Combined Androgen Deprivation Therapy Research Articles

EORTC 2238 "De-Escalate": a pragmatic trial to revisit intermittent androgen deprivation therapy in the era of new androgen receptor pathway inhibitors.

The landscape of treating metastatic prostate cancer has evolved with the addition of Androgen Receptor pathway inhibitor (ARPI) to Androgen Deprivation Therapy (ADT), significantly improving survival rates. However, prolonged use of these therapies introduces notable side effects, prompting a need to revisit intermittent treatment duration. The EORTC 2238 De-Escalate trial is a pragmatic trial seeking to reassess the role of intermittent therapy in patients undergoing maximal androgen blockade (MAB) for metastatic hormone naïve prostate cancer (mHNPC), i.e., the combination of ADT with an ARPI, with the aims of reducing side effects, enhancing Quality of Life (QoL) and optimizing resource usage, while maintaining oncological benefits.

Recommendations on the treatment of metastatic hormone-sensitive prostate cancer: Patient selection

The standard treatment for metastatic hormone-sensitive prostate cancer (mHSPC) is now a combination of androgen deprivation therapy plus an androgen receptor-targeted therapy (abiraterone, apalutamide, enzalutamide or darolutamide), with or without chemotherapy (docetaxel). The selection of suitable patients for each therapeutic approach has become a determining factor to ensure efficacy and minimize side effects. This article combines recent clinical evidence with the accumulated experience of experts in medical oncology, radiation oncology and urology, to provide a comprehensive view and therapeutic recommendations for mHSPC.

Prognostic impact of prostate-specific membrane antigen positron emission tomography (PSMA PET) staging for clinically node-positive prostate cancer.

In the current American Joint Committee on Cancer staging system, patients with pelvic nodal metastases are considered stage IV prostate cancer. This study aims to investigate whether men with prostate-specific membrane antigen positron emission tomography (PSMA PET)-detected pelvic node-positive prostate cancer at diagnosis have a better outcome compared to men with node-positive disease identified on conventional imaging. This is a retrospective cohort study comparing the outcomes of men with node-positive prostate cancer and disease confined to the pelvis, staged with conventional versus PSMA PET imaging. Men had to be treated definitively with a combination of androgen deprivation therapy and radiation treatment to the prostate and pelvic lymph nodes. Kaplan-Meier and Cox regression analysis was used to compare biochemical failure-free survival (BFFS) and overall survival (OS). Seventy-six men with nodal metastases confined to the pelvis were identified. Fifty-one were detected with PSMA PET while 25 were staged with conventional imaging. PSMA PET staged patients had a lower proportion of Gleason 8-10 disease (78% vs. 96%) as well as a lower median prostate-specific antigen (11 ng/mL vs. 26 ng/mL). BFFS at 4 years was 72% with PSMA PET-detected node-positive disease vs. 38% with conventionally detected node-positive disease. Four-year OS was 93% with PSMA PET staged patients vs. 76% with conventionally staged patients. On multivariate analysis, the PSMA PET staged group was associated with improved BFFS (Adjusted HR = 3.00, 95% CI 1.43, 6.29, P = 0.004) and OS (Adjusted HR = 5.81, 95% CI 1.43, 23.7, P = 0.007). Men with PSMA PET-detected node-positive prostate cancer confined to the pelvis have significantly better biochemical control and survival compared to those with node-positive pelvic disease identified through conventional staging.

Network meta-analysis of combination strategies in metastatic hormone-sensitive prostate cancer.

This study compared different doublet and triplet therapies for efficacy and safety in metastatic hormone-sensitive prostate cancer (mHSPC). PubMed, EMBASE, and the Cochrane Library were comprehensively searched for eligible randomized controlled trials (RCTs) published from inception to October 2023. Interventions included abiraterone, apalutamide, enzalutamide, docetaxel, darolutamide, and androgen deprivation therapy (ADT), either as doublet or triplet therapies. The outcomes examined were overall survival (OS), progression-free survival (PFS), castration-resistant prostate cancer (CRPC)-free survival, time to symptomatic skeletal event (SSE), and toxicity. The surface under the cumulative ranking curve (SUCRA) was determined to identify the preferred treatments. Ten RCTs were included. The combination of darolutamide, docetaxel, and ADT had the highest SUCRA of 84.3 for OS, followed by combined abiraterone, docetaxel, and ADT (SUCRA = 71.6). The highest SUCRAs for PFS were observed for triplet therapies (abiraterone, docetaxel, and ADT [SUCRA = 74.9], followed by enzalutamide, docetaxel, and ADT [SUCRA = 74.3]) and other androgen receptor axis-targeted therapy-based doublet therapies (SUCRAs: 26.5-59.3). Darolutamide, docetaxel, and ADT had the highest SUCRAs, i.e., 80.8 and 84.0 regarding CRPC-free survival and time to SSE, respectively. Regarding Grade >3 adverse events (AEs), the SUCRAs of triplet therapies (SUCRAs: 14.8-31.5) were similar to that of docetaxel and ADT (SUCRA = 39.5). Three studies had a low risk of bias in all categories; the remaining studies had at least an unclear risk of bias in at least one category. Triplet therapy demonstrated potentially enhanced effectiveness than doublet therapy in mHSPC, with acceptable safety concerns. Darolutamide might be the optimal option for triplet therapy in combination with docetaxel and ADT.

Current Systemic Therapy in Men with Metastatic Castration-Sensitive Prostate Cancer.

This review aims to explore the evolving landscape of treatments available for metastatic castration-sensitive prostate cancer (mCSPC) patients. In less than a decade, evidence was chronologically provided that (1) systemic treatment intensification with docetaxel improves outcomes, including survival, in men with mCSPC, (2) then that these outcomes are also improved when a second-generation androgen receptor pathway inhibitor (ARPI) is combined with androgen deprivation therapy (ADT), and (3) using a "triplet systemic therapy," which consists in the combination of ADT, an ARPI and docetaxel, further improves outcomes, including survival. Radiotherapy to the prostate combined with ADT alone is now recommended in men with low-volume mCSPC. Combining prostate radiotherapy and intensified systemic treatment including abiraterone may be synergistic as suggested in the PEACE-1 trial. Also, the role of metastases-directed local therapies (mostly stereotactic radiotherapy) is currently being assessed in phase 3 trials. Finally, the integration of biomarkers (e.g. BRCA2 gene alterations, PTEN loss, PSMA expression) for decision making is not currently established, though trials are also currently underway. Importantly, most evidence currently available was obtained in men with de novo metastases, while for those with metastatic relapse after definitive local treatment, the role of treatment intensification is less well established. Treatment intensification is nowadays the standard of care for patients with de novo mCSPC as it leads to outcomes improvement, including survival, and the standard of care is evolving almost on a yearly basis.

Recomendaciones de tratamiento en el cáncer de próstata hormonosensible metastásico: selección de pacientes

The standard treatment for metastatic hormone-sensitive prostate cancer (mHSPC) is now a combination of androgen deprivation therapy plus an androgen receptor-targeted therapy (abiraterone, apalutamide, enzalutamide or darolutamide), with or without chemotherapy (docetaxel). The selection of suitable patients for each therapeutic approach has become a determining factor to ensure efficacy and minimize side effects. This article combines recent clinical evidence with the accumulated experience of experts in medical oncology, radiation oncology and urology, to provide a comprehensive view and therapeutic recommendations for mHSPC.

Hormonal Therapy and Radiation Therapy in Prostate Cancer: 5-Year Outcomes From a Trial Evaluating Combined Androgen Blockade With 5-Alpha Reductase Inhibitors as an Alternative to Gonadotropin Releasing Hormone Agonists

BackgroundWe previously reported that for men undergoing combined androgen deprivation therapy (ADT) and radiation therapy (RT) for prostate cancer, substitution of LHRH-agonists with 5-α- reductase inhibitors (5-ARIs) led to improved preservation of 6-month hormonal quality of life (hQOL). With longer term follow-up, we evaluated disease control. MethodsIn this non-randomized trial, men with unfavorable intermediate or high-risk prostate cancer, aged ≥70 years or with Charlson Comorbidity Index ≥2, were treated with RT (78-79.2 Gy in 39-44 fractions) and either oral ADT (oADT; 5-ARI with antiandrogen) or standard of care ADT (SOC; leuprolide with antiandrogen) for up to 28 months. The primary endpoint was EPIC hQOL; secondary endpoints included biochemical control and survival as well as changes in cholesterol and hemoglobin levels. ResultsBetween 2011 and 2018, 70 men were enrolled (40 in oADT; 30 in SOC). Median follow-up was 65 months [IQR 36-94]. Five-year freedom from biochemical failure for oADT and SOC was 89% versus 86%, disease free survival was 62% versus 69%, cancer-specific survival was 100% versus 96%, and overall survival was 70% versus 81% (all P > .1). Testosterone (2 mo through 3 yr) and hemoglobin levels (2 mo through 2 yr) were higher, and cholesterol levels (1 yr) were lower in the oADT groups (all P < .05). ConclusionsIn this non-randomized study, men treated with combined RT and oADT had better preservation of hQOL and comparable 5-year disease outcomes to men treated with SOC. Eugonadal testosterone with this approach may yield measurable benefits in cholesterol and hemoglobin levels.

Abstract 3572: Role of the gut microbiome in androgen production and prostate cancer treatment resistance

Abstract Metastatic prostate cancer is often treated via a combination of androgen deprivation therapy (ADT) and the androgen receptor axis-targeted therapies abiraterone acetate + prednisone (AA/P) or enzalutamide. Unfortunately, most individuals undergoing these treatments develop resistance, termed “castration resistance”, through an unknown mechanism. Previous studies demonstrate a potential link between the gut microbiota and the treatment efficacy of endocrine therapy in metastatic castration resistant prostate cancer (mCRPC). This may be due in part to gut bacterial communities with the machinery to synthesize androgens using mechanisms distinct from human cells. For example, the bacterial desAB genes (e.g., “desmolase”) that were first described in the gut commensal bacterial species Clostridium scindens convert cortisol and prednisone to the androgenic metabolites 11β-hydroxyandrost-4-ene-3,17-dione (11OHAD) and ∆1-adrenosterone (∆1-AT), respectively. We hypothesize that androgen synthesis by the gut microbiota promotes treatment resistance to AA/P in advanced prostate cancer. This study aims to determine if androgen-converting gut bacterial species as well as circulating and fecal androgen levels correlate with AA/P treatment response in individuals with mCRPC using a combination of metagenomics and metabolomics. We further aim to demonstrate the relationship between gut bacterial androgen production and prostate cancer treatment response using an in vivo mouse model. Metagenomic sequencing showed an imbalance in microbial communities and identified the presence of androgen-synthesizing bacteria such as C. scindens in fecal samples of individuals undergoing treatment with AA/P. We also demonstrate that the relative abundance of C. scindens, as well as other species reported to generate androgens, are significantly enriched during metastatic disease progression on AA/P. Furthermore, targeted quantitative PCR of the bacterial desmolase (desA) gene demonstrated that absolute levels of desmolase are significantly higher in AA/P non-responders relative to AA/P responders, and trended higher in individuals with rising prostate-specific antigen (PSA) versus stable PSA while on AA/P. Targeted LC/MS/MS analyses of fecal samples demonstrated the presence of testosterone, dihydrotestosterone, 11OHAD, ∆1-AT, and other androgen metabolites in association with rising PSA levels in the AA/P cohort. Furthermore, we demonstrate that C. scindens converts hydrocortisone and prednisone into 11OHAD and ∆1-AT, respectively, in vitro at 48- and 72h post-treatment, which recapitulates prior published studies. Finally, we have established a prostate cancer mouse model using a VCaP xenograft in which tumor growth was significantly inhibited by abiraterone acetate in comparison to treatment with ADT alone. Additional studies will use this mouse model to study the effects of androgen metabolism by gut bacteria on AA/P efficacy. Overall, this study ascertains the ability of the human gut microbiota to harbor androgen-synthesizing bacteria, which in turn can be an alternative source of androgens that could impact the efficacy of the anti-androgen therapies used to treat metastatic prostate cancer. Citation Format: Angelica I. Cruz Lebron, Pedro A. Balbuena-Almodóvar, Luke Mummert, Sarah Ernst, Mark Markowski, Michelle Rudek, Jason Ridlon, Karen S. Sfanos. Role of the gut microbiome in androgen production and prostate cancer treatment resistance [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 3572.

Efficacy and Safety of Radiotherapy Plus Relugolix in Men With Localized or Advanced Prostate Cancer

Combination androgen deprivation therapy (ADT) with radiotherapy is commonly used for patients with localized and advanced prostate cancer. To assess the efficacy and safety of the oral gonadotropin-releasing hormone antagonist relugolix with radiotherapy for treating prostate cancer. This multicenter post hoc analysis of patients with localized and advanced prostate cancer receiving radiotherapy in 2 randomized clinical trials (a phase 2 trial of relugolix vs degarelix, and a subset of the phase 3 HERO trial of relugolix vs leuprolide acetate) included men who were receiving radiotherapy and short-term (24 weeks) ADT (n = 103) from 2014 to 2015 and men receiving radiotherapy and longer-term (48 weeks) ADT (n = 157) from 2017 to 2019. The data were analyzed in November 2022. Patients receiving short-term ADT received relugolix, 120 mg, orally once daily (320-mg loading dose) or degarelix, 80 mg, 4-week depot (240-mg loading dose) for 24 weeks with 12 weeks of follow-up. Patients receiving longer-term ADT received relugolix, 120 mg, orally once daily (360-mg loading dose) or leuprolide acetate injections every 12 weeks for 48 weeks, with up to 90 days of follow-up. Castration rate (testosterone level <50 ng/dL [to convert to nmol/L, multiply by 0.0347) at all scheduled visits between weeks 5 and 25 for patients receiving short-term ADT and weeks 5 and 49 for patients receiving longer-term ADT. Of 260 patients (38 Asian [14.6%], 23 Black or African American [8.8%], 21 Hispanic [8.1%], and 188 White [72.3%] individuals), 164 (63.1%) received relugolix. Relugolix achieved castration rates of 95% (95% CI, 87.1%-99.0%) and 97% (95% CI, 90.6%-99.0%) among patients receiving short-term and longer-term ADT, respectively. Twelve weeks post-short-term relugolix, 34 (52%) achieved testosterone levels to baseline or more than 280 ng/dL. Ninety days post longer-term ADT, mean (SD) testosterone levels were 310.5 (122.4) (106.7) ng/dL (relugolix; n = 15) vs 53.0 ng/dL (leuprolide acetate; n = 8) among the subset assessed for testosterone recovery. Castration resistance-free survival was not statistically different between the relugolix and leuprolide acetate cohorts (hazard ratio, 0.97; 95% CI, 0.35-2.72; P = .62). Adverse events grade 3 or greater for short-term or longer-term relugolix (headache, hypertension, and atrial fibrillation) were uncommon (less than 5%). The results of these 2 randomized clinical trials suggest that relugolix rapidly achieves sustained castration in patients with localized and advanced prostate cancer receiving radiotherapy. No new safety concerns were identified when relugolix was used with radiotherapy.

Updated 5-year results for short course abiraterone acetate and LHRH agonist for unfavorable intermediate and favorable high-risk prostate cancer.

Combined androgen deprivation therapy (ADT) and radiotherapy (RT) improves outcomes for intermediate and high-risk prostate cancer. Treatment intensification with abiraterone acetate/prednisone (AAP) provides additional benefit for high-risk disease. We previously reported 3-year outcomes of a single-arm prospective multicenter trial (AbiRT trial) of 33 patients with unfavorable intermediate risk (UIR) and favorable high risk (FHR) prostate cancer undergoing short course, combination therapy with ADT, AAP, and RT. Here we report the final analysis demonstrating a high rate of testosterone recovery (97%) and excellent biochemical progression-free survival (97%) at 5 years. These data support comparative prospective studies of shorter, more potent ADT courses in favorable high-risk prostate cancer.

Real-world treatment of metastatic hormone-sensitive prostate cancer in the USA, Europe and Asia.

Aim: To characterize real-world patients with metastatic hormone-sensitive prostate cancer (mHSPC) and treating physicians and evaluate treatment trends and baseline concordance versus guidelines internationally. Materials & methods: Retrospective, cross-sectional data from the Ipsos Global Oncology Monitor database 2018-2020 were used for descriptive analysis of mHSPC patients, treating physicians and treatment utilization. Results: Among the 6198 mHSPC patients from five countries, the most common treatment was either androgen deprivation therapy (ADT) monotherapy or first-generation androgen receptor inhibitor+ADT. Second-generation androgen receptor inhibitor use was only initiating but increasing over the study period. Conclusion: Despite contemporaneous guidelines recommending treatment intensification of ADT in combination with novel antihormonals or docetaxel, 76.1% of reported mHSPC patients received non-guideline-concordant care.

SAT634 The Androgen Receptor Does Not Directly Regulate The Transcription Of DNA Damage Response Genes

Abstract Disclosure: S. Hasterok: None. T.G. Scott: None. D.G. Roller: None. A. Spencer: None. A.B. Dutta: None. K. Sathyan: None. D.E. Frigo: None. M.J. Guertin: None. D. Gioeli: None. The clinical success of combined androgen deprivation therapy (ADT) and radiation therapy (RT) in prostate cancer (PCa) created interest in understanding the mechanistic links between androgen receptor (AR) signaling and the DNA damage response (DDR). Convergent data have led to a model where AR both regulates, and is regulated by, the DDR. Integral to this model is that the AR regulates the transcription of DDR genes both at steady state and in response to ionizing radiation (IR). In this study, we sought to determine which immediate transcriptional changes are induced by IR in an AR-dependent manner. Using PRO-seq to quantify changes in nascent RNA transcription in response to IR, the AR antagonist enzalutamide, or the combination of the two, we find that enzalutamide treatment significantly decreased expression of canonical AR target genes but had no effect on DDR gene sets in PCa cells. Surprisingly, we also found that the AR is not a primary regulator of DDR genes either in response to IR or at steady state in asynchronously growing PCa cells. Our data indicate that the clinical benefit of ADT and RT is not due to the direct regulation of DDR gene transcription by AR and that the clinical benefit of this therapeutic combination is instead likely due to both treatments independently reducing tumor cell fitness. Presentation: Saturday, June 17, 2023

Double trouble for prostate cancer: synergistic action of AR blockade and PARPi in non-HRR mutated patients.

Prostate cancer (PCa) is the most common cancer in men worldwide. Despite better and more intensive treatment options in earlier disease stages, a large subset of patients still progress to metastatic castration-resistant PCa (mCRPC). Recently, poly-(ADP-ribose)-polymerase (PARP)-inhibitors have been introduced in this setting. The TALAPRO-2 and PROpel trials both showed a marked benefit of PARPi in combination with an androgen receptor signaling inhibitor (ARSI), compared with an ARSI alone in both the homologous recombination repair (HRR)-mutated, as well as in the HRR-non-mutated subgroup. In this review, we present a comprehensive overview of how maximal AR-blockade via an ARSI in combination with a PARPi has a synergistic effect at the molecular level, leading to synthetic lethality in both HRR-mutated and HRR-non-mutated PCa patients. PARP2 is known to be a cofactor of the AR complex, needed for decompacting the chromatin and start of transcription of AR target genes (including HRR genes). The inhibition of PARP thus reinforces the effect of an ARSI. The deep androgen deprivation caused by combining androgen deprivation therapy (ADT) with an ARSI, induces an HRR-like deficient state, often referred to as "BRCA-ness". Further, PARPi will prevent the repair of single-strand DNA breaks, leading to the accumulation of DNA double-strand breaks (DSBs). Due to the induced HRR-deficient state, DSBs cannot be repaired, leading to apoptosis.

The oncologic and safety outcomes of low-dose-rate brachytherapy for the treatment of prostate cancer.

Around 40years have passed since a modern low-dose-rate (LDR) brachytherapy for prostate cancer was introduced. LDR brachytherapy has become one of the definitive treatment options besides radical prostatectomy (RP) and external beam radiation therapy (EBRT). LDR brachytherapy has several advantages over EBRT such as a higher prescribed dose to the prostate gland while avoiding unnecessary irradiation of organs at risk, a precipitous dose gradient, a brief treatment time, and a short hospital stay. Previous reports revealed that the long-term oncologic outcomes of LDR brachytherapy are superior to those of EBRT. The oncologic outcomes of low- to intermediate-risk patients are equivalent to those of RP using the recurrence definition of surgery of prostate specific antigen (PSA) >0.2ng/mL, while the oncologic outcomes of LDR brachytherapy as tri-modality (combined EBRT and androgen deprivation therapy) for high-risk patients is superior to that of RP using the recurrence definition of surgery. In respect of toxicity, urinary disorders such as urgency and frequency are often observed after the acute phase of treatment, but these events usually resolve, while the quality of life of urinary continence is well preserved for a long time. Erectile function decreases yearly, but is relatively preserved compared to RP. In conclusion, the most noteworthy strength of LDR brachytherapy for low- to intermediate-risk patients is the "brief treatment time" that provides long recurrence-free survival, while that for high-risk patients who received LDR brachytherapy (tri-modality) is "excellent disease control."

Abstract B007: New generation mTOR blocker sensitizes prostate cancer models to AR-targeting therapy

Abstract Advanced stage prostate cancers (PCa) can develop bone metastasis, a lethal feature of castration-resistant prostate cancer (CRPC) for which no curative options are currently available. Androgen deprivation therapy (ADT) is the main therapeutic strategy for treating advanced PCa; patients with bone metastasis, however, are frequently developing resistance to ADT, progressing to CRPC. Dysregulation of the mTOR pathway has been linked with AR reactivation and with progression to CRPC, and mutations in targets of the PI3K/Akt/mTOR pathway are frequently found in CRPC patients. This study investigates the effect of synergistic AR and mTOR pathways blockade on therapy resistance in advanced PCa in vitro and in vivo. LNCaP and LAPC4 cells were treated in vitro with AR blockers (apalutamide, enzalutamide), mTOR blockers (rapamycin, everolimus, MLN0128 or Rapalink-1) or a combination of both blockers. Viability was measured in a timecourse from 1 to 10 days after drug administration using CellTiter Acqueous 96. To mimick ADT in vitro, cells were cultured for 7 days in charcoal-stripped serum in medium without dihydroxytestosterone or phenol red before the drug screening. Two already established PDX models of bone-metastatic PCa, BM18 and LAPC9 respectively androgen-dependent and -independent, were used to assess the effect of combined ADT and mTOR-targeting therapy in vivo. Both LNCaP and LAPC4 models showed a higher sensitivity to MLN0128 and Rapalink-1 compared to rapalogs, LAPC4 cells in particular were more sensitive than LNCaP cells to mTOR inhibitors. AR blockers were moderately effective and only at concentrations between 10 and 100 µM, when used alone. However, treatment with sublethal doses of Rapalink-1 (0.001-0.01 µM) sensitized both cell lines to 2- to 3-log fold lower concentrations of apalutamide. In vivo, treatment with Rapalink-1 alone significantly reduced the growth rate of LAPC9 PDX, while co-treatment with ADT and Rapalink-1 resulted in regression in this CRPC model, a result not achievable by either treatment alone. Treatment with Rapalink-1, while effectively reducing cell viability in vitro already when used alone, could sensitize the tested models to AR blockers, at clinically relevant concentrations. In vivo treatment with Rapalink-1 was well-tolerated and sufficient to control the growth of the BM18 PDX model. When used in combination with ADT, it could induce regression of the CRPC model LAPC9. Citation Format: Shuang Li, Federico La Manna, Panagiotis Chouvardas, George Thalmann, Marianna Kruithof-de Julio. New generation mTOR blocker sensitizes prostate cancer models to AR-targeting therapy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B007.

Survival of de novo metastatic hormone sensitive prostate cancer in US Veterans based on treatment and PSA at diagnosis.

e17091 Background: Combinations of androgen deprivation therapy (ADT) plus docetaxel (DOC) or androgen signaling agents (ASIs) (i.e. abiraterone, enzalutamide) improve survival in de novo metastatic hormone sensitive prostate cancer (mHSPC). In several trials, the benefit of combination therapy is greatest in patients with a high volume of disease. We sought to study the treatment and survival of US of veterans with mHSPC and stratify by PSA level at diagnosis during a time when different types of combination therapy was available. Methods: Veterans from 2018-2021 were identified with a pathologic diagnosis of prostate cancer with SEER stage ‘distant’. All veterans had ADT initiated within 1 month prior and 4 months after diagnosis. Combination therapy was determined if DOC or an ASI was initiated from 1 month prior to 4 months after ADT. Highest PSA level within 3 months of diagnosis was collected and patients with a PSA of ≥100ng/mL were included in PSA≥100. To avoid immortal time bias, all veterans had to survive 4 months after biopsy to be included. Baseline differences were compared using ANOVA and log-rank testing was used for time to event analyses. Results: 2,227 patients with de novo mHSPC were identified with mean age of 74.0 years (yrs), and 575 (25.8%) identified as Black race. From 2018 to 2021, ADT alone was used in 1,157 (52.0%) of veterans, DOC in 189 (8.4%) and ASIs in 881 (39.6%). Veterans treated with DOC were significantly younger (median 67.7 yrs, p &lt; 0.001) compared to veterans treated with ASIs (72.9 yrs) or ADT alone (75.8 yrs). Veterans treated with combination therapies had longer median OS of 40.9 months (mos) compared to 32.9 mos for ADT alone (p &lt; 0.001) with no difference within the combination treatment groups (p = 0.63). There was a trend for veterans with PSA≥100 to receive combination therapy (50.0% vs. 46.0%, p = 0.058). For 1,071 veterans with PSA≥100, median OS of veterans treated with combination therapy (n = 536, 37.4 mos) was longer than ADT alone (n = 535, 27.5 mos, p &lt; 0.001). There was no differences in DOC combination treatment (n = 100, 37.9 mos) and ASI (n = 436, 36.6 mos) treatment groups (p = 0.37). Veterans with PSA≥100 had shorter OS compared to PSA &lt; 100 (31.2 vs. 42.5 mos, p &lt; 0.001). Conclusions: In veterans with de novo mHSPC, initial combination therapy was associated with longer survival than ADT alone. There were no differences in survival between DOC and ASI combinations observed in the entire population nor in veterans with PSA≥100. Further studies including tumor genetics or response to treatment may help guide treatment in mHSPC. [Table: see text]

Treatment and survival of de novo metastatic hormone sensitive prostate cancer among African American US Veterans.

5079 Background: Combinations of androgen deprivation therapy (ADT) plus docetaxel (DOC) or androgen signaling inhibitors (ASIs: abiraterone, enzalutamide, etc.) have revolutionized treatment of metastatic hormone sensitive prostate cancer (mHSPC), particularly for high volume disease. However, little is known about the use of and outcomes of combination therapy in African Americans (AA) with de novo mHSPC, due to their lack of representation in clinical studies. This study evaluates the patient characteristics, treatment, and survival in a cohort of US veterans with mHSPC with equal access to treatment under the Veterans Affairs Health System (VA). Methods: Veterans with mHSPC were identified from 2014-2022 in the VA using the initial pathological diagnosis of prostate cancer with SEER stage ‘distant’ and first ADT initiated within 1 month prior and 3 months after diagnosis. Therapies including DOC or ASIs were collected if initiated from 1 month prior to 4 months after ADT. Additional information at the time of diagnosis was collected including Prostate Specific Antigen (PSA), race from VA enrollment, and Charlson Comorbidity Index (CCI). Median survival was obtained for each group and stratified by PSA level &gt;100 ng/mL. Chi-square and ANOVA testing were used differences in survival (OS) were assessed by log-rank testing. Results: 4,248 veterans with de novo mHSPC were identified, 1138 (26.8%) were AA and 3110 (73.2%) white. Black veterans were younger (70.8 vs. 74.8, p&lt;0.001) and had higher median PSA (183 vs. 86.3, p&lt;0.001) with similar mean CCI (4.4 vs. 4.4, p=0.78). AA veterans were likely to have a PSA &gt;100 ng/mL at diagnosis (61.6% vs. 46.1%, p&lt;0.001) and to receive combination therapy than white veterans (36.8% vs. 32.7%, p=0.01). The median OS among AA and white veterans was similar (32.5 months vs. 32.1, p=0.75). In 2,120 veterans with PSA&gt;100 ng/mL (a surrogate for higher volume disease), AA veterans were more likely to receive combination therapy (39.5% vs. 32.9%, p=0.003) without differences in survival in AA veterans compared to white (31.0 vs. 26.9 months, p=0.18). Conclusions: In an equal access health care system, AA veterans had similar survival to white veterans despite having double the PSA levels, reflecting higher risk disease. AA presented 4 years younger and are likely treated with doublet therapy. The differences in the age of onset and burden of disease highlight persistent differences in populations with mHSPC. Further investigations to understand environmental, social, and tumor factors are warranted to explain these disparities. [Table: see text]

Enzalutamide, docetaxel and androgen deprivation (ENZADA trial) for metastatic castrate sensitive prostate cancer (mCSPC).

5072 Background: The use of contemporary androgen receptor signaling inhibitors (ARSI) in combination with docetaxel (Doc) and androgen deprivation therapy (ADT) has shown improved outcomes in recent trials. Prostate specific antigen (PSA) serologic complete response (CR) has correlated with improved overall survival (OS) in prior studies. In the E3805 study, the 12-month PSA CR rate was 28% for the ADT + Doc arm. In this study, we hypothesized the combination of androgen deprivation therapy with Doc and enzalutamide (Enz) would improve the 52-week PSA CR rate compared to the historical control with ADT + Doc in newly diagnosed patients with mCSPC. Methods: The ENZADA trial is a single institution phase II study in patients with mCSPC. Patients received ADT, Doc 75 mg/m2 IV every 3 weeks for up to 6 cycles and Enz 160mg daily until radiographic progression. The primary endpoint was 52-week PSA CR. Secondary endpoints included safety/toxicity, best PSA response, time to castration resistance (TTCR) and overall survival (OS). Patients were stratified by radiographic volume of disease by E3805 criteria. The study was designed with 90% power and 1-sided alpha 0.1 to show an improvement in the 52-week PSA CR from 25% to 45%, with rejection of the null hypothesis if 14 of 39 evaluable subjects achieved a 52-week PSA CR. Results: Between Sep 2017 and Aug 2021, 40 subjects were enrolled, and 36 were evaluable for the primary endpoint. At the data cut-off of 9/2/22, median follow up was 42.6 months. Thirty subjects (75%) had high volume disease, and 32 (80%) subjects presented with de novo metastatic disease. Median age was 64.5 years; 65% (N=26) were identified as White and 35% (N=14) were identified as Black or African American (AA). Median pretreatment PSA was 129.5 ng/ml. 67.5% (27/40) of subjects received six cycles of Doc. 10% (4/40) of subjects had Enz dose modifications. 52-week PSA CR occurred in 22/36 (61.1%) patients (P&lt;0.001). 13/23 (56.5%) White subjects and 9/13 (69.2%) Black or African American subjects experienced 52-week PSA CR (P=.50). Median TTCR was not reached; castrate resistance at 2 and 4 years was 62.4% and 53.5%, respectively. Eleven deaths occurred (3/14 Black or AA and 8/26 White); median OS was not reached. OS at 2 and 4 years was 83.2% and 63.1%, respectively. OS at 2 and 4 years was 85.7% and 78.6%, respectively, in Black or AA subjects and 82.4% and 50.9%, respectively, in White subjects (P=.26). Treatment-related Grade 3-5 adverse events occurred in 17/40 (42.5%) patients, including 3 episodes of febrile neutropenia. Conclusions: ADT+Doc+Enz improved 52-week PSA CR compared to historical control with ADT+Doc. These results are consistent with the recent ARASENS and PEACE1 studies and support the use of triplicate regimens combining ADT+Doc+ARSI in newly diagnosed mCSPC patients. No detectable difference in outcome by race has been observed to date in the study cohort. Clinical trial information: NCT03246347 .

Treating Primary Node-Positive Prostate Cancer: A Scoping Review of Available Treatment Options.

There is currently no consensus on the optimal treatment for patients with a primary diagnosis of clinically and pathologically node-positive (cN1M0 and pN1M0) hormone-sensitive prostate cancer (PCa). The treatment paradigm has shifted as research has shown that these patients could benefit from intensified treatment and are potentially curable. This scoping review provides an overview of available treatments for men with primary-diagnosed cN1M0 and pN1M0 PCa. A search was conducted on Medline for studies published between 2002 and 2022 that reported on treatment and outcomes among patients with cN1M0 and pN1M0 PCa. In total, twenty-seven eligible articles were included in this analysis: six randomised controlled trials, one systematic review, and twenty retrospective/observational studies. For cN1M0 PCa patients, the best-established treatment option is a combination of androgen deprivation therapy (ADT) and external beam radiotherapy (EBRT) applied to both the prostate and lymph nodes. Based on most recent studies, treatment intensification can be beneficial, but more randomised studies are needed. For pN1M0 PCa patients, adjuvant or early salvage treatments based on risk stratification determined by factors such as Gleason score, tumour stage, number of positive lymph nodes, and surgical margins appear to be the best-established treatment options. These treatments include close monitoring and adjuvant treatment with ADT and/or EBRT.

Androgen Deprivation and Radiotherapy with or Without Docetaxel for Localized High-risk Prostate Cancer: Long-term Follow-up from the Randomized NRG Oncology RTOG 0521 Trial

BackgroundIntensification of therapy may improve outcomes for patients with high-risk localized prostate cancer. ObjectiveTo provide long-term follow-up data from phase III RTOG 0521, which compared a combination of androgen deprivation therapy (ADT) + external beam radiation therapy (EBRT) + docetaxel with ADT + EBRT. Design, setting, and participantsHigh-risk localized prostate cancer patients (>50% of patients had Gleason 9–10 disease) were prospectively randomized to 2 yr of ADT + EBRT or ADT + EBRT + six cycles of docetaxel. A total of 612 patients were accrued, and 563 were eligible and included in the modified intent-to-treat analysis. Outcome measurements and statistical analysisThe primary endpoint was overall survival (OS). Analyses with Cox proportional hazards were performed as prespecified in the protocol; however, there was evidence of nonproportional hazards. Thus, a post hoc analysis was performed using the restricted mean survival time (RMST). The secondary endpoints included biochemical failure, distant metastasis (DM) as detected by conventional imaging, and disease-free survival (DFS). Results and limitationsAfter 10.4 yr of median follow-up among survivors, the hazard ratio (HR) for OS was 0.89 (90% confidence interval [CI] 0.70–1.14; one-sided log-rank p = 0.22). Survival at 10 yr was 64% for ADT + EBRT and 69% for ADT + EBRT + docetaxel. The RMST at 12 yr was 0.45 yr and not statistically significant (one-sided p = 0.053). No differences were detected in the incidence of DFS (HR = 0.92, 95% CI 0.73–1.14), DM (HR = 0.84, 95% CI 0.73–1.14), or prostate-specific antigen recurrence risk (HR = 0.97, 95% CI 0.74–1.29). Two patients had grade 5 toxicity in the chemotherapy arm and zero patients in the control arm. ConclusionsAfter a median follow-up of 10.4 yr among surviving patients, no significant differences are observed in clinical outcomes between the experimental and control arms. These data suggest that docetaxel should not be used for high-risk localized prostate cancer. Additional research may be warranted using novel predictive biomarkers. Patient summaryNo significant differences in survival were noted after long-term follow-up for high-risk localized prostate cancer patients in a large prospective trial where patients were treated with androgen deprivation therapy + radiation to the prostate ± docetaxel.