Androgen Receptor Signaling Inhibitors Research Articles

USP54 is a potential therapeutic target in castration-resistant prostate cancer

BackgroundUSP54, a ubiquitin-specific protease in the deubiquitinase (DUB) family, facilitates the malignant progression of several types of cancer. However, the role of USP54 in prostate cancer (PCa), especially castration-resistant prostate cancer (CRPC), remains unknown.MethodsWe established the CRPC LNCaP-AI cell line from the hormone-sensitive prostate cancer (HSPC) LNCaP cell line. RNA-Seq was utilized to explore DUB expression levels in LNCaP and LNCaP-AI. USP54 was knocked down, and its effects on cell growth were evaluated in vitro and in vivo. Bioinformatics analyses were conducted to explore signaling pathways affected by USP54 in PCa. Quantitative polymerase chain reaction was used to confirm key signaling pathways involved.ResultsUSP54 was the most strongly upregulated DUB in LNCaP-AI cells compared with LNCaP cells. USP54 levels were higher in PCa than in normal tissues. USP54 silencing suppressed the proliferation of PCa cell lines, both in vitro and in vivo. USP54 expression was positively correlated with the androgen receptor (AR) signaling level in PCa samples, and USP54 knockdown inhibited AR signaling in PCa cells.ConclusionsUSP54 was upregulated during HSPC progression to CRPC. USP54 depletion suppressed CRPC cell proliferation both in vitro and in vivo. USP54 may facilitate PCa progression by regulating AR signaling.

Somatostatin receptor 1 (SSTR1) expression as a potential predictive biomarker for response to androgen receptor signaling inhibitor (ARSI) therapy in metastatic castration-resistant prostate cancer (mCRPC).

180 Background: Overcoming ARSI resistance is an unmet need for mCRPC patients. Known resistance mechanisms include genetic alterations augmenting androgen receptor (AR) function (e.g., amplifications of the AR gene and its enhancer and AR mutations) and treatment-emergent evolution from an AR-driven to an AR-indifferent phenotype such as small cell neuroendocrine prostate cancer. Other mechanisms remain unexplored. Methods: To phenotype ARSI-resistant prostate cancer, we compared the RNA-seq profiles of paired metastatic biopsies from 31 mCRPC patients obtained before the initiation of first-line abiraterone or enzalutamide, and upon radiographic progression. The patient samples were obtained from two independent cohorts, the Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF) West Coast Prostate Cancer Dream Team (WCDT) and a multi-institutional cohort from the Netherlands sequenced through the Hartwig Medical Foundation. We first evaluated RNA-seq data to identify the most differentially expressed genes and then performed survival analysis in the retrospective WCDT cohort (n=115, including 54 ARSI-naïve and 61 ARSI-experienced tumors) to assess the association between gene expression and overall survival, defined as the time interval from biopsy to death from any cause. Results: In the analysis of paired RNA-seq data from 31 mCRPC patients, SSTR1 was identified as the most significantly altered gene; SSTR1 expression was consistently decreased in post-treatment, ARSI-resistant tumors (log2[fold change]=-2.5, p=1.08×10-16). SSTR1 encodes somatostatin receptor 1, a G-protein coupled receptor that, when activated by the endogenous peptide hormone somatostatin or exogenous somatostatin analogues, mediates anti-proliferative, anti-migratory, and anti-secretory effects on target cells. Retrospective analysis in the 115 WCDT patients demonstrated that low SSTR1 expression was associated with worse overall survival ( p=0.047); ARSI treatment improved survival for patients with SSTR1-high (≥ median) tumors (HR=0.29, p=0.0002) more significantly than those with SSTR1-low (< median) tumors (HR=0.67, p=0.17), with an interaction ( SSTR1 expression * ARSI treatment) towards statistical significance ( p=0.0598). A differential survival benefit of ARSI therapy with respect to SSTR1 expression was observed only among the 61 ARSI-experienced patients. Conclusions: SSTR1 expression is a potential predictive biomarker for response to ARSI in mCRPC, with higher SSTR1 expression predicting better response. This observation could be explained by an anti-tumor effect of SSTR1 signaling. Further work is warranted to prospectively validate these findings and to investigate SSTR1 as an actionable drug target to overcome ARSI resistance.

Nonadherence to medications for chronic conditions and risk of nonadherence to androgen receptor signaling inhibitors (ARSIs) in patients with prostate cancer.

92 Background: While ARSIs have become a cornerstone in treatment for prostate cancer, nonadherence to these oral medications is common. We investigated the association between patterns of prior nonadherence to medications for chronic conditions with ARSI nonadherence. Methods: In this retrospective cohort study, the MarketScan database was searched for patients >18 years old with a prostate cancer claim between 1/1/2014 and 12/31/2019 and who filled >2 ARSI prescriptions between 9/1/2013 and 12/31/2020. Nonadherence to medications for 4 chronic conditions (hypertension, hyperlipidemia, diabetes, benign prostatic hypertrophy (BPH)) in the 12 months before diagnosis was defined as a medication possession ratio (MPR) <80%. Nonadherence to ARSIs was defined as an MPR <80% between the first and last ARSI prescription up to 1 year. We used logistic regression to examine the relationship between nonadherence to prior medications and nonadherence to ARSIs. Results: Among 4,898 patients, 967 (19.7%) were nonadherent to ARSIs. Regarding prior medication nonadherence, of the patients prescribed hypertension medications (n=2602), 15.4% (n=402) were nonadherent to hypertension medications, of those prescribed hyperlipidemia medications (n=2234), 18.8% (n=419) were nonadherent to hyperlipidemia medications, of those prescribed diabetes mediations (n=826), 19.1% (n=158) were nonadherent to diabetes mediations, and of those prescribed BPH medications (n=1827), 13.4% (n=245) were nonadherent to BPH medications. Among those without prior medications (n=1031 [21.1%]), 21.3% of patients were nonadherent to ARSIs. Compared to those without prior medications, those who used at least 1 medication prior to ARSI and were adherent to all of them (n=2919 [59.6%]) had a 17.2% nonadherence rate to ARSI treatment (OR: 0.77; 95% CI: 0.64, 0.91; p: 0.003). Those who used at least 1 medication prior to ARSI and were nonadherent to 1 of them (n=722 [14.7%]) had a 24.0% nonadherence rate to ARSI (OR: 1.16; 95% CI: 0.93,1.46; p: 0.195), while those who used at least 1 medication prior to ARSI and were nonadherent to >2 (n=226 [4.6%]) had a 30.5% nonadherence rate to ARSI (OR: 1.62; 95% CI: 1.18,2.23; p: 0.003). Conclusions: Nonadherence to medications for chronic conditions prior to ARSI treatment is common and associated with greater nonadherence to ARSIs in patients with prostate cancer. History of medication nonadherence could serve a marker to target a high-risk population for adherence interventions. [Table: see text]

A phase 1/2 study of ONCT-534, a dual-action androgen receptor inhibitor (DAARI), in patients with metastatic castration-resistant prostate cancer.

TPS241 Background: Current therapeutic strategies for metastatic castration-resistant prostate cancer (mCRPC) include treatment with next-generation androgen receptor signaling inhibitors (ARSIs), such as enzalutamide, darolutamide, and apalutamide, which all target the ligand-binding domain (LBD) of the AR, and abiraterone, an androgen biosynthesis inhibitor. Approximately 5% to 10% of patients will have primary resistance to ARSIs and most initial responders will develop resistance within 1 to 3 years. Eventually, nearly all men with prostate cancer treated with ARSIs develop resistance via several mechanisms including activation of AR genomic alterations, epigenetic alterations, and expression of truncated constitutively active AR splice variants. Hence, there is substantial unmet need for treatment of men with mCRPC resistant to at least one next-generation ARSI. ONCT-534 is a DAARI with a novel mechanism of action that combines inhibition of AR function with degradation of the AR protein. Importantly, this activity includes interaction with the N-terminal domain (NTD), rendering it effective against splice variants and LBD mutants, unlike existing ARSIs. ONCT-534 has demonstrated preclinical activity in prostate cancer models against unmutated AR and multiple forms of AR alteration, including amplification, mutations in the LBD, and splice variants with loss of LBD. Methods: ONCT-534-101 is a phase 1/2, multi-center study to evaluate the safety, tolerability, antitumor activity, and pharmacokinetics of ONCT-534 in subjects with mCRPC without neuroendocrine differentiation or small cell features who have relapsed or are refractory (R/R) to at least one next-generation ARSI. The study will be separated into a Phase 1 Dose Escalation and a Phase 2 Dose Expansion. The Phase 1 portion will evaluate approximately 27 subjects in 5 dose levels using an adaptive Bayesian Optimal Interval (BOIN) design to assess safety, tolerability and DLT at escalating doses and to determine the MTD and inform the 2 dose levels or schedules to be tested in Phase 2. DLTs will be assessed during the first 28 days of treatment. The AR phenotype and AR levels of each subject’s disease will be evaluated pre- and post-treatment. The Phase 2 portion will evaluate approximately 32 subjects in 2 randomized cohorts to assess safety and tolerability of ONCT-534, compare the 2 different dose levels or schedules to select the optimal dose for further study, and assess the preliminary antitumor activity of ONCT-534. In both phases, after a screening period, eligible subjects with mCRPC will receive their assigned dose regimen of ONCT-534, which will be administered orally daily for 2 years or until disease progression and no longer clinically benefiting from treatment or development of unacceptable toxicity. The study was opened for enrollment September 2023. Clinical trial information: NCT05917470 .

Toxicity-benefit analysis of advanced prostate cancer trials using weighted toxicity scoring.

110 Background: The weighted toxicity score (WTS) is a metric suitable for comparing the toxicity burden in experimental versus control arms of randomized controlled trials (RCTs). When compared against clinical endpoints, the WTS can be used to evaluate the cost versus benefit of anti-cancer agents. This study sought to apply the WTS to prostate cancer (PC) clinical trials. Methods: Select phase 3 PC RCTs with reported adverse event (AE) data were compiled. The WTS was computed for each trial arm and compared to reported hazard ratios (HRs) of primary and/or secondary endpoints (i.e., overall survival (OS) and progression-free survival (PFS)). Average WTSs for the experimental versus control arms were used to calculate the toxicity differential between treatment arms. Average HRs for OS and PFS were used to compare efficacy. Results: Sixteen RCTs were analyzed (investigational agents: androgen-receptor signaling inhibitors (ARSi) [n = 4], poly (ADP-ribose) polymerase inhibitors (PARPi) monotherapy [n = 3], ARSi + PARPi as well as ARSi + ARSi combination therapies [n = 3 each], and triple therapy [n=3]). The median number of distinct reported AEs across all studies was 18 (range, 9-61). Overall, toxicity and efficacy were greater among experimental than control arms (6.62 versus 4.00 median WTS; median HR for OS 0.71, median HR for PFS 0.61). The triple therapy studies observed the lowest increase in toxicity by adding an ARSi to control therapy (10.4%), associated with 52% lower risk of progression, and 29% lower risk of death. Comparably, the ARSi + PARPi trials noted the highest increase in toxicity (79.7%), with 32% lower risk of progression and 12% lower risk of death. The PARPi monotherapy, ARSi monotherapy, and ARSi + ARSi combination therapy studies reported increased toxicity due to experimental therapy in descending order (Table). Conclusions: The WTS enables toxicity versus benefit assessment for anti-cancer regimens. Clinical application of this metric may facilitate individualized treatment planning in advanced PC management. [Table: see text]

Systemic and tumor-directed therapy for oligorecurrent metastatic prostate cancer (SATURN): Primary endpoint results of a phase II clinical trial.

174 Background: Nearly all men with metastatic hormone-sensitive prostate cancer who receive intermittent androgen deprivation therapy (ADT) will experience a relapse within six months of testosterone recovery. We hypothesized that intensifying intermittent ADT with dual next-generation androgen receptor signaling inhibitors (ARSIs) and adding metastasis-directed stereotactic body radiotherapy (SBRT) would significantly increase the number of men who remain relapse-free six months after testosterone recovery. Methods: Men with 1-5 extrapelvic metastases on prostate-specific membrane antigen (PSMA) PET/CT after initial treatment with definitive-intent radical prostatectomy were enrolled on this phase II study (NCT03902951). Men with visceral metastases were excluded. Patients were treated with 6 months of androgen annihilation therapy (AAT) using leuprolide, abiraterone acetate plus prednisone, and apalutamide. After the first month of AAT, patients received SBRT to all metastases with or without radiotherapy directed to the prostate bed and pelvic lymph nodes. The primary endpoint was the percentage of patients who maintained PSA <0.05 ng/mL six months after testosterone recovery to ≥150 ng/dL, with the study powered to detect an improvement from 1% to 12%. Secondary endpoints included progression-free survival (PFS) starting from AAT initiation and, for patients whose testosterone recovered, eugonadal PFS starting from the time of testosterone recovery. Progression was defined as PSA ≥0.05 ng/mL. Results: 28 men enrolled from March 2021-June 2022. Median follow-up was 20 months (range: 14–27 months). Twenty patients (71.4%) completed six months of ADT with dual ARSIs and SBRT, 5 patients (17.9%) completed ADT with a single ARSI and SBRT, 1 patient (3.6%) completed six months of ADT monotherapy with SBRT, and 2 patients (7.1%) withdrew prematurely. 13/26 patients (50%) maintained PSA <0.05 ng/mL six months after testosterone recovery (95% confidence interval [CI]: 32–67%) compared to the study hypothesis of 12%. Median PFS was 19.3 months (95% CI: 12.8–25.7). 1-year PFS was 69.2%. 21/26 patients (81%) had testosterone recovery at a median of 9.4 months (95% CI: 8.5–10.4) from the start of AAT. Median eugonadal PFS was 11.4 months (95% CI: 4.9–18.0). AAT had 21.4% grade 2 and 21.4% 3 toxicity rates. SBRT had 7.7% grade 2 and no grade 3 toxicity. Conclusions: Half of men with PSMA PET-defined oligorecurrent M1a-b disease who received six months of AAT and metastasis-directed SBRT remained relapse-free six months after testosterone recovery. The regimen was well tolerated, with 90% of patients completing six months of ADT and at least one next-generation ARSI. Further prospective data will evaluate whether dual ARSIs are necessary and the extent to which SBRT with short-course AAT outperforms SBRT with ADT monotherapy in this patient population. Clinical trial information: NCT03902951 .

Real-world clinical outcomes of patients treated with Lu-177-PSMA-617 for metastatic castration-resistant prostate cancer (mCRPC): A single-institution experience.

83 Background: The radiopharmaceutical Lu177-PSMA-617 (LuPSMA) was FDA approved in March 2022 for patients with mCRPC previously treated with both an androgen receptor signaling inhibitor (ARSI) and a taxane, if eligible based on PSMA PET. However, data regarding real world LuPSMA treatment outcomes are limited. Methods: This is a retrospective analysis of the first 100 mCRPC patients who received at least 1 cycle of LuPSMA at a single institution from June 2022 to August 2023. Demographic and clinical characteristics as well as laboratory values were collected. Central review of qualifying PSMA PET/CT was performed to assess disease distribution. A PSA decrease of 30%, 50%, or 90% from baseline at any point during treatment was the primary measure of response (PSA30, PSA50, and PSA90 respectively). Results: Of the 100 patients identified, 2 were excluded from analysis due to prior receipt of LuPSMA on clinical trial. Three patients were still receiving LuPSMA at the time of data collection. Median age was 72 (range, 50 - 93) and median number of treatments received was 4.0. On baseline PET/CT, 43 patients (44%) had bone + nodal metastases only, 19 (19%) had bone metastases only, 8 (8%) had nodal metastases only, and 11 (11%) had liver metastases. As for prior therapies, 47% had received ≥2 ARSIs (n=47/98), 48% had received 2 prior taxanes (n= 47/98), 42% had received 1 prior taxane (n=41/98), 17% received radium-223 (n=17/98), and 10% were treated off-label with no prior chemotherapy (n=10/98). Median follow up from the start of LuPSMA treatment was 7.6 months (range= 0.6-14.1 months, n=98). During treatment, 21 (21%) patients achieved a PSA90 response, 51 (52%) patients achieved a PSA50 response and 60 (61%) patients achieved a PSA30 response. An increase or no change in baseline PSA was seen in 28% (n=26/94 evaluable patients). Among patients with an initial rise in PSA after the first treatment, 10% had a subsequent reduction from baseline PSA (n=3/29). Conclusions: In this cohort of heavily pretreated mCRPC patients, we observed a PSA50 response of 54% and 21% of patients experiencing a PSA reduction ≥90%. This data supports the clinical benefit of LuPSMA in real-world clinical practice. Characterization of response rates within subgroups by prior treatment and disease characteristics are ongoing.

A multi-center retrospective cohort study of patients with mCRPC who received lutetium Lu177 vipivotide tetraxetan.

89 Background: Lu177-vipivotide tetraxetan (Pluvicto) (Lu177-Plu) is the first FDA approved theragnostic for mCRPC. Since FDA approval in March 2022, there have been no published multicenter evaluations of real-world experiences with Lu177-Plu in the United States (US). We therefore present data from 2 academic centers on patient (pt) characteristics, treatment patterns and outcomes for mCRPC pts receiving SOC Lu177-Plu. Methods: Retrospective data was aggregated from University of Chicago & Vanderbilt University on pt demographics, disease course and treatment for mCRPC pts who received SOC Lu177-Plu between 6/1/2022 and 9/1/2023. Research was conducted under IRBs VU211334 and IRB23-0718. 146 pts were identified who completed Lu177-Plu treatment by data cutoff 9/1/2023; their data is reported here. Results: Median age at cycle 1 (C1) was 72 years (range 49-93). Self-reported race was Black (23%), White (65%), Other/Unknown (UNK) (12%). Mean distance from home to treatment center was 79 mi. (range 1-1,317); 37% travelled > 50 mi. At diagnosis, Gleason score was >8 in 57%; 55% had locoregional disease, 44% had metastases, 1% were UNK. Median lines of prior systemic therapy were 4 (range 1-6), 95% received prior taxane(s) and 100% received prior androgen receptor signaling inhibitor (ARSI); 67% received 2 prior ARSI classes. PSMA-PET scan reported disease in bone in 93% of pts, lymph node 63%, liver 14%, lung 6%, other 25% (mostly prostate & soft tissue). While undergoing 177Lu-Plu, 10% received concurrent ARSI (n=9 abiraterone, n=6 enzalutamide). Median cycles received was 3.5. 27 pts (18%) discontinued after C1, 46 (32%) after C2/3, 24 (16%) after C4/5 and 49 (34%) completed 6 cycles. 38% had a PSA > 50% decline on treatment. 71 pts (49%) got scans between C1 and C6. Reasons cited for discontinuation prior to 6 cycles (n=97) included: progressive disease (including radiographic and/or PSA progression) (31%), progressive disease and toxicity (13%), toxicity (30%), clinical decline (including ECOG PS, transition to hospice or death) (23%), other (3%). 36 pts (25%) required supportive care with blood products (n=35 RBC, n=2 platelets). At data cutoff, 73 of 146 pts were alive (confirmed (n=66), unconfirmed (n=7)). Of deceased patients, median survival from C1 to death was 4.8 months (range 0.4-11.7). Conclusions: To our knowledge, this is the largest multicenter retrospective analysis of a racially diverse cohort of mCRPC pts receiving SOC Lu177-Plu following FDA approval in the US. PSA decline, median number of cycles received, fraction not requiring blood products in this cohort were all lower than in the VISION trial, likely due to baseline pt characteristics and potentially more liberal pt selection. Our data highlights numerous areas of need: expanded geographic access, optimized pt selection, standardization of scan type and interval on therapy and further data on concurrent therapy.

Analysis of real-world survival for patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) or abiraterone acetate (ABI) in an oncology database: ROMA study.

58 Background: Androgen receptor signaling inhibitors (ARSI), including APA and ABI plus prednisone, are approved for the treatment of mCSPC. However, studies evaluating survival for these agents in clinical trials or the real-world have not been investigated. This study describes real-world survival among men with mCSPC who initiated APA or ABI in the United States (US). Methods: Data from the Flatiron Metastatic Prostate Cancer (PC) Core Registry Electronic DataMart (1/1/2013–05/31/2023) was used to identify ARSI-naïve patients with chart-confirmed metastasis and without evidence of castration resistance at ARSI initiation. Patients were classified into two treatment cohorts based on the start date for APA or ABI (index date) on/after 9/17/2019. Patients had ≥12 months of clinical data pre-index and were followed from the index date until the earliest of 24 months post-index, end of clinical activity, or end of data availability. Patients’ date of death was obtained by integrating data from electronic medical records, the Social Security Death Index, and or other confirmed sources. Using an intention-to-treat approach, Kaplan-Meier analysis was used to describe the proportion of patients surviving by 24 months post-index. An unadjusted Cox proportional hazards model was used to describe crude differences in survival rates between patients initiating APA and ABI. Results: This study included 242 APA (mean age: 73.0 years; 60.3% White, 13.6% Black) and 607 ABI (mean age: 73.1 years; 57.3% White, 16.8% Black) patients. APA median time on-treatment was 11.4 months over a median observation period of 14.3 months. ABI median time on-treatment was 10.8 months over a median observation of 14.0 months. By 24 months, 85.7% of the APA cohort and 75.9% of the ABI cohort were living (unadjusted hazard ratio=0.60, 95% confidence interval: 0.38, 0.96; p=0.033; Table). Conclusions: In this study, we observed that more ARSI-naïve patients with mCSPC survived by 24 months after initiating APA than those who initiated ABI. While the current study presents unadjusted comparisons, additional causal analyses controlling for confounding variables should be conducted to confirm these initial findings. [Table: see text]

Understanding variation in treatment intensification for de novo metastatic castration-sensitive prostate cancer (mCSPC): A population-based cohort study.

69 Background: Treatment intensification using androgen receptor signaling inhibitors (ARSIs) or chemotherapy is guideline-recommended for patients with mCSPC based on improved survival and preserved quality of life. However, numerous studies across jurisdictions have shown relatively limited uptake, with most patients receiving androgen deprivation therapy (ADT) monotherapy. Therefore, we sought to understand patient, physician, and tumor characteristics associated with treatment intensification. Methods: This population-based cohort study in Ontario, Canada included older men (age ≥66 years) diagnosed with de novo mCSPC between Jan 2014 and Nov 2021 for whom the ADT-prescribing physician could be identified (>99.5% of all mCSPC patients). We used hierarchical regression modelling to assess the association (presented as odds ratio, OR) between patient sociodemographic characteristics and comorbidities, tumor characteristics, and physician characteristics with receipt of intensified treatment for mCSPC, defined as receipt of an ARSI, docetaxel, or both within 6mo. We used Darlington’s method to assess the relative importance of these predictors (presented as standardized regression coefficients, SRC). Results: Among 4450 eligible older men newly diagnosed with de novo mCSPC, 18.8% received treatment intensification, with rates increasing from 6.3% in 2014 to 31.9% by 2021. In multivariable modeling, patient age was the most influential variable, with older patients significantly less likely to receive treatment intensification (SRC -43.8, OR 0.91, 95% CI 0.90-0.92). Socioeconomic status (SRC -12.2; OR 0.54, 95% CI 0.33-0.88 for quintile 1 vs 5) and a history of stroke (SRC -11.5, OR 0.28, 95% CI 0.09-0.86), but no other patient factors including comorbidity, were significantly associated with intensification. Patients prescribed ADT for mCSPC by radiation oncologists were less likely to receive intensification (SRC -16.5; OR 0.47, 95% CI 0.23-0.95) compared to other providers without significant differences between patients treated by urologists, medical oncologists, or other physicians. No other physician-level characteristic (age, sex, years in practice, or annual volume of prostate cancer patients) was associated with treatment intensification. More contemporary year of diagnosis was also strongly predictive (mean SRC 31.2) of intensification. We noted significant geographic variation (mean SRC 10.2; p<0.0001), that could not be explained by rurality (p=0.08) and persisted after adjustment for socioeconomic status and patient characteristics. Conclusions: Patient, disease, and physician characteristics contribute to variation in treatment intensification for mCSPC. These data may allow focused intervention to improve guideline-concordant care for patients with mCSPC.

Survival Outcomes of APA as a Starting treatment: Impact in real-world patients with mCSPC (OASIS).

65 Background: Over the last decade,androgen receptor signaling inhibitors (ARSIs; apalutamide [APA], enzalutamide [ENZ], abiraterone acetate + prednisone [AAP]) in combination with androgen-deprivation therapy (ADT) have emerged as more effective life-prolonging treatment options for mCSPC. We examined the impact of ARSI starting therapy in mCSPC on long-term clinical outcomes in real-world clinical practice in the US. Methods: This retrospective, observational cohort study evaluated clinical outcomes in adult patients with mCSPC using the ConcertAI RWD 360 prostate cancer dataset. All patients with newly diagnosed mCSPC from 1 Jan 2018 to 30 Sept 2022 were enrolled and followed up until 31 Mar 2023. Among other outcomes, PSA50 and PSA90 (PSA response defined as a ≥50% and ≥90% decline from baseline, respectively) and undetectable PSA (PSA ≤0.2 ng/mL) were assessed using the Kaplan-Meier method. Relative risks of onset of castration resistance (CR) and death were estimated using multivariate Cox proportional hazard models adjusted for potential confounding factors (age, comorbidities, BMI, baseline PSA). Results: 165 patients with mCSPC started on APA + ADT, 643 started on ENZ + ADT, 1064 on AAP +ADT, 293 on docetaxel (DTX) + ADT, and 543 on ADT alone (Table). A higher proportion of patients initiating APA achieved PSA50, PSA90, or undetectable PSA compared with other treatments. CR-free survival was significantly longer in patients first treated with an ARSI + ADT than those treated with DTX + ADT or ADT alone. Reduced risk of developing CR was observed in patients starting with APA + ADT compared with ADT alone (adjusted hazard ratio [aHR] 0.36, 95% CI 0.19, 0.67; p=0.0016). OS was longer in patients started on ARSIs compared to ADT alone. Patients starting with APA + ADT were observed to have a lower risk of death compared with ENZ + ADT (aHR 0.48, 95% CI 0.23, 0.99; p<0.05) or AAP + ADT (aHR 0.43, 95% CI 0.21, 0.90; p<0.05). Conclusions: ADT alone continues to be used widely despite the availability of newer and more effective life prolonging therapies. Use of APA + ADT as starting treatment for mCSPC demonstrated significantly better clinical outcomes than other ARSIs, DXT + ADT, or ADT alone in real-world clinical practice in the US. [Table: see text]

Real-world survival of men with metastatic castration-sensitive prostate cancer (mCSPC) initiated on apalutamide (APA) or enzalutamide (ENZ) in an oncology database: ROME Study.

57 Background: Androgen receptor signaling inhibitors (ARSIs), including APA and ENZ, have demonstrated progression-free and overall survival benefits for men with mCSPC in the clinical trial setting, but data evaluating real-world treatment effectiveness remains limited. The aim of this study was to describe real-world survival among men with mCSPC who initiated APA or ENZ in the United States (US). Methods: In this retrospective longitudinal cohort study, clinical data from the Flatiron Metastatic Prostate Cancer (PC) Core Registry Electronic DataMart (1/1/2013–05/31/2023) were used. Patients with chart-confirmed metastasis and without castration resistance were classified into two treatment cohorts based on earliest initiation of APA or ENZ on/after 12/16/2019 (index date). Patients had ≥12 months of clinical data pre-index and were followed from the index date until the earliest of 24 months post-index, end of clinical activity, or end of data availability. Patients’ date of death was obtained from electronic medical records, Social Security Death Index, or other confirmed sources. Using an intention-to-treat approach, Kaplan-Meier analysis was used to describe the proportion of patients surviving by 24 months post-index. An unadjusted Cox proportional hazards model was used to describe crude differences in survival rates between patients initiating APA and ENZ. Results: There were 234 APA (mean age: 73.2 years; 59.8% White, 13.7% Black) and 527 ENZ (mean age: 73.9 years; 55.2% White, 13.1% Black) patients included in this study (Table). APA median time on-treatment was 10.9 months over a median observation period of 13.3 months, while ENZ median time on-treatment was 11.1 months over a median 14.8 months observation period. By 24 months, a higher proportion of patients in the APA cohort survived than in the ENZ cohort (85.4% vs 73.9%; unadjusted hazard ratio=0.59, 95% confidence interval: 0.39, 0.95; p=0.030; Table). Conclusions: In this real-world analysis of patients with mCSPC, more patients treated with APA survived by 24 months following treatment initiation as compared to treatment with ENZ. While the current study reports unadjusted analyses, future studies adjusting for potential confounding variables should be conducted to confirm these findings in order to inform clinicians on treatment selection for patients with mCSPC. [Table: see text]

Prostate-specific antigen (PSA) response among patients with metastatic castration-sensitive prostate cancer (mCSPC) initiated on apalutamide (APA) or abiraterone acetate (ABI) in real-world urology practices.

53 Background: Recently approved oral therapies APA and ABI (plus prednisone) are effective mCSPC treatments. Prior real-world evidence showed that, relative to ABI, patients who initiated APA had significantly higher rates of PSA decline ≥90% (PSA90), which has been associated with longer overall survival. The objective of this study was to compare PSA90 response among an enhanced cohort of patients with mCSPC initiated on APA or ABI. Methods: Electronic medical records from PPS Analytics including data from US community urology practices were linked with administrative claims from the Komodo Health Solutions Research Database. Androgen receptor signaling inhibitor (ARSI)-naïve patients with mCSPC with ≥12 months of pre-index clinical activity were selected into the APA or ABI cohort based on their first paid claim/dispensation on or after 17 Sep 2019 (index date). Patients were followed to earliest of index ARSI discontinuation or switch, radiopharmaceutical use, end of insurance or clinical activity, or end of data availability (30 Sep 2022). Inverse probability treatment weighting (IPTW) was used to reduce potential pre-index confounding, controlling for age, race, region, insurance payer, index year, time from metastasis to index date, time from first prostate cancer (PC) diagnosis to index date, metastasis locations, de novo PC, use of androgen deprivation therapy, first-generation antiandrogens or chemotherapy, most recent PSA and testosterone levels, and most recent Gleason score. PSA90 was defined as the earliest attainment of ≥90% decline in PSA relative to pre-index (most recent value within 13 weeks). The proportion of patients achieving PSA90 was compared using a weighted Kaplan-Meier analysis and the time-to-PSA90 response was compared using a weighted Cox proportional hazards model. Results: A total of 917 APA and 632 ABI patients were identified. Patient characteristics were balanced with IPTW (Table). By 6 months post-index, 80.9% of APA and 72.8% of ABI patients had a PSA measurement. By 6 months, significantly more APA patients attained a PSA90 response, as compared to ABI patients (P < 0.001; Table). Median time-to-PSA90 was 3.5 months for APA patients and 8.8 months for ABI patients. Conclusions: This real-world study supports previous findings that a greater percentage of patients with mCSPC in the US initiating APA achieved deep PSA response compared to those initiating ABI. [Table: see text]

Post radical prostatectomy (RP) PSA outcomes following 6 versus 18 months of perioperative androgen receptor signaling inhibitors (ARSI) in men with localized high-risk prostate cancer: Results of Part 2 of a randomized phase 2 trial.

326 Background: Patients with localized high-risk prostate cancer have an increased risk of relapse following RP. We previously reported on Part 1 of a phase 2 trial testing neoadjuvant apalutamide, abiraterone acetate, prednisone, plus leuprolide (AAPL) or abiraterone, prednisone, and leuprolide (APL) for 6 months followed by RP. We demonstrated favorable pathologic responses (tumor ≤5 mm) in 20.3% of patients (n=24/118). Herein, we report the results of Part 2 testing adjuvant AAPL. Methods: At Part 2, patients were randomized 1:1 to AAPL for 12 months (Arm 2A) or observation (Arm 2B), stratified by neoadjuvant therapy and pathologic T stage (<ypT3 or ≥ypT3). The primary endpoint was biochemical progression-free survival (bPFS) at 3 years post-RP. Secondary endpoints included safety and time to testosterone recovery (>200 ng/dL). Results: Overall, 69% (n=82/118) of patients enrolled to Part 1 were randomized to Part 2, of whom 58.5% (n=48) had ≥ ypT3 disease at RP. Patient preference was the main reason for non-randomization in Part 2. Of patients not randomized to Part 2, 32.3% (n=10) had a pathologic complete response or minimum residual disease (tumor ≤5 mm) at RP. In the intent-to-treat analysis, 3-year bPFS was 81% for Arm 2A and 72% for Arm 2B; the difference was not statistically significant (HR 0.81 90% CI 0.43-1.49). In a post-hoc per-protocol analysis, the 3-year bPFS was 83% for AAPL treated patients and 69% for patients on observation (HR 0.50 90% CI 0.26-0.97). Of patients randomized to Part 2, 81% of patients had testosterone recovery in the AAPL treated group compared to 95% in the observation group with median to recovery of 8.7 months compared to 4.0 months, respectively. Of the 37 patients receiving AAPL on Arm 2A, 28 (75.7%) experienced any grade treatment-related adverse event (TRAE) and 4 (10.8%) had grade 3-4 TRAE. The most common any grade TRAE were fatigue (27%) and hypertension (16%). Conclusions: Neoadjuvant ADT in localized high-risk prostate cancer resulted in favorable pathologic responses and 3-year bPFS in a subset of patients. As 30% of patients declined an additional 12 months of adjuvant treatment, Part B of the study was underpowered to detect a difference between treatment arms. Subsequent studies will evaluate clinical and molecular predictors of bPFS. Clinical trial information: NCT02903368 .

Real-world economic burden of patients with metastatic castration-sensitive prostate cancer (mCSPC).

64 Background: In patients with prostate cancer (PC), progression to a metastatic disease stage is associated with substantial decline in prognosis as well as incremental economic burden. There is limited real-world evidence combining clinical data and payer claims to evaluate economic outcomes of patients with mCSPC. This study described healthcare costs of patients with mCSPC before and after the initiation of advanced therapy. Methods: Linked data from the Flatiron Metastatic PC Core Registry and all-payer claims data from Komodo Health Solutions were evaluated (Jan 2016 to Dec 2021). Patients in Flatiron who initiated advanced therapy for mCSPC (index date) in 2017 or later and had a corresponding pharmacy or medical claim in Komodo, following evidence of metastasis in the absence of castration resistance were included. Advanced therapies considered were androgen-receptor signaling inhibitors, chemotherapies, estrogens, immunotherapies, poly ADP-ribose polymerase inhibitors, and radiopharmaceuticals. Patients were excluded if they initiated a clinical trial drug as their index regimen or had <12 months of health insurance eligibility pre-index. All-cause and PC-related total costs (medical and pharmacy) per-patient-per-month (PPPM) were described from a payer’s perspective in the 12-month pre- and post-index period using 2022 US dollars. The post-index period was censored at evidence of castration resistance. Flatiron Health, Inc. did not participate in data analyses. Results: In total, 418 patients with mCSPC were identified (mean age 68 years, 56% white, 53% commercially insured, and 37% on Medicare). Pre-index androgen deprivation therapy was observed in 74% of patients. Pre-index, mean all-cause costs were $2,334 PPPM and PC-related costs were $964 PPPM with $90 PPPM attributable to PC-related pharmacy costs (Table). Post-index, patients averaged 14.5 months of follow-up, in which mean all-cause costs were $8,829 PPPM with PC-related costs of $7,232 PPPM, an increase of >7 times compared to pre-mCSPC therapy initiation. Conclusions: This real-world study demonstrated that costs associated with disease progression in PC are significant and lead to a need for more innovative therapies and medical management in this patient population. Approaches that effectively slow disease progression at earlier stages of PC disease may result in better overall outcomes and lower overall costs associated with progression to metastatic disease. [Table: see text]

Interaction of age and benefit of treatment intensification in advanced prostate cancer: An aggregate meta-analysis of 14 randomized trials.

118 Background: Treatment intensification (TI) for men with advanced prostate cancer consistently demonstrates improvements in overall survival (OS) when compared to androgen deprivation therapy (ADT) alone. However, TI increases morbidity and may contribute to worsening other-cause mortality. Herein, we aim to determine if there is an interaction of age and TI on OS in men with advanced prostate cancer. Methods: A systematic literature search in MEDLINE, Embase, and conference proceedings were searched to identify contemporary randomized phase 3 trials in advanced prostate cancer evaluating the role of TI with chemotherapy and/or androgen receptor-signaling inhibition (ARSI) between 1/1/2010-9/1/2023. Trials in metastatic hormone-sensitive prostate cancer (mHSPC) and non-metastatic castration-resistant prostate cancer (nmCRPC) were included given potential for competing risks; mCRPC trials were excluded. Meta-analyses were performed with random-effect modeling. Meta-regression was performed using Hartung-Knapp methods in mHSPC trials accounting for drug (docetaxel, abiraterone acetate/prednisone (AAP), non-AAP ARSIs (apalutamide, enzalutamide, or darolutamide)), use of RT to primary, percent high volume disease, percent synchronous metastatic disease, and median PSA. Age was dichotomized as < or ≥ 70 in 8 trials, and < or ≥ 65 in 6 trials. Results: Fourteen trials with 16 randomized comparisons (n=17,765 patients) were included. A total of 9,229 younger and 7,458 older men were included in age-specific analyses. Overall, TI significantly improved OS (HR 0.72, 95%CI 0.69-0.76, p<0.0001), which was consistent irrespective of disease state (mHSPC HR 0.72, 95%CI 0.78-0.77; nmCRPC HR 0.74, 95%CI 0.66-0.83). There was a significant interaction between age and TI on OS (p-interaction <0.001); TI in younger men significantly improved OS (HR 0.65, 95%CI 0.59-0.72, p<0.0001). Older men derived less benefit from TI, but TI did improve OS (HR 0.80, 95%CI 0.74-0.87, p<0001). In subgroup of older men in mHSPC trials, a significant treatment effect difference based on drug class was observed (p=0.047); AAP (HR 0.92, 95%CI 0.78-1.10, p=0.38), docetaxel (HR 0.86, 95%CI 0.70-1.05, p=0.13), and non-AAP ARSIs (HR 0.71, 95%CI 0.63-0.81, p<0.001). On meta-regression of mHSPC trials, age remained an independent variable associated with TI benefit (p=0.005). Limitations include the post-hoc nature of this aggregate meta-analysis and use of dichotomized age. Conclusions: TI improves OS for men with mHSPC and nmCRPC, but a significant interaction between age and TI on OS was identified. Further work leveraging individual patient data is needed to understand drivers of this observation, including impact of treatment compliance, comorbid conditions, adrenal suppression, outcomes in different prognostic groups, and competing risks in older patients.

Time to next systemic therapy after stereotactic body radiation therapy for oligoprogressive metastatic castrate-resistant prostate cancer.

62 Background: Patients with castrate-resistant prostate cancer (CRPC) with progressive disease are generally require a change/escalation in systemic therapy. For patients with limited ( ≤3) sites of progressive disease (oligoprogression), metastasis-directed therapy with stereotactic body radiation therapy (SBRT) may allow a longer interval before next line systemic therapy, but there is limited data describing this approach. Methods: This is a retrospective study of patients with oligoprogressive metastatic CRPC (omCRPC) treated with SBRT at a single center between 2011-2022. The primary endpoint was time to next systemic therapy (TTNST) after SBRT. Secondary endpoints included overall survival (OS) after SBRT and TTNST stratified by presence of untreated non-progressing metastases. Results: Thirty-two patients with omCRPC received SBRT to 38 metastases. Patients had a median age of 72.5 years (range 50.6-84.3) and median PSA 6.85 ng/mL (range 0.39-922.0) at time of SBRT. The majority had an ECOG of 1-2 (29 patients, 90.6%) and metastases detected on conventional CT and/or bone scans (26 patients, 81.3%). The most commonly utilized SBRT regimen was 3000 cGy in 5 fractions (18 metastases, 47.4%) (Table). Sixteen patients were treated to all known sites of disease, whereas 16 patients received SBRT to oligoprogressive metastases but had at least one untreated non-progressing metastasis at the time of SBRT. Of 32 patients, 23 (65.7%) received SBRT to bone only, 3 (9.4%) to lymph node (LN) only, and 6 (18.8%) to other sites (pelvic tumor, n=2; pelvic tumor + LN, n =1; LN + bone, n=1; dura + bone, n=1; liver, n=1). Patients had received a median of 1.0 prior line of androgen receptor signaling inhibitors and were predominantly (26 patients, 81.3%) chemotherapy naïve. Following SBRT, the median TTNST was 10.1 months and median OS was 41.3 months. For patients with 0 versus ≥1 untreated non-progressing metastasis, TTNST was 11.3 versus 8.7 months, respectively (HR 0.67, 95% CI 0.33-1.36, logrank p=0.24). There were no grade ≥3 toxicities due to SBRT. Conclusions: In this cohort, patients with omCRPC treated with SBRT delayed the next line of systemic therapy for a median of 10.1 months. SBRT in patients with omCRPC may delay initiation of next line systemic therapy in well selected patients, including those with ≥1 untreated non-progressing metastases. [Table: see text]

How We Treat Metastatic Castration-Sensitive Prostate Cancer.

The treatment of metastatic castration-sensitive prostate cancer (mCSPC) has seen remarkable breakthroughs over the last few years. Diagnostic and therapeutic advances have given rise to debates about risk stratification and optimal first-line treatment selection, as well as to concerns about potential overtreatment in a disease state with a highly heterogeneous clinical behavior. Here, we use case reports from our practice to review the clinical trials exploring intensified triplet regimens combining androgen deprivation therapy with second-generation androgen receptor signaling inhibitors and docetaxel, and we offer our recommendations on how to best select candidates for these novel combinations. Furthermore, the growing adoption of PET imaging with increasingly sensitive and prostate tissue-specific tracers replacing conventional staging technologies has led to the identification of a subset of low-volume mCSPC with nodal metastases which would otherwise not be considered abnormal by RECIST criteria. We describe our PSA-adapted approach to treatment in this unique population with non-measurable low-volume mCSPC which has not been specifically investigated in any phase III clinical trials. We also discuss ongoing clinical trials evaluating treatment de-escalation strategies. Finally, we review how local treatment modalities directed at the prostate or distant sites of disease in oligometastatic CSPC may benefit patients, and how we incorporate metastasis-directed therapy in the management of mCSPC.

Treatment-related Neuroendocrine Prostate Carcinoma-Diagnostic and Molecular Correlates.

Treatment-related neuroendocrine prostate cancer is a distinctive category of prostate cancer that arises after intensive suppression of the androgen receptor by next-generation therapeutic inhibition of androgen receptor signaling. The biological processes that set in motion the series of events resulting in transformation of adenocarcinoma to neuroendocrine carcinoma include genomic (loss of tumor suppressors TP53 and RB1, amplification of oncogenes N-MYC and Aurora Kinase A, dysregulation of transcription factors SOX2, achaete-scute-homolog 1, and others) as well as epigenomic (DNA methylation, EZH2 overexpression, and others). Pathologic diagnosis is key to effective therapy for this disease, and this is aided by localizing metastatic lesions for biopsy using radioligand imaging in the appropriate clinical context. As our understanding of biology evolves, there has been increased morphologic recognition and characterization of tumor phenotypes that are present in this advanced post-treatment setting. New and promising biomarkers (delta-like ligand 3 and others) have been discovered, which opens up novel therapeutic avenues including immunotherapy and antibody-drug conjugates for this lethal disease with currently limited treatment options.

Mechanism-centric regulatory network identifies NME2 and MYC programs as markers of Enzalutamide resistance in CRPC

Heterogeneous response to Enzalutamide, a second-generation androgen receptor signaling inhibitor, is a central problem in castration-resistant prostate cancer (CRPC) management. Genome-wide systems investigation of mechanisms that govern Enzalutamide resistance promise to elucidate markers of heterogeneous treatment response and salvage therapies for CRPC patients. Focusing on the de novo role of MYC as a marker of Enzalutamide resistance, here we reconstruct a CRPC-specific mechanism-centric regulatory network, connecting molecular pathways with their upstream transcriptional regulatory programs. Mining this network with signatures of Enzalutamide response identifies NME2 as an upstream regulatory partner of MYC in CRPC and demonstrates that NME2-MYC increased activities can predict patients at risk of resistance to Enzalutamide, independent of co-variates. Furthermore, our experimental investigations demonstrate that targeting MYC and its partner NME2 is beneficial in Enzalutamide-resistant conditions and could provide an effective strategy for patients at risk of Enzalutamide resistance and/or for patients who failed Enzalutamide treatment.