidence of adverse events were generally similar in the treatment groups during the recovery phase, with 96% of men experiencing at least one adverse event and 15% of men experiencing a grade ≥3 adverse event in both treatment groups during the recovery phase. Conclusions: Relugolix, an oral nonpeptide GnRH receptor antagonist, had a faster and more complete recovery of testosterone to normal levels after treatment discontinuation versus leuprolide in a subgroup of men from the phase 3 HERO study. Clinical trial information: NCT03085095.