mCSPC Patients Research Articles

Novel Treatment Strategies for Low-Risk Metastatic Castration-Sensitive Prostate Cancer.

The treatment strategy for metastatic castration-sensitive prostate cancer (mCSPC) has changed significantly in recent years. Based on various guidelines, an upfront androgen receptor signaling inhibitor (ARSI) is the first choice, but in patients of Asian descent, including Japanese patients, there are a certain number of cases in which androgen deprivation therapy (ADT) and CAB are more effective. If patients can be identified who show a marked response to ADT within 12 weeks after the initiation of ADT, which is the inclusion criterion for ARSI clinical trials targeting mCSPC, it would be valuable from an economic standpoint. A total of 218 patients with pure prostate adenocarcinoma and treated with ADT at the Kanazawa University Hospital between January 2000 and December 2020 were included in this study. As a risk classification for mCSPC, in addition to the LATITUDE and CHAARTED criteria, we used the castration-sensitive prostate cancer classification proposed by Kanazawa University (Canazawa), developed by the Department of Urology of Kanazawa University. The Canazawa classification was based on three factors: Gleason pattern 5, bone scan index (BSI) ≥ 1.5, and lactate dehydrogenase (LDH) ≥ 300 IU/L. It defined patients with one factor or less as low-risk and patients with two or three factors as high-risk. The overall survival (OS) and time to castration resistance (TTCR) were estimated retrospectively using the Kaplan-Meier method, and factors associated with TTCR were identified using univariate and multivariate analyses. The median follow-up period was 40.4 months, the median OS period was 85.2 months, and the median TTCR period was 16.4 months. The Canazawa risk classification provided the clearest distinction between the OS and TTCR in mCSPC patients. Multivariate analysis revealed a decrease in PSA levels of <95% at 12 weeks after ADT initiation and was a predictor of short TTCR in low-risk, low-volume patients across all risk classifications. The Canazawa classification differentiated the prognosis of mCSPC patients more clearly. A PSA reduction rate of <95% at 12 w after starting ADT in low-risk, low-volume patients of all risk classifications was significantly shorter than the TTCR. We propose a new treatment strategy, in which patients with low-risk mCSPC are treated with ADT and switched to ARSIs based on the rate of PSA reduction at 12 w.

Real-world evidence of triplet therapy efficacy in patients with metastatic castration-sensitive prostate cancer: a Japanese multicenter study.

Two randomized trials demonstrated that the survival benefits afforded by triplet therapy were greater than those of doublet therapy, thus changing the treatment paradigm for metastatic castration-sensitive prostate cancer (mCSPC). This is the first study to assess the real-world use, performance, and safety of triplet therapy in Japanese patients. This retrospective multicenter study included 45 consecutive mCSPC patients who received triplet therapy composed of androgen deprivation therapy (ADT), docetaxel, and darolutamide between January 2023 and June 2024. Baseline patient characteristics and their clinical parameters during triplet therapy were collected. Adverse events (AEs) were graded using Common Terminology Criteria for Adverse Events version 5.0, and imaging responses were evaluated following the RECIST criteria. The prostate-specific antigen (PSA) nadir was defined as the lowest PSA value during follow-up, and the PSA decrease was the initial PSA value minus the PSA nadir. The median patient age was 70years and the median follow-up duration was 10months. High-volume disease was present in 82.2% of patients. Concurrent administration of docetaxel and darolutamide was scheduled for 22.2% of cases. The incidence of any AE was 86.7%, with 55.5% of patients experiencing grade 3-4 AEs. Neutropenia was common, but prophylactic granulocyte colony-stimulating factor (G-CSF) significantly reduced the incidence of neutropenia of grade 3 or higher. Febrile neutropenia occurred in four patients (8.9%); these patients had not received prophylactic G-CSF. A decline in PSA of 90% was observed in 95.6% of patients, and an imaging response was seen in 97.8%. Triplet therapy with ADT, darolutamide, and docetaxel was highly efficacious and tolerable in Japanese mCSPC patients, particularly those with high-volume disease. Prophylactic G-CSF prescription is crucial to manage neutropenia effectively. Further studies with longer follow-ups are needed to confirm these findings and explore the long-term outcomes.

Prognostic outcomes in Japanese patients with metastatic castration-sensitive prostate cancer: Comparative assessments between conventional androgen deprivation therapy (ADT) and ADT with novel androgen receptor signal inhibitor.

The objective of this study was to compare the prognostic outcomes between metastatic castration-sensitive prostate cancer (mCSPC) patients receiving conventional androgen deprivation therapy (ADT) and those receiving ADT plus a novel androgen-receptor signaling inhibitor (ARSI) in routine clinical practice in Japan. This was conducted as a retrospective multicenter study including 581 mCSPC patients, consisting of 305 receiving ADT alone or in combination with bicalutamide (group 1) and 276 receiving ADT plus one of the following ARSIs: abiraterone acetate, apalutamide, or enzalutamide (group 2). Prognostic outcomes between these 2 groups were comprehensively compared. In the entire cohort, prostate-specific antigen-progression-free survival (PSA-PFS) in group 2 was significantly longer than that in group 1, while no significant difference was noted in overall survival (OS) between the two groups. In patients corresponding to the LATITUDE high-risk group, however, both PSA-PFS and OS in group 2 were significantly longer than those in group 1. Of several factors examined, the following were identified as independent predictors of poor PSA-PFS in the entire cohort as well as the LATITUDE high-risk group: high C-reactive protein, high lactate dehydrogenase, high alkaline phosphatase, high Gleason score, and group 1. Furthermore, it was possible to precisely classify both the entire cohort and LATITUDE high-risk group into 3 risk groups regarding PSA-PFS according to the positive numbers of independent factors: positive for ≤1 factor, favorable; 2 factors, intermediate; and ≥3 factors, poor. Combined use of ARSIs with ADT could improve the prognostic outcomes of mCSPC patients, particularly those in the LATITUDE high-risk group, in real-world clinical practice in Japan.

Abstract 7286: Optimizing prediction of metastatic castration-resistant prostate cancer: Multimodal fusion of clinicopathological and genomic features with machine learning

Abstract Background: Transitioning from metastatic castration-sensitive prostate cancer (mCSPC) to its resistant variant poses risks of intensified medication, toxic side effects, and financial burdens for men undergoing treatment. Our study proposes a multimodal approach that integrates clinical, pathological, and genomic features to optimize prediction of metastatic castration-resistant prostate cancer (mCRPC) events. By applying machine learning (MML) techniques to multimodal data, we aim to stratify these patients based on the risk of developing mCRPC, contributing to the development of safer and personalized treatment strategies. Methods: We analyzed a large cohort of patients with mCSPC (n=399) with a minimum of 36 month follow-up, annotated with clinical, pathological, and genomic features, encompassing relevant variables such as disease volume, PSA, metastases timing, variant classification, Grade Group, fraction of genome altered, MSI score, mutation counts, karyotypes, tumor mutational burden, and purity. Using a multimodal machine learning framework, we extracted informative features and employed eight distinct machine learning algorithms: K-Nearest Neighbor, Support Vector Machine, Decision Tree, and Logistic Regression, Support Vector Machine with RBF Kernel, Random Forest, and Gradient Boosting, in addition to a Deep Neural Networks architecture for building predictive models in supervised binary classification experiments. The models' performance was evaluated on separate training (80%) and testing sets (20%), and standard evaluation metrics, such as the area under the receiver operating characteristic curve (AUROC), and accuracy, were computed. Correlations were utilized to explore the relationships between features, and permutation analysis was employed to determine the importance of predictors. All raw data included in the analysis are available on cBioPortal database. The study is supported by the NIH-NCI-T32 for Next Generation Pathologists Program at our institution. Results: Of the 399 mCSPC patients, 56% developed castration resistance, 50% had Grade Group 5 disease, and 69% exhibited missense mutations. In a series of 8 experiments, the Support Vector Machine with RBF Kernel ensemble model and SVC exhibited the highest performance with an AUROC score of 0.77, while the remaining models tested in the study demonstrated AUROC scores ranging from 0.62 to 0.75. Notably, the fraction of altered genome emerged as the top-ranked predictor, displaying the highest importance score. Conclusions: Our study demonstrates the strong predictive performance of MML models in accurately identifying mCRPC events by leveraging routine clinical, pathological, and genomic data, offering valuable guidance for optimizing patient stratification and tailoring personalized therapeutic interventions. Citation Format: Mohammad K. Alexanderani, Francesca Khani, Matthew Greenblatt, Brian Robinson, Massimo Loda, Luigi Marchionni. Optimizing prediction of metastatic castration-resistant prostate cancer: Multimodal fusion of clinicopathological and genomic features with machine learning [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 7286.

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

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

Real-World Incidence and Severity of Hypertension Caused by Abiraterone Acetate in Patients With Metastatic Prostate Cancer.

Abiraterone acetate (AA) is used in treatment of patients with metastatic prostate cancer. Despite the survival advantage, AA is associated with hypertension due to mineralocorticoid excess syndrome. We conducted a single-center retrospective analysis to evaluate the real-world incidence and severity of AA-induced hypertension. Electronic health records were used to collect baseline characteristics and prostate cancer history. Patient data, including blood pressure at each 4 (±2)-week interval, were collected for 24 weeks after the initiation of AA therapy. The primary endpoint was the incidence and severity of AA-induced hypertension. The secondary endpoints include effect of different prednisone dosing regimens and prostate cancer types on hypertensive incidence and the impact of clinical pharmacists' involvement in managing AA-induced hypertension. A total of 142 patients who met our inclusion criteria received AA for metastatic prostate cancer, 73 (51.4%) with metastatic castration-resistant prostate cancer (mCRPC), and 69 (48.6%) with metastatic castration-sensitive prostate cancer (mCSPC). Of all, 43.7% experienced all-grade hypertension, and 28.2% experienced grade 3-4 hypertension. There was no difference in incidence of hypertension between patients receiving 5 mg of prednisone daily and those receiving 5 mg of prednisone twice daily. All-grade hypertension occurred in 39.7% of mCRPC and 47.8% of mCSPC patients (P = 0.33). Thirty-two percent of patients were actively managed by a clinical pharmacist and had an overall trend of reduced hypertension severity after 12 weeks. This single-center, retrospective cohort study found that real-world metastatic prostate cancer patients who received AA had substantially higher incidence and severity of hypertension compared with clinical trials regardless of prednisone dose. In patients with mCRPC and mCSPC, the role of prednisone dose in hypertension incidence and severity warrants further investigation. Overall, results indicate the need for closely monitoring hypertension and optimization of anti-hypertensive therapy by multidisciplinary teams in metastatic prostate cancer patients receiving AA.

Role of Bone Scan Index (BSI) in the Prognosis and Treatment Efficacy in Castration-Sensitive Prostate Cancer Patients with Bone Metastasis

Bone is the most common metastatic site in prostate cancer (PCa). Although the extent of disease (EOD) grade is used for evaluating burden of bone metastasis, the accuracy of bone metastasis classification needs improvement. Bone scan index (BSI) was developed as a quantitative tool to enhance the interpretability and clinical relevance of the bone scan. This study aimed to explore the role of BSI using BONENAVI® software in determining the prognosis and treatment efficacy in castration-sensitive PCa (mCSPC) patients with bone metastasis. We retrospectively reviewed 61 mCSPC patients with bone metastasis who had received primary androgen deprivation therapy (PADT) at our institution. All patients received PADT with luteinizing hormone-releasing hormone agonist or surgical castration accompanied by first-generation antiandrogen, bicalutamide. Bone scans were performed with ⁹⁹[m]Tc-MDP. BSI (%) was divided into two groups (＜1.0 and ≧1.0), and BSI response rates(change at 0 months to after 6 months) were determined using thresholds of 45% decline. Castration-resistant prostate cancer (CRPC) -free survival (CRPC-FS) and Overall survival (OS) rates were analyzed using the Kaplan-Meier method. The median follow-up was 41. 9 months. Overall, 16 patients (26. 2%) died. Multivariate analysis on pretreatment factors revealed that hemoglobin (P＝0.03) and BSI (P＝0.04) were independent prognostic factors for OS. The 5-year OS rates in patients with low BSI and high BSI were 84.6% and 39.2%, respectively (P＝0.02). In 40 patients who had a bone scan before and after PADT, OS rates in patients with a good response (≧45%) were significantly higher than those with a poor response (＜45%) (P＝0.001). Nadir PSA titers within 6 months after the start of treatment (P＝0.005), Hb (P＝0.003), and BSI change (P＝0.014) were independent prognostic factors for OS. In mCSPC patients with bone metastases, BSI at diagnosis was an important predictor of CRPC progression and OS as a pre-treatment factor, and BSI change rate and PSA nadir as post-treatment factors.

Adverse outcomes (AOs) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) treated with intensified androgen deprivation therapy (ADT+).

113 Background: mCSPC pts experience adverse outcomes (AOs) with intensified androgen deprivation, resulting in treatment discontinuation; however, there is limited data to identify those at risk. The IRONMAN registry is a global initiative to enroll advanced prostate cancer patients worldwide, and survey data on AOs, patient-reported outcomes (PROs), and clinico-epidemiologic (demographic, cancer, and treatment) details. We report the prevalence and predictors of AOs from baseline demographic, clinical, and PRO information with the onset of AOs and present a risk prediction model for clinical use. Methods: We analyzed data from 553 mCSPC patients in the IRONMAN registry from inception to March 2023 who received ADT+ alone (Abiraterone 47.6%, Enzalutamide 26.9%, Apalutamide 22.6%, Darolutamide 2.9%) and had completed baseline PROs. We defined AOs, reported by 60 global sites, as non-progression-related clinically significant serious adverse events (csSAE), treatment discontinuation, and dose reductions (DR/DC), delineated as a composite outcome based on first event. We processed baseline variable groups: Demographics (race, ethnicity, marital status, study site), Clinical Factors (age, ECOG score, metastatic sites, ADT+, concurrent medications, labs [ALP, Hb, LDH, and PSA]), Concurrent therapies (steroid use within 30 days [d] &amp; steroid dose, radiation/surgery prior or planned in 6months) and PROs (EORTC QLQ-C30 and EPIC-23). We developed a multifactorial logistic regression model to predict adverse outcomes (AOs) within two years of initiating ADT+ therapy. All variables with less than 25-30% missing data were included. Variable selection was conducted in two layers: intra-group stepwise selection followed by an inter-group selection of variables retained from the first layer. The model's discriminatory ability was evaluated using the area under curve (AUC). Results: 553 pts met inclusion (51.6% North America, 72% White, mean age: 71 years [range, 40 to 96 years], and 62.9% confirmed bone-metastatic mCSPC). 119 pts (21.5%) developed AOs (61 csSAEs [18 dead; Median: 140 d; IQR 81-360 d], 58 DR/DC [Median: 122 d; IQR 43-262 d]). &lt;5% went off study. The multifactorial model (n=314 pts) performed well at predicting AOs (AUC 0.77 [0.70-0.84]), with significant factors being more self-reported pain, greater urinary frequency, prednisone&gt;5mg within 30d, more self-reported weakness and poor sexual function within 3 months of ADT+ initiation. Conclusions: 1 in 5 mCSPC patients on ADT+ experienced non-progression-related AOs at 2 years. Significant, easily assessed predictive factors are identified and may be utilized in their clinical management. A novel multifactorial model is presented to predict AOs at 2 years. Further validation, assessment of missingness bias, and imputation are planned.

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 (&gt;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&lt;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.

Outcomes of elderly patients (pts) treated with docetaxel (DOC) for metastatic castration-sensitive prostate cancer (mCSPC): Results from ECHOS, a multicenter Italian observational study.

153 Background: ECHOS trial is a large real-world study which is collecting data on mCSPC patients treated in the daily clinical practice in Italy from 2015. To date, &gt; 1500 pts were included in the study, most of them treated with DOC, according to the availability of the active agents over the time in Italy. In the present analysis, we assessed the outcomes of pts ≥75 yrs old who received DOC for mCSPC. Methods: We retrospectively and prospectively reviewed the clinical records of a consecutive series of mCSPC pts treated with DOC in the daily clinical practice in 69 Italian Hospitals. The treatment mostly consisted of DOC at the standard dose of 75 mg/sqm every 3 wks for six courses. For each pt we recorded the pre and post-DOC clinical history, the baseline characteristics of the pts, the treatment details and clinical outcomes. For the purpose of the present study, we considered only pts who ended chemotherapy by September 2022. Results: Among 920 mCSPC pts treated with DOC, 132 (14.4%) were ≥ 75 yrs old. Most of them (76%) presented de novo disease with high-volume features. Their baseline characteristics were similar to those of younger pts excepting for baseline hemoglobin levels which were significantly lower in older pts (median 12.6 vs 13.5; p = 0.001). Older pts received either a reduced dose (16.7%) or a modified schedule (8.4%) more frequently than younger one (p &lt; 0.0001). Thirty-six pts experienced a grade 3-4 toxicity, which was mainly hematological (75% of the cases). The median progression-free survival (PFS) was 12.6 mos in older pts compared to 14.9 mos observed in younger ones (p 0.2). The median number of life prolonging agents administered after DOC progression was 1 in pts ≥75 yrs as well as in pts &lt; 75 yrs. The median overall survival (OS) was 27.9 mos and 42.4 mos in older and younger pts, respectively (p &lt; 0.0001). Conclusions: Our data suggest that DOC was efficacious and well-tolerated in mCSPC pts ≥75 yrs although the treatment was administered with either dose or schedule modifications in about 25% of the cases. No differences were observed in terms of PFS between pts ≥75 and ones &lt; 75 yrs. Nevertheless, the median OS of older pts was significantly worse compared to that of younger ones.

A cost-effectiveness analysis assessing systemic treatments in metastatic castration-sensitive prostate cancer (mCSPC) by volume of disease.

93 Background: The treatment paradigm for mCSPC patients has rapidly evolved over the last few years with the emergence of triplet therapy and prognostication by volume of disease. However, the health economic implications of triplet therapy by disease volume remain unclear. Methods: A Markov model where patients transitioned between the progression-free, progression and death states was developed. State utilities were derived from the LATITUDE trial. Point probabilities for overall survival, progression-free survival, grade ≥ 3 and 5 toxicities were obtained from the eligible mCSPC phase III clinical trials. Medicare Advantage and commercial total paid amounts (2022 US$) of treatments were obtained from OptumLabs Data Warehouse. Costs and disutilities of adverse events were derived from published literature. Half-cycle corrected costs and utilities were accrued monthly over a 20-year lifetime horizon and were discounted at 3%. Monte Carlo simulation was used to calculate incremental cost-effectiveness ratios (ICERs). A willingness-to-pay (WTP) threshold of US$100,000 was used. Results: In terms of Medicare Advantage payer’s perspective (Table), docetaxel (D)+ADT was observed to provide additional 0.068 QALYs compared to ADT at an ICER of US$16,544 per QALY in high volume disease. Compared to D+ADT, abiraterone (AAP) triplet provided additional 1.03 QALYs at US$56,641 per QALY. Compared to AAP triplet, apalutamide (APA)+ADT provided additional 0.048 QALYs at US$5,846,248 per QALY in high volume disease. In low volume disease, D+ADT provided 0.45 more QALYs at US$20,690 per QALY compared to ADT alone. Compared to D+ADT, AAP triplet provided an additional 1.51 QALYS at US$44,267 per QALY. In terms of total paid commercial costs, AAP triplet provided an additional 1.19 QALYs compared to ADT at US$91,952 per QALY in high volume disease. In low volume, D+ADT provided additional 0.38 QALYs at US$22,058 per QALY compared to ADT. Compared to D+ADT, AAP triplet provided a 0.97 QALY gain at US$105,958 per QALY. Compared to AAP triplet, darolutamide (DARO) triplet provided a 0.47 QALY at US$689,196 per QALY. Compared to DARO triplet, APA+ADT provided an additional 0.49 QALYs at an ICER of US$971,389 per QALY. All other treatments (not reported here) were dominated. Conclusions: At the selected WTP of US$100,000 per QALY, AAP triplet therapy was most likely the cost-effective strategy in overall mCSPC population particularly in patients with high volume disease. However, these results should be interpreted with careful accounting for timing of metastases. [Table: see text]

Real world US community urology adherence to prostate cancer guidelines.

449 Background: According to a 2010 Surveillance, Epidemiology, and End Results (SEER) Medicare analysis of prostate cancer (PCa) patients between 1992 and 2005, urologists accounted for more health services provided to PCa patients than any other specialty. Our study assessed the concordance of PCa care with two treatment-related Performance Indicators (PIs) derived from National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) in a real-world setting of community urologists. Methods: This retrospective analysis used PPS Analytics (Specialty Networks) Patient Population Health Management Platform, capturing 90 community urology practices with approximately 539,000 PCa patients treated between 7/1/2019-6/30/2022. Two PIs were identified from NCCN Guidelines through consultation with expert urologists to measure the quality of PCa care. PI-1 was defined as the proportion mCSPC patients who initiated an NCCN Category 1 preferred regimen for mCSPC. Guideline changes on 01/01/2020 created a need for two patient stratifications in PI-1. Patients in PI-1.1 had a mCSPC diagnosis between 05/2002 - 12/2019. Patients in PI-1.2 had a mCSPC diagnosis between 01/2020 - 06/2021. PI-2 was defined as the proportion of newly diagnosed intermediate-to-high risk localized PCa (Gleason score ≥ 7 or PSA ≥ 10) who received concurrent ADT with external beam radiation therapy (EBRT) based on the NCCN Guidelines recommendation for concurrent ADT in newly diagnosed intermediate-to-high risk localized PCa (LPC) receiving EBRT. Multi-level multi-variable regression was used to assess factors associated with concordance for each PI. Results: See table. Conclusions: Although changes in NCCN guidelines after 1/2020 led to improved systemic treatment in mCSPC, most patients still did not receive care concordant with recent NCCN recommendations. Our findings highlight opportunities for improving the quality of PCa care in a real-world community urology setting, notably for treatment in mCSPC. Future research should investigate reasons for deviating from NCCN preferred systemic regimens in mCSPC and intervene as appropriate.[Table: see text]

The Impact of TP53 Mutations and Use of the TP53-Mutation-Reactivating Agent APR-246 on Metastatic Castrate-Sensitive Prostate Cancer.

TP53 mutations appear to be enriched over the spectrum of metastatic castration-sensitive prostate cancer (mCSPC) and are associated with worse survival outcomes. We chose to further explore the impact of dominant negative (DN) TP53 mutations on mCSPC progression and pro-metastatic behaviors in addition to studying the ability of APR-246, a small molecule targeting TP53 mutants, to blunt pro-metastatic behaviors. We retrospectively analyzed 531 mCSPC patients who underwent next-generation sequencing. Patients were stratified by metastasis timing (synchronous if metastasis present at diagnosis or metachronous if arising after definitive treatment of localized disease) and the number of metastatic lesions (oligometastatic ≤5 or polymetastatic >5 lesions). Tumors were classified based on TP53 mutation status (missense, truncating, or wild-type [WT]) and dominant negativity, which was defined as the production of a mutant protein that reduces the residual WT protein's transcriptional activity according to the World Health Organization TP53 database. Clinical outcomes were radiographic progression-free survival (rPFS) and overall survival (OS), evaluated with Kaplan-Meier and multivariable Cox regression. To verify the impact of TP53 mutation on metastasis, we created isogenic 22Rv1 prostate cancer cell lines that carried either TP53 WT or TP53 R175H and tested this mutation for migration, invasion, and anchorage-independent growth. APR-246 (25-80 µM) was tested for anti-metastatic properties in vitro and anti-tumor growth in 22Rv1 xenografted nude mice. In our cohort, 155 (29.2%) had a TP53 mutation, which mostly occurred in the DNA-binding domain (85.16%). DN TP53 mutations were associated with more aggressive disease states: DN TP53 mutations were enriched in patients with synchronous (vs. metachronous: 20.7% vs. 6.3%, p < 0.01) and polymetastatic disease (vs. oligometastatic: 14.4% vs. 7.9%, p < 0.01). On multivariable analysis, DN TP53 mutations were correlated with shorter rPFS (HR = 1.97, 95% CI: 1.31-2.98, p < 0.01) and OS (HR = 2.05, 95% CI: 1.14-3.68, p = 0.02) compared to those with TP53 WT. In vitro, 22Rv1 cells with DN TP53 R175H mutation had increased abilities to migrate, invade, and form colonies compared to TP53 WT. APR-246 treatment of TP53 R175H mutants blunted the pro-metastatic effects of the cell line in vitro (p < 0.01 for all assays by unpaired t-test). Interestingly, APR-246 also inhibited xenograft tumor growth of 22Rv1 TP53 R175H mutants (p < 0.0001 by two-way ANOVA). DN TP53 mutations were associated with poorer survival outcomes for mCSPC patients. DN TP53 mutations also promoted prostate cancer pro-metastatic behaviors in vitro, which was effectively counteracted by APR-246, making it a promising treatment option that should be explored further in early-phase clinical studies.

A Real-World Evidence Study Using Alberta-Population-Based Data to Describe Treatment Patterns for Metastatic Castration-Sensitive Prostate Cancer Patients (AWARENESS).

Over the past decade, the treatment of metastatic castration-sensitive prostate cancer (mCSPC) has changed significantly. Current guidelines suggest the use of androgen deprivation therapy (ADT) plus an additional systemic therapy, regardless of disease burden and risk, based on phase 1 evidence showing improved overall survival. We sought to describe treatment patterns of patients with mCSPC in the province of Alberta. This was a retrospective, population-based, cohort study of male patients aged ≥18 with mCSPC at the time of diagnosis and who initiated ADT between 1 January 2016 and 31 December 2020. Data were obtained from the Alberta Cancer Registry. Patients were assigned to an ADT-alone cohort or a treatment intensification cohort (cohorts 2-5). The primary objectives of this study were to describe baseline characteristics and the treatment of mCSPC patients who initiated ADT with or without treatment intensification. Overall survival between cohorts was a secondary objective. Descriptive statistics were used to describe differences in baseline characteristics of each cohort. Overall survival was calculated using the Kaplan-Meier method. All statistical tests were two-sided and are used to call out likely cohort differences descriptively. Between 1 January 2016 and 31 December 2020, we identified a total of 960 patients with mCSPC (median age 74 years, IQR 66-82). Most patients received ADT alone (67%), followed by ADT plus abiraterone (18%), ADT plus docetaxel (12%), and ADT plus enzalutamide or apalutamide (3%). Over the study period, we observed an increase in the utilization of treatment intensification over time, in particular, the increased use of androgen-receptor-axis-targeted (ARAT) therapies. Patients who received ADT alone were older, were more likely to have more than one comorbid condition, had fewer sites of metastatic disease, and were less likely to be on opioid medications. In this study, we show that patients who received ADT alone as treatment for mCSPC are older, have more comorbidities, and have less extensive disease. While there has been a decline over time in the number of patients treated with ADT alone, over 50% of all patients with mCSPC continue to receive ADT alone. Further work is needed to understand barriers to treatment intensification and for knowledge translation initiatives to improve the treatment of patients with mCSPC.

How reliable is the high-volume definition in prostate cancer patients: the potential game-changing role of PSMA.

To evaluate whether metabolic and volumetric data from 68Ga-PSMA PET/CT performed during staging of de-novo high-volume mCSPC patients who received docetaxel could be used to predict survival. Forty-two de-novo high-volume mCSPC patients, who received ADT + Docetaxel and underwent 68Ga-PSMA PET/CT for staging, were included in the study. The association between patients' pathological data, all PSA measurements, treatments they received, the data obtained from 68Ga-PSMA PET/CT and progression-free and overall survival were examined. In the multivariate analysis, PSMA-TV (primary) and PSMA-TV (WB) variables were shown to be independent negative predictors of overall survival. For the threshold value of 19.91 cm3 obtained for PSMA-TV (primary), HR was calculated as 6.31, the 95% confidence interval (CI): 1.01-39.18, P = 0.048. For the threshold value of 1226.5 cm3 obtained for PSMA-TV (WB) variable, HR was calculated as 58.62, the 95% CI: 2.55-1344.43, P = 0.011. In our study, SUVmax (WB) variable was found to be an independent and negative predictor of progression-free survival. For the determined threshold value of 17.74, HR was calculated as 16.24, 95% CI: 1.18-22.76, P = 0.037. Metabolic and volumetric data obtained from 68Ga-PSMA PET/CT can be used to predict survival in de-novo high-volume mCSPC. Our results show that in ADT + Docetaxel receiving patients, a subgroup with higher PSMA-TV (WB) values have a significantly worse prognosis. This situation suggests that the high-volume disease definition in the literature may be insufficient for this group, and that 68Ga-PSMA PET/CT can play an essential role in demonstrating the heterogeneity within the group.

The impact of TP53 mutations and use of the TP53-mutation-reactivating agent APR-246 on metastatic castrate-sensitive prostate cancer.

e17077 Background: TP53 mutations appear to be enriched over the spectrum of metastatic castration-sensitive prostate cancer (mCSPC) and are associated with worse survival outcomes. We chose to further explore the impact of dominant negative (DN) TP53 mutations on mCSPC progression and pro-metastatic behaviors in addition to studying the ability of APR-246, a small molecule targeting TP53 mutants, to blunt pro-metastatic behaviors. Methods: We retrospectively analyzed 531 mCSPC patients who underwent next generation sequencing. Patients were stratified by metastasis timing (synchronous if metastasis present at diagnosis or metachronous if arising after definitive treatment of localized disease) and the number of metastatic lesions (oligometastatic &lt;5 or polymetastatic &gt; 5 lesions). Tumors were classified based on TP53 mutation status (missense, truncating, or wild-type [WT]) and dominant negativity, which was defined as production of a mutant protein that reduces the residual WT protein's transcriptional activity according to World Health Organization TP53 database. Clinical outcomes were radiographic progression-free survival (rPFS) and overall survival (OS), evaluated with Kaplan-Meier and multivariable Cox regression. To verify the impact of TP53 mutation on metastasis, we created isogenic 22Rv1 prostate cancer cell lines that carried either TP53 WT or TP53 R175H and tested this mutation for migration, invasion, and anchorage-independent growth. APR-246 (25-80 µM) was tested for anti-metastatic properties in vitro and anti-tumor growth in 22Rv1 xenografted nude mice. Results: In our cohort, 155 (29.2%) had a TP53 mutation, which mostly occurred in the DNA-binding domain (85.16%). DN TP53 mutations were associated with more aggressive disease states: DN TP53 mutations were enriched in patients with synchronous (vs. metachronous: 20.7% vs. 6.3%, p &lt; 0.01) and polymetastatic disease (vs. oligometastatic: 14.4% vs. 7.9%, p &lt; 0.01). On multivariable analysis, DN TP53 mutations were correlated with shorter rPFS (HR = 1.97, 95%CI: 1.31-2.98, p &lt; 0.01) and OS (HR = 2.05, 95%CI: 1.14-3.68, p = 0.02) compared to those with TP53 WT. In vitro, 22Rv1 cells with DN TP53 R175H mutations had increased ability to migrate, invade, and form colonies compared to TP53 WT cells. APR-246 treatment of TP53 R175H mutants blunted the pro-metastatic effects of the cell line in vitro (p &lt; 0.01 for all assays by unpaired t-test). Interestingly, APR-246 inhibited xenograft tumor growth of 22Rv1 TP53 R175H prostate cancer cells (p &lt; 0.0001 by two-way ANOVA). Conclusions: DN TP53 mutations were associated with poorer survival outcomes for mCSPC patients. DN TP53 mutations also promoted prostate cancer pro-metastatic behaviors in vitro, which was effectively counteracted by APR-246, making it a promising treatment option that should be explored further in early-phase clinical studies.

The role of volume of disease for treatment selection in patients with metastatic castration sensitive prostate cancer (mCSPC): A living meta-analysis.

5088 Background: Previous evidence suggests that there may be no additional benefit of triplet therapy in low volume disease based on limited data. Therefore, we investigated the efficacy of triplet therapy as compared to docetaxel (D) and androgen pathway inhibitor (API) doublets by volume of disease using the most up to date results from the ARASENS trial. Methods: Phase III randomized controlled trials (RCTs) assessing treatment intensification with API, and/or D in patients with mCSPC were included. Precomputed hazard ratios (HR) with 95% confidence intervals (CI) for OS were pooled using an inverse-variance approach. A DerSimonian-Laird random-effects meta-analysis was conducted to assess the efficacy of triplet therapy compared to D doublet therapy. P-value of interaction was computed to assess difference between high (HV) and low volume (LV) disease subgroups (Pint &lt;0.1 - statistical significance). Additionally mixed treatment comparisons were computed using network meta-analysis (NMA) to assess the comparative effectiveness of triplet therapy compared to API doublets by volume of disease. Results: Pairwise meta-analysis included a total of 3 RCTs (ARASENS, PEACE-1, ENZAMET) with 2518 patients (HV: 1820; LV: 698) as shown. In patients with HV disease, 385 (43%) and 484 (53%) deaths were observed with triplet therapy, and D doublet, respectively. Triplet therapy significantly improved OS as compared to D doublet in HV (HR: 0.73; 95% CI: 0.64-0.84). In patients with LV disease, 73 (20%) and 94 (28%) deaths were observed with triplet therapy, and D doublet, respectively. Triplet therapy significantly improved OS as compared to D doublet in LV (HR: 0.71; 95% CI: 0.52-0.97). There was no statistically significant interaction by volume of disease for triplet therapy vs. D doublet (Pint: 0.86). NMA including 10 clinical trials and over 11500 patients updated as of 13th Feb 2023 showed that in HV mCSPC, triplet therapy was ranked as potentially the most efficacious treatment option and may improve OS compared to API doublet therapy (HR: 0.83; 95% CI: 0.66-1.03). In LV mCSPC, API doublet therapy was ranked as potentially the most efficacious treatment followed by triplet therapy. There was no significant difference between triplet therapy and API doublet therapy (HR: 1.12; 95% CI: 0.74-1.12). Conclusions: These results underscore that triplet therapy may be preferred in mCSPC patients with HV disease whereas API doublet therapy may be preferred in LV disease. [Table: see text]

Early results from CASCARA: A phase 2 study of cabazitaxel/carboplatin plus abiraterone in high-volume metastatic castrate-sensitive prostate cancer (mCSPC).

5071 Background: Best treatment of mCSPC involves doublet therapy (ADT + novel hormonal agent) or triplet therapy (ADT + novel hormone + docetaxel); however, opportunity remains for further improvement. Studies show that homologous recombination repair (HRR) gene mutations are enriched in metastatic prostate cancer, and may portend resistance to docetaxel. CASCARA tested quadruplet therapy (ADT + cabazitaxel/carboplatin + abiraterone) in high-volume mCSPC, aiming to enhance PSA responses and decrease progression at 1 year. Methods: This phase 2 study enrolled 61 mCSPC patients with high-volume disease who received ADT plus cabazitaxel (20 mg/m2 q21d x 6) and carboplatin (AUC=4 q21d x 6) followed by abiraterone (1000 mg, plus prednisone 5 mg). Primary endpoint was freedom from PSA/radiographic progression at 1 year. Other endpoints included PSA50 response, freedom from PSA progression, and safety. Archival biopsies were retrospectively evaluated for HRR ( BRCA1/2, ATM, CHEK2, CDK12, BRIP1, RAD51B) mutations at a CLIA-certified lab. A sample size of 61 was determined using a Simon two-stage design (stage 1: 32 men, stage 2: 29 men) with a null hypothesis of a 1-year PSA/radiographic progression-free rate of 0.80 against a one-sided alternative of 0.92. Results: From 11/2019 to 06/2022, 61 men enrolled at 7 sites. Median age was 64 (range, 45–76) years; 21% were African American. Median baseline PSA was 8.9 (range, 0.1–1021) ng/mL. 44% of men had ECOG=1. 91% had Gleason sum 8–10. Prevalence of DNA alterations (50 evaluable pts) was 18% for HRR mutations, 38% for TP53 muts, 22% for ERG fusions, 10% for SPOP muts. Freedom from PSA/radiographic progression at 1 year was 77% (95% CI, 63–87%), and freedom from PSA progression at 1 year was 81% (95% CI, 67–90%). The PSA50 rate response was 97%. PSA ≤0.2 ng/mL at month-7, a surrogate for survival in other mCSPC studies, was 61%; PSA ≤4 ng/mL at month-7 was 82%. Outcomes according to mutation status are shown. AEs included 7% grade (Gr)-3/4 myelosuppression, 8% Gr-3/4 infections, 10% Gr-3 GI disorders, and 3% Gr-3 fatigue. There were 4 treatment-related discontinuations. Conclusions: Quadruplet therapy with ADT + cabazitaxel/carboplatin + abiraterone was well tolerated. At 1 year, 77% of pts were progression-free. PSA ≤0.2 ng/mL at month-7 was 61%, exceeding the historical month-7 PSA ≤0.2 ng/mL rate of 45% in CHAARTED–docetaxel arm. Further exploration of this quadruplet strategy in randomized phase III studies is warranted. Clinical trial information: NCT03934840 . [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 .

MP29-14 PROSTATE-SPECIFIC ANTIGEN RESPONSE AND TIME-TO-CASTRATION RESISTANCE AMONG PATIENTS WITH METASTATIC CASTRATION SENSITIVE PROSTATE CANCER INITIATED ON APALUTAMIDE, ENZALUTAMIDE, OR ABIRATERONE ACETATE

You have accessJournal of UrologyCME1 Apr 2023MP29-14 PROSTATE-SPECIFIC ANTIGEN RESPONSE AND TIME-TO-CASTRATION RESISTANCE AMONG PATIENTS WITH METASTATIC CASTRATION SENSITIVE PROSTATE CANCER INITIATED ON APALUTAMIDE, ENZALUTAMIDE, OR ABIRATERONE ACETATE Benjamin Lowentritt, Shawn Du, Carmine Rossi, Frederic Kinkead, Dexter Waters, Bronwyn Moore, Patrick Lefebvre, Dominic Pilon, and Erik Muser Benjamin LowentrittBenjamin Lowentritt More articles by this author , Shawn DuShawn Du More articles by this author , Carmine RossiCarmine Rossi More articles by this author , Frederic KinkeadFrederic Kinkead More articles by this author , Dexter WatersDexter Waters More articles by this author , Bronwyn MooreBronwyn Moore More articles by this author , Patrick LefebvrePatrick Lefebvre More articles by this author , Dominic PilonDominic Pilon More articles by this author , and Erik MuserErik Muser More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003257.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Next-generation androgen inhibitors (AI), including apalutamide (APA), enzalutamide (ENZ), and abiraterone acetate (ABI), are approved to treat patients with metastatic castration sensitive prostate cancer (mCSPC). Among patients with mCSPC, prostate-specific antigen (PSA) response is associated with increased overall survival and decreased castration resistance (CR), an important indicator of disease progression. This study described real-world PSA response and progression to CR among patients with mCSPC treated with APA, ENZ, or ABI in the US. METHODS: Data from 77 community-based urology practices (9/2018–4/2022) were used to evaluate patients with mCSPC newly initiated on APA, ENZ, or ABI using in-office dispensing data (index date is first dispensation date). On-treatment PSA response was defined as: 1) a post-index ≥90% decline in PSA (PSA90) from baseline (using the closest PSA value within 13 weeks prior to or on the index date) and 2) a post-index decline to ≤0.2 ng/mL (PSA0.2) among those with baseline PSA >0.2 ng/mL. The descriptive proportion of patients achieving a PSA response or progressing to CR was described separately for each cohort using Kaplan-Meier (KM) analysis up to 12- and 24-months post-index, respectively. RESULTS: A total of 589 APA, 597 ENZ, and 553 ABI patients were evaluated. Mean age at index was 76 years in each group. Mean baseline PSA was 19.2 ng/mL (APA), 18.8 ng/mL (ENZ), and 24.3 ng/mL (ABI). KM rates for PSA response and progression to CR are shown in the Table. PSA90 by 12 months was achieved by 72% (APA), 62% (ENZ), and 55% (ABI) of patients. PSA0.2 by 12 months was achieved by 81% (APA), 63% (ENZ), and 58% (ABI) of patients. By 24 months, progression to CR was observed in 34% (APA), 39% (ENZ), and 45% (ABI) of patients. CONCLUSIONS: This is among the first observational studies to describe real-world PSA response and progression to CR in mCSPC patients treated with AIs in US community urology practices. While AIs with higher proportions achieving PSA90 or PSA0.2 were observed to have lower rates of progression to CR, further studies adjusting for baseline characteristics are needed to understand this relationship. Source of Funding: Janssen Scientific Affairs, LLC. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e387 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Benjamin Lowentritt More articles by this author Shawn Du More articles by this author Carmine Rossi More articles by this author Frederic Kinkead More articles by this author Dexter Waters More articles by this author Bronwyn Moore More articles by this author Patrick Lefebvre More articles by this author Dominic Pilon More articles by this author Erik Muser More articles by this author Expand All Advertisement PDF downloadLoading ...