Androgen Receptor-targeted Agents Research Articles

Ultralow Prostate-Specific Antigen (PSA) Levels and Improved Oncological Outcomes in Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) Patients Treated with Apalutamide: A Real-World Multicentre Study.

Background/Objectives: Androgen receptor-targeted agents have significantly improved the prognosis of metastatic hormone-sensitive prostate cancer (mHSPC). Prostate-specific antigen (PSA) levels are key prognostic markers, with rapid and deep reductions associated with better outcomes. This study aims to assess the association between the new PSA cut-offs and survival in mHSPC patients treated with Apalutamide. Methods: We conducted a multicentre, retrospective analysis of mHSPC patients treated with Apalutamide between March 2021 and January 2023. Overall survival (OS) and radiographic progression-free survival (rFPS) were analyzed and stratified by the following PSA ranges: <0.02 ng/mL (ultralow), 0.02-0.2 ng/mL, and >0.2 ng/mL. Cox regression was applied to identify variables associated with OS and rPFS. Results: Among 193 patients, 34.2% had de novo mHSPC, with the majority classified as M1b. A total of 58.2% (110) of our cohort achieved ultralow PSA levels, with 20.6% between 0.02 and 0.2 ng/mL, and 21.2% of PSA levels > 0.2 ng/mL. Most patients reached ultralow PSA within six months. Low-volume, metachronous, and M1a subgroups displayed a higher prevalence of patients reaching ultralow PSA levels. At 18 months, OS was 100% in the ultralow PSA group, 94.4% for the 0.02-0.2 ng/mL group, and 67.7% in the >0.2 ng/mL group. Similarly, rPFS at 18 months was 100%, 93.5%, and 50.7%, respectively. Cox regression revealed that both ultralow PSA levels and ISUP grade had a significant impact on OS (HR of 8.256 and 0.164, respectively). For rPFS, only ultralow PSA levels had a significant impact (HR = 0.085). Conclusions: This real-world study of mHSPC patients treated with Apalutamide plus ADT revealed that achieving ultralow PSA levels is strongly associated with better oncological outcomes.

Quality of Life Determinants in Patients with Metastatic Prostate Cancer: Insights from a Cross-Sectional Questionnaire-Based Study.

Prostate cancer is one of the most prevalent malignancies affecting men globally, with a significant impact on health-related quality of life (HRQOL). With the recent therapeutic advancements and improvements in survival, there is a need to understand the determinants of HRQOL in metastatic prostate cancer patients to optimize treatment strategies for quality of life as the number of survivors increases. The aim of this study was to identify clinical variables that affect HRQOL and its domains in patients with metastatic prostate cancer. We conducted a cross-sectional questionnaire-based study in patients diagnosed with metastatic prostate cancer at a tertiary cancer center in India. Baseline clinical features, treatment details, and completed Functional Assessment of Cancer Therapy-Prostate (FACT-P), composed of FACT-general (FACT-G) and prostate cancer-specific concerns subscale (PCS) and FACT-P Trial Outcome Index (FACT-P TOI) questionnaires, were collected. The mean total, as well as individual domain scores, were calculated. Additionally, these were stratified by the current treatment being received by patients. Linear regression was used to identify independent factors affecting HRQOL in these patients. Of the 106 enrolled patients, 84 completed the FACT-P questionnaire and were included in the analysis. The median age was 66 years, and at the time of assessment, 3 patients (3.6%) were receiving androgen deprivation therapy only, 53 patients (63.1%) were on ADT + androgen receptor-targeted agents (ARTAs), and 18 patients (21.4%) patients received ADT + chemotherapy. The mean (±standard deviation) of the FACT-P TOI score was 70.33 (±15.16); the PCS subscale was the most affected, followed by functional well-being. Patients on chemotherapy scored significantly higher on PCS, but the composite scores were not significantly different. Univariable regression identified obesity (body mass index > 25 kg/m2) and duration of first-line treatment as significant predictors of better HRQOL; however, obesity was the only independent predictor in multivariable analysis (β = 8.2; 95% confidence interval, 1.2 to 15.0; p = 0.022). Obesity also independently predicted a better FACT-P and its physical well-being domain score and PCS. Prostate cancer patients experience impaired QoL, especially in the prostate cancer-specific and functional well-being domains. Lower BMI is an independent predictor of poor QoL, and this requires efforts to assess the impact of strategies to manage the nutritional status of patients with metastatic disease on QoL outcomes.

Cardiovascular risks of Asian patients on androgen-receptor-targeted agents for prostate cancer: a systematic review and meta-analysis

BackgroundProstate cancer is now one of the most prevalent cancers in men in Asia. As the average life expectancy of Asian males with prostate cancer increases with the availability of treatment options, the possible risk of cardiac-related adverse effects arising from androgen-receptor-targeted agents (ARTAs) may be increased due to the greater exposure. We aim to perform a meta-analysis on the incidence of cardiac-related adverse events in Asian patients with prostate cancer treated with ARTAs. Materials and methodsDatabases were thoroughly searched for relevant articles. The Patient Intervention Comparison Outcome Study type model was used to frame our clinical question, and 2 independent authors went through several rounds of screening to select the final included studies. A meta-analysis was conducted using the Cochran–Mantel–Haenszel method. Quality assessment was carried out with the Cochrane risk-of-bias tool RoB 2. ResultsSeven randomized controlled trials were included for the final meta-analysis. Use of ARTA in Asian men did not show any significant increase in the total number of cardiac-related adverse events (risk ratio [RR]: 1.66 [0.84–3.26], p = 0.14). However, there was increase in incidence of hypertension (RR: 2.30 [1.41–3.73], p = 0.0008) and hypertension crises (RR: 16.87 [2.13–133.34], p = 0.007). A subgroup analysis of the type of ARTA used showed enzalutamide having the highest risk of hypertension (RR: 5.86 [2.10–16.38], p = 0.0008). Conclusion:Although ARTAs did not show any significant increase in incidence of cardiac-related adverse events, there is an increased risk of hypertension especially with the use of enzalutamide. With this knowledge, closer blood pressure monitoring is needed for patients started on ARTA, especially enzalutamide.

Stereotactic Body Radiotherapy for Oligoprogression in Castration-Resistant Prostate Cancer: Early Toxicity Analysis of the TRAP Trial

AimsTo assess toxicity and patient quality of life after stereotactic body radiotherapy (SBRT) to oligoprogressive disease (OPD) in patients with metastatic castrate-resistant prostate cancer (CRPC) on androgen receptor targeted agents (ARTA). Material and methodsThis phase II trial enrolled patients with metastatic CRPC with ≤ 2 oligoprogressive lesions in bone, lymph node, lung, or prostate. All patients were receiving systemic treatment with abiraterone or enzalutamide at the time of oligoprogression. All patients received SBRT to the OPD site(s) and continued the current ARTA. Patients received 30 Gy in 5 fractions (alternate days) to the OPD site. The primary endpoint of the trial is to assess if SBRT to OPD sites results in progression free survival of >6 months. The primary endpoint for this toxicity analysis is the rate of grade 3 or higher adverse events at any timepoint up to 6 months after SBRT. Secondary endpoints included comparing pre- and post-SBRT patient-related outcomes reported using visual analogue scale scores and EQ-5D health questionnaire. ResultsForty enrolled patients had at least 6 months of follow-up at the time of analysis. Grade 3 or higher toxicity from any cause recorded using common terminology criteria for adverse events and radiation therapy oncology group was found in 8/40 (20%) of patients, but only 1/40 (2.5%) was deemed possibly related to SBRT. There was no significant difference in mean EQ5D visual analogue scale score from baseline to each timepoint after SBRT (p = 0.449). ConclusionIn this prospective phase II clinical trial for OPD whilst on ARTA in the CRPC setting, we report low grade ≥ 3 toxicity after SBRT. There is no discernible change in patient-reported quality of life due to SBRT treatment. The final results of progression-free survival and toxicity of SBRT treatment will be reported once further follow-up is complete.

전이성 호르몬 민감성 전립선암 치료를 위한 안드로겐 수용체 표적 저해제 사용의 비용-효용 분석 방법에 대한 체계적 문헌고찰

As the clinical effectiveness of androgen receptor targeting agents (ARTAs) has been proven, countries worldwide recommend ARTAs treatment to delay the progression of metastatic hormone-sensitive prostate cancer (mHSPC). This study aimed to summarize the methods and data resources by systematically reviewing the cost-utility analysis (CUA) studies of ARTAs in patients with mHSPC. PubMed, Embase and Cochrane Library databases were utilized for literature searches, and the relevant studies were selected with pre-defined inclusion/exclusion criteria according to the PRISMA guideline. The Consolidated Health Economic Evaluation Reporting Standards checklist was used to assess selected studies’ risk-of-bias. Of the 362 publications identified initially, ten eligible studies from six countries were included. All studies were trial-based CUA studies. Ten studies were selected which included eighteen CUAs (eight abiraterone acetate, four apalutamide, and six enzalutamide as interventions, and the comparator was ADT with ARTAs or docetaxel, or ADT alone). Eight studies used Markov models with key health states (mHSPC, mCRPC, death), while the rest were structured as partitioned survival analysis model and descriptive-analytical model, respectively. All the transition probabilities were derived from the pivotal clinical studies. Utility values were calculated by referring to studies that directly measured utility values such as randomized controlled trials or previous literature on economic evaluations or utility, while costs were estimated from real-world data from each country. The reporting quality of studies is valid from 79.2% to 100% (median 95.8%). The results of this study can serve as valid input values for elaborating CUA studies of ARTAs in the future.

Clinical implications of AR alterations in advanced prostate cancer: a multi-institutional collaboration.

AR gene alterations can develop in response to pressure of testosterone suppression and androgen receptor targeting agents (ARTA). Despite this, the relevance of these gene alterations in the context of ARTA treatment and clinical outcomes remains unclear. Patients with castration-resistant prostate cancer (CRPC) who had undergone genomic testing and received ARTA treatment were identified in the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) database. Patients were stratified according to the timing of genomic testing relative to the first ARTA treatment (pre-/post-ARTA). Clinical outcomes such as time to progression, PSA response, and overall survival were compared based on alteration types. In total, 540 CRPC patients who received ARTA and had tissue-based (n = 321) and/or blood-based (n = 244) genomic sequencing were identified. Median age was 62 years (range 39-90) at the time of the diagnosis. Majority were White (72.2%) and had metastatic disease (92.6%) at the time of the first ARTA treatment. Pre-ARTA genomic testing was available in 24.8% of the patients, and AR mutations and amplifications were observed in 8.2% and 13.1% of the patients, respectively. Further, time to progression was longer in patients with AR amplifications (25.7 months) compared to those without an AR alteration (9.6 months; p = 0.03). In the post-ARTA group (n = 406), AR mutations and AR amplifications were observed in 18.5% and 35.7% of the patients, respectively. The most common mutation in post-ARTA group was L702H (9.9%). In this real-world clinicogenomics database-driven study we explored the development of AR alterations and their association with ARTA treatment outcomes. Our study showed that AR amplifications are associated with longer time to progression on first ARTA treatment. Further prospective studies are needed to optimize therapeutic strategies for patients with AR alterations.

Cardiovascular risks of androgen receptor targeted agents in prostate cancer: a systematic review and meta-analysis.

Androgen receptor targeted agents (ARTA) have increasingly been incorporated into treatment regimens for various stages of prostate cancer. Patients are living longer with prostate cancer, and thus have a higher cumulative exposure to the treatment and its accompanying side effects, especially those of cardiovascular disease. We aim to assess the differences in the incidence of cardiac-related adverse events after treatment of prostate cancer with ARTA versus placebo. Three databases were thoroughly searched for relevant articles. The PICOS model was used to frame our clinical question, with which 2 independent authors went through several rounds of screening to select the final included studies. Meta-analysis was done using the Cochran-Mantel-Haenszel Method. Quality assessment was carried out with the Cochrane Risk of Bias tool RoB 2. The use of ARTA in prostate cancer increases the incidence of cardiac-related adverse events (RR: 1.56, 95% CI: 1.29-1.90, p < 0.00001), such as hypertension (RR: 1.69, 95% CI: 1.46-1.97, p < 0.00001), ischaemic heart disease (RR: 1.84, 95% CI: 1.36-2.50, p < 0.0001), and arrhythmia (RR: 1.38, 95% CI: 1.11-1.71, p = 0.004), although this did not manifest in an increased incidence of cardiac arrests/deaths (RR: 1.28, 95% CI: 0.87-1.88, p = 0.21). ARTA increases the risk of cardiac-related adverse events, hypertension, ischaemic heart disease and arrhythmia. Armed with this knowledge, we will be better poised to manage cardiac risks accordingly and involve a cardiologist as required when starting patients on ARTA.

Abiraterone and enzalutamide in the first line therapy of metastatic castration resistant prostate cancer.

The aim was to assess therapeutic outcomes and tolerance in patients with metastatic castration resistant prostate cancer (mCRPC) treated with androgen receptor targeted agents (ARTA) treatment at one oncological center in the Czech Republic. Retrospective analysis of 64 patients with mCRPC treated with abiraterone (50 patients) and enzalutamide (14 patients) in the first line of this disease was conducted. Kaplan-Meier analysis was used to calculate progression free survival (PFS) and overall survival (OS). We performed a multivariate analysis of risk factors for treatment outcomes (PFS, OS) by Cox regression analysis. The median follow-up was 28.4 months. The median PFS was 15.4 months [95% confidence interval (CI): 12.3-18.5], median OS was 38.2 months (95% CI: 19.9-56.5). Regression analysis demonstrated a favorable prognostic effect on PFS in patients with reduction of PSA ≥ 50 %, in patients with early reduction of prostate-specific antigen (PSA) ≥ 50% within 3 months, in patients younger than 74 years and in overall performance status (PS) 0. Regression analysis demonstrated a favorable prognostic effect on OS in patients with reduction of PSA ≥ 50 %, in patients with early reduction of PSA ≥ 50 % within 3 months and in patients with overall PS 0. Adverse effects grade 3-4 were reported in 17 (27.9%) patients in abirateron arm and in 1 (7.1%) patient in enzalutamide arm. The analysis of patients with mCRPC treated with ARTA in the first line showed that ARTA represents an effective and safe therapy and contributes to longer survival.

Therapeutic Approaches to Targeting Androgen Receptor Splice Variants.

Therapeutic options for advanced prostate cancer have vastly expanded over the last decade and will continue to expand in the future. Drugs targeting the androgen receptor (AR) signaling pathway, i.e., androgen receptor targeting agents (ARTAs), remain the mainstream treatments that are increasingly transforming the disease into one that can be controlled for an extended period of time. Prostate cancer is inherently addicted to AR. Under the treatment pressure of ARTA, molecular alterations occur, leading to the clonal expansion of resistant cells in a disease state broadly categorized as castration-resistant prostate cancer (CRPC). One castration resistance mechanism involves AR splice variants (AR-Vs) lacking the ligand-binding domain. Some AR-Vs have been identified as constitutively active, capable of activating AR signaling pathways without androgenic ligands. Among these variants, AR-V7 is the most extensively studied and may be measured non-invasively using validated circulating tumor cell (CTC) tests. In the context of the evolving prostate cancer treatment landscape, novel agents are developed and evaluated for their efficacy in targeting AR-V7. In patients with metastatic CRPC (mCRPC), the availability of the AR-V7 tests will make it possible to determine whether the treatments are effective for CTC AR-V7-positive disease, even though the treatments may not be specifically designed to target AR-V7. In this review, we will first outline the current prostate cancer treatment landscape, followed by an in-depth review of relatively newer prostate cancer therapeutics, focusing on AR-targeting agents under clinical development. These drugs are categorized from the standpoint of their activities against AR-V7 through direct or indirect mechanisms.

Abstract B119: First-in-class orally active pharmacological inhibitors of TRPV6 for the treatment of advanced prostate cancer

Abstract The highly calcium selective ion channel TRPV6, has pronouced overexpression in many prostate cancers, is a promotor of prostate cancer growth and has been proposed as a prognostic marker in prostate cancer. A novel series of first-in-class TRPV6 inhibitors has been developed by the Queensland Emory Drug Discovery Initiative (QEDDI), a drug discovery and development group aiming to collaborativey translate academic biomedical research into new medicines. The preclinical lead drug candidate QED-203, is orally active and potently inhibits (low nM) calcium influx mediated by TRPV6 as assessed by both Ca2+ probe and electrophysiology assays, and TRPV6-driven NFAT activation as assessed by a luciferase reporter assay. Using RNAseq and qPCR analysis TRPV6 pharmacological inhibition and/or siRNA-mediated silencing was shown to remodel the expression of genes related to both NFAT and WNT signalling, as well as ER stress and the cell cycle. In prostate cancer cell lines that had increased levels of TRPV6, TRPV6 inhibition promoted cell cycle arrest, decreased proliferation and promoted apoptosis. Proliferation of enzalutamide resistant prostate cancer cell lines was also inhibited by QED-203. QED-203 exhibited greater potency over enzalutamide, darolutamide and apalutamide [androgen receptor targeting agents (ARTA)] in prostate cancer cell lines with clinically relevant AR mutations or those with the ARV7 splice variant. QED-203 appeared well suited to once-a-day oral dosing with a high bioavailability and an advantageous pharmacokinetic profile. In preclinical models, QED-203 was well tolerated in rodents and had similar in vivo efficacy to enzalutamide in a castrated LNCaP mouse model of prostate cancer as assessed by tumour growth and PSA levels. Increases in urine calcium levels and gene expression changes consistent with TRPV6 inhibition in isolated xenograft tumours, confirmed QED-203 TRPV6 target engagement in vivo. These studies suggest that the orally active TRPV6 inhibitor QED-203 represents a first-in-class mechanism to treat prostate cancer patients whose tumours have become resistant to current ARTA therapies. Pharmacological inhibitors of TRPV6, could be particularly valuable during the advanced stages of prostate cancer, where there is a clear unmet clinical need. Citation Format: Gregory Monteith, Kimberley Beaumont, Rebecca Pouwer, Rebecca Farrow, Matthew McLachlan, Mei Yeh, Therese Johnson, Raphael Rahmani, Claire Levrier, Hasanthi Wijesekera, Malika Kumarasiri, Grant Stuchbury, Terrie-Anne Cock, Andrew Harvey, Brian Dymock. First-in-class orally active pharmacological inhibitors of TRPV6 for the treatment of advanced prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B119.

Research protocol to identify progression and death amongst patients with metastatic hormone-sensitive prostate cancer treated with available treatments: PIONEER IMI's "big data for better outcomes" program.

Androgen deprivation therapy-based with or without first-generation anti-androgens, was the standard of care for patients with metastatic hormone-sensitive prostate cancer (mHSPC) for decades. However, the development of docetaxel chemotherapy and new androgen receptor-targeted agents, abiraterone acetate and prednisolone, apalutamide , enzalutamide and darolutamide (in combination with docetaxel chemotherapy) has proven that combination of treatments is more effective. Recently, intensification therapy, so-called "triplets", have emerged in the armamentarium of mHSPC treatment. Metastatic disease is a clinical state that remains poorly understood. The optimal diagnostic and management of patients with mHSPC are changing thanks to the development of new imaging techniques and therapies. The primary objective of this study is to develop and validate a predictive model for the occurrence of symptomatic progression, initiation of new treatments and death amongst patients with mHSPC treated with one of the approved treatment plans, on characteristics present at admission.

Nonregional Lymph Node Metastasis as a Predictor of Early Progression When Using Androgen Receptor Targeting Agents in Patients With Metastatic Castration-Resistant Prostate Cancer Without Previous Chemotherapy

Purpose: In present, the use of androgen receptor targeting agents (ARTA) is one of the standard treatments for metastatic castration-resistant prostate cancer (mCRPC) without previous chemotherapy. However, some patients may experience early progression despite ARTA use. Therefore, we analyzed predictors of early progression.Materials and Methods: We retrospectively analyzed patients treated with ARTA for mCRPC before chemotherapy at Inha University Hospital. Patients were divided into an early progression group and a late progression group. The 2 groups were defined as a group that used ARTA for more than 1 year without progression and a group that did not. Clinical and pathological parameters were analyzed to evaluate the oncologic outcomes. Univariate and multivariate logistic regression analyses were used to predict progression markers.Results: The final analysis included 70 patients. The mean progression-free duration with ARTA use was 334.90±364.716 days. There were 44 and 26 patients in the early and late progression groups, respectively. Univariate and multivariate logistic regression analyses did not show statistically significant results for the ARTA medication type, body mass index, Gleason grade group, visceral metastasis, bone metastasis, regional lymph node (LN) metastasis, time to CRPC, and prostate-specific antigen kinetics. In contrast, age (odds ratio [OR], 1.154; 95% confidence interval [CI], 1.043–1.251) and nonregional LN metastasis (OR, 8.819; 95% CI, 1.165–66.746) were significantly associated with the progression-free duration of ARTA use in multivariate logistic regression analysis.Conclusions: We think that nonregional LN metastasis is a predictor of early progression when using ARTA in patients with mCRPC without previous chemotherapy.

Real-world prostate-specific antigen reduction and survival outcomes of metastatic hormone-sensitive prostate cancer patients treated with apalutamide: An observational, retrospective, and multicentre study.

Backgroundetastatic hormone-sensitive prostate cancer (mHSPC) treatment has changed drastically during the last years with the emergence of androgen receptor–targeted agents (ARTAs). ARTA combined with androgen deprivation therapy has demonstrated better oncological and survival outcomes in these patients. However, the optimal choice among different ARTAs remains uncertain due to their analogous efficacy. ObjectivesThe objective of this study was to describe prostate-specific antigen (PSA) response and oncological outcomes of patients with mHSPC treated with apalutamide. Material and methodsMedical records from three different hospitals in Spain were used to conduct this study. Patients diagnosed with mHSPC and under apalutamide treatment were included between March 2021 and January 2023. Data regarding PSA response, overall survival (OS), and radiographic progression-free survival (rPFS) were collected and stratified by metastasis volume, timing, and stating. Results193 patients were included; 34.2% of patients were de novo mHSPC, and the majority was classified as m1b. The 18-month OS and rPFS were 92.5% and 88.9%, respectively. Patients with PSA levels ≤0.2 ng/ml showcased an 18-month OS rate of 98.7%, contrasting with 65.3% for those with PSA >0.2 ng/ml. Similar trends emerged for rPFS (97.4% and 53.7%, respectively). When differentiating between low-volume and high-volume metastasis, the OS rate stood at 98.4% and 80.7%, respectively, while the rPFS rates were 93% and 81.6%, respectively. No significant differences were found between groups stratified by metastasis timing. ConclusionThis real-world study on patients with mHSPC treated with apalutamide plus androgen deprivation therapy revealed robust oncological outcomes, aligning with the emerging evidence. The study's hallmark finding highlights the significance of rapid and deep PSA response as a predictor of improved oncological and survival outcomes.

Myocardial bridge in a patient with castration-resistant metastatic prostate cancer treated with enzalutamide.

Myocardial bridge is a morphological anomaly of the heart characterised by the presence of a myocardial segment above a coronary artery, which results in a higher risk of cardiovascular events. In patients with prostate cancer treated with androgen receptor-targeted agents, a higher risk of cardiotoxicity was observed. An 88 years old man with metastatic castration-resistant prostate cancer in treatment with enzalutamide, denosumab, and triptorelin presented to our attention complaining dyspnoea and angina pectoris. Blood examinations revealed normal Troponin I levels. Transthoracic echocardiography revealed no signs of acute myocardial ischaemia. The treadmill stress test revealed S-T tract under levelling in V4-V6 with a very slow resolution. Coronary angiography identified a myocardial bridge in the medium tract of the interventricular anterior artery. Due to these findings, ranolazine and simvastatin were started and, after multidisciplinary assessment, we decided to continue the treatment with enzalutamide. At the first follow-up visit echocardiography found out the cardiological reports stability and no therapy changes were performed. During follow-up visit cardiological revaluation showed reports stability and no therapy changes were performed. Due to the high prevalence of prostate cancer in elderly patients at high cardiovascular risk and the increasing use of androgen receptor-targeted agent, a multidisciplinary approach is highly recommended to weigh survival benefits on toxicities. This case report may support the use of androgen receptor-targeted agent in elderly patients with controlled cardiovascular diseases, a population that is often excluded from randomised trials.

Abstract PR010: First-in-class TRPV6 inhibitors for the treatment of prostate cancer

Abstract TRPV6, a calcium channel, is an oncochannel that is overexpressed in epithelial cancers including prostate cancer. We have developed a novel series of first-in-class small molecule TRPV6 inhibitors for the treatment of advanced prostate cancer. Our preclinical candidate QED-203 has been shown to inhibit calcium influx at low nM potency in TRPV6 cellular assays (FLIPR, electrophysiology), and has low nM potency in a TRPV6-driven NFAT assay (NFAT luciferase reporter). Inhibition of TRPV6 with our TRPV6 inhibitors or by siRNA knockdown causes changes in genes related to NFAT and WNT signalling, ER stress and the cell cycle (RNAseq and qPCR analysis), and causes cell cycle arrest, decreased proliferation and apoptosis in prostate cancer cells (demonstrated via imaging and FACS analysis). Importantly, QED-203 demonstrates potency in enzalutamide resistant cell lines (in vitro proliferation inhibition) and has superior potency over enzalutamide and darolutamide [androgen receptor targeting agents (ARTA)] in prostate cancer cell lines with clinically relevant AR mutations or the ARV7 splice variant. The ARV7 variant in particular is represented in a significant portion of patients no longer responding to ARTA SoC interventions. QED-203 has high bioavailability with a pharmacokinetic profile amenable to once-a-day oral dosing. QED-203 is well tolerated in rodents and has similar in vivo efficacy (tumour growth and PSA inhibition) to enzalutamide in a castrated LNCaP mouse model of prostate cancer. We have also shown QED-203 target engagement in rodents by demonstrating a change in calcium levels in the urine, and have observed changes in genes consistent with a TRPV6-specific mode of action in xenograft tumours (demonstrated via qPCR). QED-203 targets a novel, non-hormonal mechanism in prostate cancer, and could be used to treat prostate cancer patients who have developed resistance to AR therapies, where there is a large unmet need. Citation Format: Kimberley Beaumont, Rebecca Pouwer, Raphael Rahmani, Matthew McLachlan, Claire Levrier, Rebecca Farrow, Mei Yeh, Therese Johnson, Malika Kumarasiri, Hasanthi Wijesekera, Grant Stuchbury, Terrie-Anne Cock, Andrew Harvey, Gregory Monteith, Brian Dymock. First-in-class TRPV6 inhibitors for the treatment of prostate cancer [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 PR010.

Combination Treatment with Sipuleucel-T and Abiraterone Acetate or Enzalutamide for Metastatic Castration-Resistant Prostate Cancer: STAMP and STRIDE Trials.

We present long-term outcomes from 2 randomized studies [STAMP (with abiraterone, NCT01487863) and STRIDE (with enzalutamide, NCT01981122)] that were performed to study the impact of sequential or concurrent administration of androgen receptor-targeting agents (ARTAs) on sipuleucel-T immune response and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T was administered per current prescribing information. Results from STRIDE are presented together with updated STAMP results. Survival status of patients was updated using demographic information to query the National Death Index (NDI). Kaplan-Meier methodology was used to analyze survival. Updated data reduced patient censoring in each study compared with the original analyses; the 95% confidence intervals (CIs) for OS are now estimable. Updated median OS (95% CI) is 33.3 (24.1-40.7) months for STAMP and 32.5 (26.0-45.1) months for STRIDE. There was no notable impact on median OS [HR, 0.727 (0.458-1.155); P = 0.177, reference = STRIDE]. OS with sequential administration was similar to concurrent administration [NDI update: HR, 0.963 (0.639-1.453); P = 0.845, reference = concurrent arm]. Sipuleucel-T potency, measured as antigen-presenting cell (APC) activation, was higher in subsequent infusions compared with the first infusion. Humoral responses (IgG + IgM antibody titers) to PA2024 and prostatic acid phosphatase were significantly elevated versus baseline. No new safety signals were observed. Median OS was consistent regardless of whether the agents were administered sequentially or concurrently, including after NDI update. Results suggest that sipuleucel-T induces an immunologic prime-boost effect after initial sipuleucel-T exposure, even when combined with ARTAs.

Activity and safety of KEES - an oral multi-drug chemo-hormonal metronomic combination regimen in metastatic castration-resistant prostate cancer

BackgroundMetastatic castration-resistant prostate cancer (mCRPC) remains a therapeutic challenge and evidence for late-line treatments in real-life is limited. The present study investigates the efficacy and safety of an oral metronomic chemo-hormonal regimen including cyclophosphamide, etoposide, estramustine, ketoconazole and prednisolone (KEES) administered in a consecutive biweekly schedule.MethodsA retrospective cohort study in two Swedish regions was conducted. Overall (OS) and progression-free survival (PFS), biochemical response rate (bRR) and toxicities were analyzed.ResultsOne hundred and twenty-three patients treated with KEES after initial treatment with at least a taxane or an androgen-receptor targeting agents (ARTA) were identified. Of those, 95 (77%) had received both agents and were the primary analysis population. Median (95% CI) OS and PFS in the pre-treated population were 12.3 (10.1–15.0) and 4.4 (3.8–5.5) months, respectively. Biochemical response, defined as ≥ 50% prostate-specific antigen (PSA) reduction, occurred in 26 patients (29%), and any PSA reduction in 59 (65%). PFS was independent of prior treatments used, and KEES seemed to be effective in late treatment lines. The bRR was higher compared to historical data of metronomic treatments in docetaxel and ARTA pre-treated populations. In multivariable analyses, performance status (PS) ≥ 2 and increasing alkaline phosphatase (ALP) predicted for worse OS. Nausea, fatigue, thromboembolic events and bone marrow suppression were the predominant toxicities.ConclusionsKEES demonstrated meaningful efficacy in heavily pre-treated CRPC patients, especially those with PS 0–1 and lower baseline ALP, and had an acceptable toxicity profile.

A Practical Guide to Relugolix: Early Experience With Oral Androgen Deprivation Therapy.

Relugolix is the newest form of androgen deprivation therapy (ADT) approved for prostate cancer. However, as an oral drug, several real-world concerns exist, particularly medication compliance, safety with other androgen receptor-targeted agents, and financial burden to patients. A single institution retrospective chart review was conducted evaluating all patients who were prescribed relugolix for any prostate cancer indication from January 1, 2021 to January 31, 2022. Demographic data, cardiac risk factors, concomitant therapy usage, and PSA/testosterone levels, were abstracted from the chart review. Adverse effects were obtained by examining progress notes. Compliance was assessed by clinic notes as well as prescription fills by specialty pharmacy records. The reasons patients did not fill or discontinued the medication were noted. Hundred and one patients were prescribed relugolix, and 91 patients consented to research. Seventy-one (78%) patients filled the prescription to relugolix, with a median follow-up of 5 months. Prescription fill data were available for 45 (63%) patients, with 94% of days covered. The most commonly reported reason not to fill was cost at 50%. Sixty-six (93%) patients reported never missing a dose. PSA levels were available in 71 (100%) patients with 69 (97%) showing stable or improved PSA. Testosterone levels were available in 61 (86%) of patients, which showed 61 (100%) stable or successful castration. Twenty-four (34%) patients used relugolix in combination. No new major safety signals were seen in combination therapy. Nineteen (27%) patients had switched to another form of ADT. Fifteen of these (79%) felt similar or better on relugolix therapy. Compliance with relugolix seemed acceptable. No major new safety signals were seen, even in combination. Among patients who switched therapy, most tolerated relugolix similarly or better than the previous form of ADT. The cost was a major reason for patients not initiating and for discontinuing therapy.

Based on ARASENS trial: efficacy and safety of darolutamide as an emerging option of endocrinotherapy for metastatic hormone-sensitive prostate cancer-an updated systematic review and network meta-analysis.

The newly published ARASENS trial has demonstrated the clinical efficacy of darolutamide for metastatic hormone-sensitive prostate cancer (mHSPC). However, the use of darolutamide as the latest first-line androgen receptor pathway inhibitor for mHSPC has not been compared with other androgen receptor targeted agents (ARTAs). Given the lack of head-to-head randomized trials, we performed this updated meta-analysis to conduct indirect comparison for the efficacy and safety of darolutamide with other new-generation ARTAs. By searching the databases of PubMed, Scopus, Cochrane Library, and Embase, 9 large randomized controlled trials evaluating ARTAs for mHSPC patients were eventually screened according to PRISMA. We extracted data from overall survival, castration-resistant progression, and adverse events for network meta-analysis using the Bayesian and standard frequentist models. Darolutamide combination emerged with superiority (HR = 0.68, 95%CrI = 0.57-0.81) among four androgen receptor inhibitors for patients with high Gleason score (HR = 0.71, 95%CrI = 0.59-0.86). Darolutamide was best tolerated in several androgen suppression-related adverse events (AEs). Darolutamide appears to be an optional androgen receptor inhibitor for mHSPC patients, especially for patients with Gleason score ≥ 8. Its well-tolerated characteristic may provide a preferred drug option for patients with poor cardiovascular function and bone health.

Treatment and survival of de novo metastatic prostate cancer in US veterans.

87 Background: Combination therapies using the androgen deprivation therapy (ADT) backbone have revolutionized treatment of metastatic hormone sensitive prostate cancer (mHSPC). Combinations include ADT plus docetaxel (DOC) or the androgen receptor targeting agents (ARTAs) abiraterone (AA), enzalutamide (ENZ), apalutamide (APA), and darolutamide (DAR). This study evaluates the utilization of these therapies in de novo mHSPC in a cohort of veterans and assesses recent overall survival (OS) of these therapies. Methods: Veterans were identified from 2012-2021 in the Veterans Affairs Prostate Cancer Data Core (VAPC) and oncology tumor registries using the initial pathological diagnosis of prostate cancer with SEER stage ‘distant’. All veterans had ADT initiated within 1 month prior and 3 months after diagnosis in VAPC. Additional therapies including DOC or ARTAs were collected from VAPC if initiated from 1 month prior to 4 months after ADT initiation. Data cut point was June 2022. Results: 5,006 patients with de novo mHSPC were identified with median age of 73.1 years (yrs), and 1338 (26.7%) identified as Black race. From 2012 to 2021, ADT alone was used in 3,569 (71.3%) of veterans, DOC in 438 (8.7%) and ARTAs in 999 (20.0%), wherein use of different ARTAs was AA in 783 (78.4%), ENZ in 204 (20.4%), APA in 10 (1.0%), and DAR in 2 (0.2%). Use of combination therapy for mHSPC increased from 3.1% in 2012-2013 to 61.2% in 2020-2021. Use of DOC peaked in 2016 and was used in 16.3% of veterans that year. Veterans treated with DOC were significantly younger (median 67.3 yrs, p&lt;0.001) compared to veterans treated with ARTAs (73.1 yrs) or ADT alone (74.3 yrs). Veterans treated with combination therapies had longer median OS compared to ADT alone (37.2 vs. 29.3 months, p&lt;0.001), with no significant difference between DOC and ARTA combinations (p=0.84). For 2,042 veterans with de novo mHSPC treated from 2018-2021, median OS of veterans treated with ADT+DOC (n=161, 35.3 months) and ADT+ARTA (n=849, 41.2 months) was longer than ADT alone (n=1,032, 29.3 months, p&lt;0.001). There was no significant difference in median OS between DOC and ARTA combinations in this group (p=0.69). Conclusions: In veterans presenting with de novo mHSPC, use of initial combination therapy has increased, with the majority of veterans treated with ADT and an ARTA in 2020-2021. In this cohort, combination therapy was associated with longer OS compared to ADT alone and no significant differences were found between type of combination and OS. [Table: see text]