Treatment Of mCRPC Research Articles

Clinical factors associated with prescribing patterns of bone modifying agents in men with metastatic castration-resistant prostate cancer.

e18878 Background: Bone metastases occur in up to 90% of men with metastatic prostate cancer and cause skeletal-related events (SREs) such as fracture and spinal cord compression. Although bone modifying agents (BMAs) have been shown to decrease the risk of SREs in men with metastatic castration-resistant prostate cancer (mCRPC), BMAs are not widely used in this patient population. In this retrospective study, we report the prescribing patterns of BMAs and predictors of BMA use in a large national cohort. Methods: We used the VA corporate data warehouse to identify patients with mCRPC who were treated with first-line mCRPC therapy (abiraterone, enzalutamide, docetaxel, or ketoconazole) between 2010 and 2017. BMA prescribing frequency and patterns were analyzed. Multivariable regression analysis was used to evaluate clinical and disease-specific factors associated with BMA use which are presented as adjusted odds ratios (OR) with 95% confidence intervals (CI). Results: In the final cohort of 4,079 patients, the median age at mCRPC diagnosis was 73 years (IQR 66-81). 29% of patients in the cohort were Black. Diagnosis codes identified bone metastases at mCRPC diagnosis in 48% of the cohort (ICD-9 and 10 coding for sites of metastases are known to underestimate the actual incidence of metastases). Only 48% of patients received a BMA following initiation of treatment for mCRPC, 47% of which had already received a BMA 6 months prior to mCRPC diagnosis. For those who were new BMA starts, the median time to BMA administration from mCRPC treatment was 3.4 months (IQR 1.2-8.8). Factors associated with BMA use were having an ICD-9 or 10 diagnosis code for bone metastases at time of mCRPC treatment (OR 1.28, 95% CI 1.10-1.48), concurrent corticosteroid use (OR 1.90, 95% CI 1.53-2.38), and docetaxel use as first-line mCRPC therapy (OR 1.78, 95% CI 1.45-2.18). Factors associated with decreased BMA use were Charlson comorbidity index score of ≥ 2 (OR 0.75, 95% CI 0.62-0.90), advancing age (OR 0.86 per 10 years, 95% CI 0.79-0.94), and decreased eGFR (eGFR 30-59, OR 0.81, 95% CI 0.68-0.96; eGFR 0-29, OR 0.23, 95% CI 0.14-0.37). Having a diagnosis code for a SRE before mCRPC diagnosis (e.g., bone fracture and cord compression) did not impact BMA use, but the incidence of those events was low. Conclusions: Less than half of this VA cohort received a BMA after starting therapy for mCRPC. Key factors associated with BMA use were corticosteroid use and first-line docetaxel use, which likely represented more aggressive disease. Notably, patients who were older and had more comorbid conditions were less likely to receive a BMA despite being highest risk for frailty and SREs. Future quality improvement efforts aimed at increasing BMA use may address the needs of the geriatric mCRPC patient population.

Use of circulating tumor DNA (ctDNA) to complement tumor tissue homologous recombination repair (HRR) gene alteration testing in TALAPRO-2, a phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

5056 Background: In TALAPRO-2 (NCT03395197), pts unselected for tumor genetic alterations in DNA damage repair pathways, directly or indirectly involved with HRR, received TALA + ENZA (n=402) or PBO + ENZA (n=403) as 1L treatment for mCRPC. HRR status was informed by tumor tissue for 804 pts (99.9%), by tumor tissue and ctDNA for 114 (14.2%), and by ctDNA only for 1 (0.1%). TALA + ENZA demonstrated statistically significant and clinically meaningful improvements in imaging-based progression-free survival over standard of care PBO + ENZA regardless of HRR gene alteration status (presented by Agarwal N at ASCO-GU 2023). Here we assessed the overall agreement of solid tissue vs ctDNA-based testing in assessing tumor HRR gene alteration status. Methods: HRR status for pts randomized in TALAPRO-2 was determined prospectively by testing for the presence of HRR gene alterations using FoundationOne CDx and/or FoundationOne Liquid CDx. Pts were considered HRR-deficient if they had ≥1 alteration in ≥1 of 12 HRR genes by either test. Plasma samples collected at screening were retrospectively tested using FoundationOne Liquid CDx to examine retrospective test performance and to support exploratory resolution of pts with unknown prospective HRR status. Results were reported as HRR-deficient, non-HRR-deficient, or unknown. Results: In prospective testing, high concordance in HRR status was observed between ctDNA and tumor tissue sample results: 95% agreement (90/95) between tests was observed in pts evaluable as either HRR-deficient or non-HRR-deficient by both tests. Retrospective ctDNA test results were reported for 739 pts (207 [28%] with a status of HRR-deficient, 480 [65%] non-HRR-deficient, and 52 [7%] unknown; 66 pts had samples not collected or reported). There was high concordance in pt-level alteration status between prospective molecular profiling (mainly based on solid tumor tissue per above) and retrospective ctDNA testing: the agreement was 84% (438/519) between tests for pts evaluable as HRR-deficient or non-HRR-deficient both prospectively and retrospectively (421/501 [84%] for prospective tumor tissue only vs retrospective ctDNA). Conclusions: Results show 95% agreement between prospective tissue and ctDNA-based HRR status using FoundationOne, consistent with tumor vs ctDNA results recently reported (Tukachinsky. Clin Cancer Res. 2021;27:3094–3105). The high agreement between prospective test results based primarily on tumor tissue and retrospectively assessed ctDNA collected at screening is supportive of exploratory retrospective testing of ctDNA to inform the HRR status of pts whose alteration status is unknown based on prospective testing. Clinical trial information: NCT03395197 .

Patient-reported outcomes (PROs) among men receiving talazoparib (TALA) + enzalutamide (ENZA) vs placebo (PBO) + ENZA as first-line (1L) treatment for metastatic castration-resistant prostate cancer (mCRPC): Results from a phase 3 study (TALAPRO-2).

5013 Background: TALAPRO-2 (NCT03395197) showed statistically significant improvement in radiographic progression free survival with TALA + ENZA (n=402) vs PBO + ENZA (n=403) (HR=0.63 95% CI 0.51-0.78; P<0.001) in men receiving 1L treatment for mCRPC. Here we report PRO endpoints from TALAPRO-2. Methods: PROs were assessed at day 1 (baseline) and at scheduled visits until radiographic progression (every 4 weeks until week 53, and then every 8 weeks) using the EORTC QLQ-C30 and its prostate cancer module, QLQ-PR25. Prespecified PRO analyses included overall mean change from baseline (per longitudinal repeated measures mixed-effects model) and time to definitive clinically meaningful (≥10-point change) deterioration (TTD). Between-arm comparisons of TTD were made using a stratified log-rank test and a Cox proportional hazards model. Results: Of the 805 men randomized and treated, 793 had a baseline score followed by at least 1 post-baseline score; TALA + ENZA (n=395), PBO + ENZA (n=398). Although the treatment effect on global health status (GHS)/quality of life (QoL) significantly favored PBO + ENZA, the predefined threshold of clinical meaningfulness was not met; moreover, no significant differences between the arms were observed in any functioning scales. A significantly longer TTD in GHS/QoL was observed for TALA + ENZA; HR=0.780 (95% CI: 0.62, 0.99), P=0.038; median: 30.8 months vs 25.0 months. A numerical greater delay in TTD in urinary symptoms was longer for TALA + ENZA; HR=0.759 (95% CI: 0.543, 1.061), P=0.105; median not reached vs 35.9 months. Additional PRO results will be presented. Conclusions: Compared with PBO + ENZA, in the TALA + ENZA arm there was 1) a modest deterioration disfavoring GHS/QoL (deterioration was not clinically meaningful based on the predefined threshold), and 2) a maintenance in all functioning scales. TTD in GHS/QoL was significantly longer with TALA + ENZA vs PBO + ENZA, reflecting improved disease control. These results complement the benefit-risk assessment of TALAPRO-2. Clinical trial information: NCT03395197 . [Table: see text]

Final results from phase I study of PSCA-targeted chimeric antigen receptor (CAR) T cells in patients with metastatic castration resistant prostate cancer (mCRPC).

5019 Background: Chimeric antigen receptor (CAR)-engineered T cell therapies are being pursued for the treatment of mCRPC. Prostate Stem Cell Antigen (PSCA) is highly expressed on the surface membrane in mCRPC and with limited expression on normal tissues. We are completing a phase I study of PSCA-targeted 4-1BB-co-stimulated CAR T cell therapy in mCRPC. Methods: CAR T cells were manufactured at City of Hope’s cGMP facility. Patients (pts) were required to have disease progression after at least 1 androgen receptor targeted therapy but there was no limit on other prior treatments. The primary objective was to define the dose limiting toxicities (DLT) as well as to describe preliminary bioactivity and activity. CAR T persistence and cytokine levels were evaluated by flow cytometry and Luminex. Circulating tumor cells (CTC) were measured by an unselected assay (Kuhn). Results: 14 pts were treated, median age 69, median baseline PSA 88. 12(86%) had previously been treated with chemotherapy; 9 received two taxanes and 3 docetaxel only. 79% of screened pts had PSCA expression >2+ in >80% of cancer cells. Two of 6 pts encountered DLT (grade 3 cystitis) at 100M + lymphodepletion (LD) chemotherapy. The protocol was amended to reduce the LD dose to 300 mg/m2 cyclophosphamide D1-3. No DLTs occurred in 5 pts treated in the modified LD 100M cohort. Cytokine release syndrome (CRS), best response by RECIST, CAR T cell expansion and persistence are presented by dose level in the table. CAR T expansion was greater with LD than without. PSA declines were seen, as well as radiographic improvement, though RECIST response was limited to stable disease (SD) by concurrent bone metastases. Cytokine peaks were higher in patients with anti-tumor effect noted. CTC decreases in both marrow and peripheral blood were seen, associated with PSA declines. Conclusions: PSCA-CAR T cells have anti-cancer activity in mCRPC with DLT of cystitis. LD was required for greater expansion and activity; lower dose LD improved toxicity without clear negative impact on expansion. Clinical trial information: NCT03873805 . [Table: see text]

Metastatic Castration-Resistant Prostate Cancer: Insights on Current Therapy and Promising Experimental Drugs.

The therapeutic landscape of metastatic hormone sensitive and metastatic castration-resistant prostate cancer (mCRPC) is rapidly changing. We reviewed the current treatment options for mCRPC, with insights on new available therapeutic strategies. Chemotherapy with docetaxel or cabazitaxel (for patients progressing on docetaxel), as well as treatment with androgen receptor axis targeted therapies, and Radium-223 are well-established treatment options for patients with mCRPC. The advent of theragnostic in prostate cancer established Lutetium-177 (177Lu)-PSMA-617 as a new standard of care for PSMA-positive mCRPC previously treated with ARAT and taxane-based chemotherapy. Olaparib, a poly-ADP-ribose polymerase (PARP) inhibitor, is approved for selected patients with mCRPC progressed on ARATs and in combination with abiraterone acetate as first-line treatment for mCRPC. Immunotherapy showed limited efficacy in unselected patients with mCRPC and novel immunotherapy strategies need to be explored. The search for biomarkers is a growing field of interest in mCRPC, and predictive biomarkers are needed to support the choice of treatment and the development of tailored strategies.

Clinical outcomes and treatment patterns in REASSURE: planned interim analysis of a real-world observational study of radium-223 in metastatic castration-resistant prostate cancer.

Radium-223, a targeted alpha therapy, is approved to treat bone-dominant metastatic castration-resistant prostate cancer (mCRPC), based on significantly prolonged overall survival versus placebo and a favourable safety profile in the phase 3 ALSYMPCA study. ALSYMPCA was conducted when few other treatment options were available, and prospectively collected data are limited on the use of radium-223 in the current mCRPC treatment landscape. We sought to understand long-term safety and treatment patterns in men who received radium-223 in real-world clinical practice. REASSURE (NCT02141438) is a global, prospective, observational study of radium-223 in men with mCRPC. Primary outcomes are adverse events (AEs), including treatment-emergent serious AEs (SAEs) and drug-related AEs during and ≤30 days after radium-223 completion, grade 3/4 haematological toxicities ≤6 months after last radium-223 dose, drug-related SAEs after radium-223 therapy completion, and second primary malignancies. Data collection commenced on Aug 20, 2014, and the data cutoff date for this prespecified interim analysis was Mar 20, 2019 (median follow-up 11.5 months [interquartile range 6.0-18.6]), 1465 patients were evaluable. For second primary malignancies, 1470 patients were evaluable, 21 (1%) of whom had a total of 23 events. During radium-223 therapy, 311 (21%) of 1465 patients had treatment-emergent SAEs, and 510 (35%) had drug-related AEs. In the 6 months after completion of radium-223 therapy, 214 (15%) patients had grade 3/4 haematological toxicities. Eighty patients (5%) had post-treatment drug-related SAEs. Median overall survival was 15.6 months (95% confidence interval 14.6-16.5) from radium-223 initiation. Patient-reported pain scores declined or stabilised. Seventy (5%) patients had fractures. REASSURE offers insight into radium-223 use in global real-world clinical practice with currently available therapies. At this interim analysis, with a median follow-up of almost 1 year, 1% of patients had second primary malignancies, and safety and overall survival findings were consistent with clinical trial experience. Final analysis of REASSURE is due in2024. Bayer HealthCare.

Cost-effectiveness analysis of olaparib treatment for metastatic castration-resistant prostate cancer with BRCA 1/2 mutations following a new hormonal agent in China

BackgroundThe poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor, olaparib has been approved for the treatment of mCRPC in patients with BRCA1/2 mutations who have progressed following prior therapy that included a new hormonal agents. Patients with prostate cancer carrying BRCA gene mutations exhibit a more aggressive disease progression and poorer prognosis, posing challenges for the effectiveness of current treatment options. MethodsFrom the perspective of healthcare payers in China, a three-state partition survival model (progression-free survival, progressed disease and death) was constructed to conduct a cost-effectiveness analysis of olaparib versus enzalutamide for the approved indication. The efficacy and safety of olaparib and enzalutamide were obtained from PROfound trial. Cost were from pricing records and the literature. The model was simulated for 10 years with monthly cycles. Costs and health outcomes were discounted by 5%. Sensitivity analyses were conducted to evaluate the robustness of parameters on the results. ResultsIn the base-case analysis, the total cost of olaparib was ¥ 101,012, with a total of 1.1576 QALYs gained. The total cost of enzalutamide was ¥ 52,425, with a total of 0.5929 QALYs gained. Compared to enzalutamide, olaparib had an ICER of ¥ 86,043 per QALY, with an increase in total costs of ¥ 48,587 and an increase in QALYs of 0.5647. At a threshold of three times per capita GDP of China (¥ 257,094 in 2022), the probability of olaparib being cost-effective compared to enzalutamide was 99.0%. ConclusionFrom the healthcare payer perspective, olaparib is cost-effective compared to enzalutamide for the treatment of metastatic castration-resistant prostate cancer in patients with BRCA1/2 mutations who have progressed following prior therapy that included a new hormonal agent.

γδ-Enriched CAR-T cell therapy for bone metastatic castrate-resistant prostate cancer.

Immune checkpoint blockade has been largely unsuccessful for the treatment of bone metastatic castrate-resistant prostate cancer (mCRPC). Here, we report a combinatorial strategy to treat mCRPC using γδ-enriched chimeric antigen receptor (CAR) T cells and zoledronate (ZOL). In a preclinical murine model of bone mCRPC, γδ CAR-T cells targeting prostate stem cell antigen (PSCA) induced a rapid and significant regression of established tumors, combined with increased survival and reduced cancer-associated bone disease. Pretreatment with ZOL, a U.S. Food and Drug Administration-approved bisphosphonate prescribed to mitigate pathological fracture in mCRPC patients, resulted in CAR-independent activation of γδ CAR-T cells, increased cytokine secretion, and enhanced antitumor efficacy. These data show that the activity of the endogenous Vγ9Vδ2 T cell receptor is preserved in CAR-T cells, allowing for dual-receptor recognition of tumor cells. Collectively, our findings support the use of γδ CAR-T cell therapy for mCRPC treatment.

PARP inhibitors in metastatic prostate cancer.

Poly-ADP ribose polymerase inhibitors (PARPi) are an emerging therapeutic option for the treatment of prostate cancer. Their primary mechanism of action is via induction of synthetic lethality in cells with underlying deficiencies in homologous recombination repair (HRR). In men with metastatic castrate-resistant prostate cancer (mCRPC) and select HRR pathway alterations, PARPi treatment has been shown to induce objective tumor responses as well as improve progression free and overall survival. Presently, there are two PARPi, olaparib and rucaparib, that are FDA approved in the treatment of mCRPC. Ongoing research is focused on identifying which HRR alterations are best suited to predict response to PARPi so that these therapies can be most effectively utilized in the clinic. While resistance to PARPi remains a concern, combination therapies may represent a mechanism to overcome or delay resistance.

Abstract 2307: Targeted cell-free DNA methylation signature in metastatic castration-resistant prostate cancer

Abstract Background: DNA methylation of cytosines in CpG sites serves as an important epigenetic regulator for gene expression. In prostate cancer (PC), differences in DNA methylation regions have been observed between normal and tumor cells. However, acquiring the samples to study these patterns can be challenging through standard biopsies. Therefore, liquid biopsies provide a minimally invasive method which can be utilized to investigate the methylome of PC patients. In this study, we used liquid biopsies from a well-defined group of PC patients to examine cell-free DNA (cfDNA) methylation signatures and determine their clinical significance in metastatic castration-resistant prostate cancer. Methods: Plasma was prospectively collected from a cohort 108 PC patients representing localized PC (n=24), metastatic hormone-sensitive PC (mHSPC) (n=28), and metastatic castration resistant PC (mCRPC) (n=37 pre-, n=19 post- mCRPC treatments). cfDNA from the patient plasma was used for an enzymatic methylation sequencing (EM-seq) that targeted a panel of genes (n=441) implicated in prostate cancer biology. Methylation status at CpG islands of these genes were examined using Twist targeted cfDNA methylation assay. The Bismark program was used for methylation calling. Differentially methylated regions (DMRs) across various patient outcomes were assessed by linking the CpG methylation data from target genes to the associated clinical data. Results: We identified DMRs in 305 out of the 411 target genes in the plasma epigenome when comparing the mCRPC to non-mCRPC states (localized PC and mHSPC) (false discovery rate, FDR < 0.2). From these 305 genes, we found that in patients experiencing only PSA relapse after failure of mHSPC (biochemical mCRPC) versus patients with clinical progression (clinical mCRPC), 261 out of the 305 genes had DMRs (p <0.05). We also compared DMRs before and after 3-months of treatment in the mCRPC state and found that 175 out of the 305 genes showed significant changes after 3-months of mCRPC-specific treatment. Furthermore, from these 175 genes, 24 genes showed significant methylation differences when comparing patients with and without disease progression during mCRPC treatment and 20 genes showed significant differences when comparing patients with neuroendocrine features to those with common adenocarcinoma of PC at the mCRPC state (p<0.05). These differentially methylated genes include RUNX3, FOXA2, HIC1 and MYCN. Conclusions: cfDNA-based liquid biopsies provide a minimally invasive method to investigate the methylome of mCRPC patients. Our observations that cfDNA methylation was correlated with disease progression provide evidence that DMRs across a select panel of genes may serve as predictive biomarker for poor response to therapy and survival. Citation Format: Jodie Wong, Yijun Tian, Amir Bitaraf, Claire Hanson, Matthew Larson, Jennifer Lloyd, Julia Batten, Neeraj Agarwal, Umang Swami, Anna Neibling, Jonathan Tward, Benjamin Maughan, Sumati Gupta, Manish Kohli, Liang Wang. Targeted cell-free DNA methylation signature in metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2307.

Real-World Treatment Patterns Among Patients With Metastatic Castration-Resistant Prostate Cancer: Results From an International Study.

There is limited real-world evidence on how increasing use of treatment intensification in metastatic castration-sensitive prostate cancer (mCSPC) has influenced treatment decisions in metastatic castration-resistant prostate cancer (mCRPC). The study objective was to evaluate the impact of novel hormonal therapy (NHT) and docetaxel use in mCSPC on first-line treatment patterns among patients with mCRPC in 5 European countries and the United States (US). Physician-reported data on patients with mCRPC from the Adelphi Prostate Cancer Disease Specific Program were descriptively analyzed. A total of 215 physicians provided data on 722 patients with mCRPC. Across 5 European countries and the US, 65% and 75% of patients, respectively, received NHT, and 28% and 9% of patients, respectively, received taxane chemotherapy as first-line mCRPC treatment. In Europe, patients who had received NHT in mCSPC (n = 76) mostly received taxane chemotherapy in mCRPC (55%). Patients who had received taxane chemotherapy, or who did not receive taxane chemotherapy or NHT in mCSPC (n = 98 and 434, respectively) mostly received NHT in mCRPC (62% and 73%, respectively). In the US, patients who had received NHT, taxane chemotherapy, or neither in mCSPC (n = 32, 12, and 72, respectively) mostly received NHT in mCRPC (53%, 83%, and 83%, respectively). Two patients in Europe were rechallenged with the same NHT. These findings suggest that physicians consider mCSPC treatment history when making first-line treatment decisions in mCRPC. Further studies are needed to better understand optimal treatment sequencing, especially as new treatments emerge.

MP29-05 TREATMENT PATTERN AND HEALTH-RELATED QUALITY OF LIFE (HRQOL) OF PATIENTS (PTS) WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (MCRPC) IN THE UNITED STATES (US)

You have accessJournal of UrologyCME1 Apr 2023MP29-05 TREATMENT PATTERN AND HEALTH-RELATED QUALITY OF LIFE (HRQOL) OF PATIENTS (PTS) WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (MCRPC) IN THE UNITED STATES (US) Neal Shore, Lawrence Karsh, Daniel Shevrin, James Symanowski, Daniel Lin, Jeff Turner, David Russell, Yi Song, James Spalding, Filipa Negreiro, and David Penson Neal ShoreNeal Shore More articles by this author , Lawrence KarshLawrence Karsh More articles by this author , Daniel ShevrinDaniel Shevrin More articles by this author , James SymanowskiJames Symanowski More articles by this author , Daniel LinDaniel Lin More articles by this author , Jeff TurnerJeff Turner More articles by this author , David RussellDavid Russell More articles by this author , Yi SongYi Song More articles by this author , James SpaldingJames Spalding More articles by this author , Filipa NegreiroFilipa Negreiro More articles by this author , and David PensonDavid Penson More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003257.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Therapeutic advances in the management of mCRPC have given clinicians multiple treatment options and the potential for sequencing therapeutic agents, increasing the complexity of treatment decisions. This study aims to describe the treatment patterns and HRQoL of pts with mCRPC in the US from 2015 to 2021. METHODS: This prospective, observational, multicentre study (TRUMPET) enrolled male adult pts who initiated treatment for mCRPC from 147 urology and oncology sites in the US. The data from routine clinic visits and periodic HRQoL questionnaires were collected from Mar 2015 to Apr 2021. The study outcomes assessed patterns of care and HRQoL outcomes (Functional Assessment of Cancer Therapy-Prostate [FACT-P] and Brief Pain Inventory – Short Form [BPI-SF]) associated with mCRPC management. Descriptive analyses were used to evaluate results. RESULTS: Among the enrolled patients, the full analysis set included 832 patients with M1 mCRPC; the safety analysis set included 869 patients with M1 mCRPC. The median duration from initial diagnosis to baseline visit was 4.9 years, median initial prostate-specific antigen (PSA) level at diagnosis was 16.3 ng/mL, and mean (SD) Gleason score was 8.0 (1.18). Novel hormonal therapy (NHT) (enzalutamide and/or abiraterone) and immunotherapy were the most frequent initial treatments (Table). During the follow-up period, 43.8% (n=381) discontinued from the study before the first treatment switch, while 50.1% (n=435) switched treatment, with the majority of pts switching to NHT (n=280, 32.2%). At 1 year follow-up, cumulative first switches were 128 of 158 (81%) from immunotherapy to NHT, 41 of 88 (47%) switched from NHT to a different NHT, 11 of 17 (65%) switched from first-generation anti-androgens (AA) to NHT, 19 of 26 (73%) switched from chemotherapy to NHT, and 6 of 11 (55%) switched from radionuclide therapy to NHT. HRQoL measures showed similar trends (overlapping confidence intervals) of mean change from baseline across different first-line treatment options, irrespective of the initial treatment. CONCLUSIONS: NHT was the preferred first and second-line treatment option in pts with M1 mCRPC. HRQoL was similar regardless of initial treatment. Source of Funding: This study was funded by Astellas Pharma Inc. and Pfizer Inc., the co-developers of enzalutamide. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e382 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Neal Shore More articles by this author Lawrence Karsh More articles by this author Daniel Shevrin More articles by this author James Symanowski More articles by this author Daniel Lin More articles by this author Jeff Turner More articles by this author David Russell More articles by this author Yi Song More articles by this author James Spalding More articles by this author Filipa Negreiro More articles by this author David Penson More articles by this author Expand All Advertisement PDF downloadLoading ...

MP11-16 PROSTATE-SPECIFIC ANTIGEN ANALYSES IN PROPEL: ABIRATERONE AND OLAPARIB VERSUS ABIRATERONE AND PLACEBO AS FIRST-LINE THERAPY FOR METASTATIC CASTRATION-RESISTANT PROSTATE CANCER

MP11-16 PROSTATE-SPECIFIC ANTIGEN ANALYSES IN PROPEL: ABIRATERONE AND OLAPARIB VERSUS ABIRATERONE AND PLACEBO AS FIRST-LINE THERAPY FOR METASTATIC CASTRATION-RESISTANT PROSTATE CANCER

MP54-11 THE INTERSECTION OF INSURANCE WITH SHARED DECISION MAKING FOR ADVANCED PROSTATE CANCER CARE

You have accessJournal of UrologyCME1 Apr 2023MP54-11 THE INTERSECTION OF INSURANCE WITH SHARED DECISION MAKING FOR ADVANCED PROSTATE CANCER CARE Rand Wilcox Vanden Berg, Karissa Tu, J. Kelly Davis, Ada Campagna, Sharron Docherty, Daniel George, Peter Ubel, and Deborah Kaye Rand Wilcox Vanden BergRand Wilcox Vanden Berg More articles by this author , Karissa TuKarissa Tu More articles by this author , J. Kelly DavisJ. Kelly Davis More articles by this author , Ada CampagnaAda Campagna More articles by this author , Sharron DochertySharron Docherty More articles by this author , Daniel GeorgeDaniel George More articles by this author , Peter UbelPeter Ubel More articles by this author , and Deborah KayeDeborah Kaye More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003307.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Multiple medications have been approved for metastatic castrate-resistance prostate cancer (mCRPC). Clinicians are tasked with navigating the side effects, uncertain comparative efficacy, and patient preferences and values to create a treatment plan; this plan, however, must be approved by the insurance company. Herein, we qualitatively examine the relationship between the shared decision-making (SDM) process and insurance approval/authorization. METHODS: Semi-structured interviews with medical oncologists and urologist who treat patients with mCRPC within the United States were performed. Interviews were transcribed and iteratively content coded. Central themes related to the interaction between insurance companies and implemented mCRPC treatments were summarized. RESULTS: Twenty-seven physicians (19 oncology, 8 urology) were interviewed. Common themes amongst participants included treatment delays, financially motivated changes to treatment plans, dedicated staff for the insurance process, and frequent requirement of third-party financial assistance. While 16 (59%) stated a cost-agnostic approach to selecting their initial recommendation, 23 (85%) mentioned the insurance auth/approval process can change the initial treatment plan. 18 (67%) have dedicated help to navigate the insurance auth/approval process. 19 (70%) stated that they have patients who changed treatment due to out-of-pocket costs; 10 (37%) mentioned these changes happening at the beginning of the year due to deductibles or insurance changes. 8 (30%) explicitly mentioned having met delays in treatment initiation due to the auth/approval process; as stated by one physician “[when requesting enzalutamide after abiraterone failure], they usually delay authorizing the drug, unacceptably long for weeks.” Figure 1 summarizes the relationship between SDM and insurance auth/approval. CONCLUSIONS: The insurance process can interfere with SDM and lead to treatment delays and high financial burden for patients. Future research should quantify the financial impact of the considerable resources required to navigate the current approval/authorization process on oncology practices and on patients. These data can guide policymakers to improve the process for all involved parties. Source of Funding: UCF Research Scholar Award, SUO © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e757 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Rand Wilcox Vanden Berg More articles by this author Karissa Tu More articles by this author J. Kelly Davis More articles by this author Ada Campagna More articles by this author Sharron Docherty More articles by this author Daniel George More articles by this author Peter Ubel More articles by this author Deborah Kaye More articles by this author Expand All Advertisement PDF downloadLoading ...

Complete Cycles of Radium-223 Improve Overall Survival in Patients With Metastatic Castration-resistant Prostate Cancer: A Retrospective Study.

The aim of this study was to investigate whether complete cycles of Radium-223 (Ra-223) improved survival in patients with metastatic castration resistant prostate cancer (mCRPC). We retrospectively analyzed mCRPC patients treated with Ra-223 at Taichung Veterans General hospital. Patient and disease characteristics, laboratory results, number of bone metastases, mCRPC treatment sequence, Ra-223 treatment cycles and survival outcomes were collected. Overall survival and progression-free survival (PFS) were analyzed with Kaplan-Meier analysis. Uni- and multivariate analysis was used to identify clinical-radiologic factors that influence outcomes. From October 2016 to December 2020, 42 patients with mCRPC were enrolled. Twenty-three patients received <4 cycles of Ra-223 for mCRPC and 19 patients received 5-6 cycles. The median PSA progression free survival was 2.07 months in the <4 cycles group, compared to 3.93 months in the 5-6 cycles group (log rank p=0.006). The median overall survival was 3.93 months in the <4 cycles group, compared to 28.5 months in the 5-6 cycles group (log rank p<0.001). In the multivariate model, the course number of Ra-223 and pre-treatment alkaline phosphatase (ALP) levels were independent risk factors for overall survival. Patients who complete 5-6 cycles of Ra-223 had significantly better overall survival than those who didn't. Patients with a lower pre-treatment ALP were more likely to benefit from Ra-223 treatment.

Dynamic assessment of serum chromogranin A and treatment response with abiraterone acetate in metastatic castration-resistant prostate cancer.

Elevated serum chromogranin A (CGA) is associated with intrinsic or treatment-related neuroendocrine differentiation (NED) in men with metastatic castration-resistant prostate cancer (mCRPC). Fluctuations in serum CGA during treatment of mCRPC have had conflicting results. We analyzed the impact of (i) rising serum CGA and (ii) baseline CGA/PSA ratio during treatment to identify associations with abiraterone acetate (AA) therapy. Between June 2013 and August 2015, 92 men with mCRPC were enrolled in a prospective trial with uniform serum CGA processing performed before initiating abiraterone acetate/prednisone (AA/P) and serially after 12 weeks of AA/P treatments. Serum CGA was measured using a homogenous automated immunofluorescent assay. Patients receiving proton pump inhibitors or with abnormal renal function were excluded due to possible false elevations of serum CGA (n = 21 excluded), therefore 71 patients were analyzed. All patients underwent a composite response assessment at 12-weeks. Kaplan-Meier estimates and Cox Regression models were used to calculate the association with time-to-treatment failure analyses and overall survival. An increase in chromogranin was associated with a lower risk of treatment failure (hazard ratio [HR]: 0.52, p = 0.0181). The median CGA/PSA ratio was 7.8 (2.6-16.0) and an elevated pretreatment CGA/PSA ratio above the median was associated with a lower risk of treatment failure (HR: 0.54 p value = 0.0185). An increase in CGA was not found to be associated with OS (HR: 0.71, 95% CI: 0.42-1.21, p = 0.207). An elevated baseline CGA/PSA ratio was not associated with OS (HR: 0.62, 95% CI: 0.37-1.03, p = 0.062). An increase in PSA after 12 weeks of treatment was associated with an increased risk of treatment failure (HR: 4.14, CI: 2.21-7.73, p = < 0.0001) and worse OS (HR: 2.93, CI: 1.57-4.45, p = < 0.0001). We show that an increasing chromogranin on AA/P and an elevated baseline CGA/PSA in patients with mCRPC were associated with a favorable response to AA/P with no changes in survival. There may be limited clinical utility in serum CGA testing to evaluate for lethal NED as AA/P did not induce lethal NED in this cohort. This highlights that not all patients with an increasing CGA have a worse OS.

Neuroendocrine differentiation predicts the therapeutic efficacy of abiraterone and docetaxel as first-line therapy in metastatic castration-resistant prostate cancer.

We aim to explore the predictive value of neuroendocrine differentiation (NED) in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone or docetaxel as first-line therapy. We retrospectively analyzed data of 262 mCRPC patients receiving abiraterone or docetaxel as first-line mCRPC treatment. NED was evaluated using prostate biopsy samples at the time of mCRPC by immunohistochemical staining. Kaplan-Meier curves and Cox regression were used to assess the association between NED and treatment outcomes including PSA progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival (OS). NED was confirmed in 100/262 (38.2%) mCRPC patients, with 76/100 (76.0%) and 24/100 (24.0%) men harboring NED < 10% and NED ≥ 10%, respectively. 203/262 (77.5%) and 59/262 (22.5%) patients received abiraterone and docetaxel, respectively. In abiraterone treatment, NED was associated with a significantly shorter median PSA-PFS (mPSA-PFS, 7.5 vs. 10.3-Mo, P < 0.001), median rPFS (mrPFS, 15.9 vs. 19.5-Mo, P = 0.010), and median OS (mOS, 23.2 vs. 34.3-Mo, P = 0.014)). Likewise, for mCRPC patients receiving docetaxel, the positive detection of NED also predicted shorter mPSA-PFS (3.8 vs. 5.9-Mo, P = 0.052), mrPFS (8.4 vs. 20.4-Mo, P = 0.016) and mOS (13.6 vs. 29.0-Mo, P = 0.033). The adverse prognostic trait of NED is consistent in most subgroups. Additionally, patients' survival outcomes deteriorated as the NED proportion grew in both therapies. After propensity score matching, NED-positive patients showed comparable prognosis in abiraterone and docetaxel therapy. For mCRPC patients receiving abiraterone or docetaxel, NED and its proportion were critical predictive factors. NED detection at mCRPC might aid in predicting patients' outcomes and optimizing treatment decisions.

CD46 targeted 212Pb alpha particle radioimmunotherapy for prostate cancer treatment

We recently identified CD46 as a novel prostate cancer cell surface antigen that shows lineage independent expression in both adenocarcinoma and small cell neuroendocrine subtypes of metastatic castration resistant prostate cancer (mCRPC), discovered an internalizing human monoclonal antibody YS5 that binds to a tumor selective CD46 epitope, and developed a microtubule inhibitor-based antibody drug conjugate that is in a multi-center phase I trial for mCRPC (NCT03575819). Here we report the development of a novel CD46-targeted alpha therapy based on YS5. We conjugated 212Pb, an in vivo generator of alpha-emitting 212Bi and 212Po, to YS5 through the chelator TCMC to create the radioimmunoconjugate, 212Pb-TCMC-YS5. We characterized 212Pb-TCMC-YS5 in vitro and established a safe dose in vivo. We next studied therapeutic efficacy of a single dose of 212Pb-TCMC-YS5 using three prostate cancer small animal models: a subcutaneous mCRPC cell line-derived xenograft (CDX) model (subcu-CDX), an orthotopically grafted mCRPC CDX model (ortho-CDX), and a prostate cancer patient-derived xenograft model (PDX). In all three models, a single dose of 0.74 MBq (20 µCi) 212Pb-TCMC-YS5 was well tolerated and caused potent and sustained inhibition of established tumors, with significant increases of survival in treated animals. A lower dose (0.37 MBq or 10 µCi 212Pb-TCMC-YS5) was also studied on the PDX model, which also showed a significant effect on tumor growth inhibition and prolongation of animal survival. These results demonstrate that 212Pb-TCMC-YS5 has an excellent therapeutic window in preclinical models including PDXs, opening a direct path for clinical translation of this novel CD46-targeted alpha radioimmunotherapy for mCRPC treatment.

Development and validation of a survival nomogram and calculator for male patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate and/or enzalutamide

BackgroundDespite the widespread availability of medication choices for metastatic castration-resistant prostate cancer (mCRPC), biomarkers to predict the efficacy of each mCRPC treatment have not yet been established. This study developed a prognostic nomogram and a calculator to predict the prognosis of patients with mCRPC who received abiraterone acetate (ABI) and/or enzalutamide (ENZ).MethodsIn total, 568 patients with mCRPC who underwent ABI and/or ENZ between 2012 and 2017 were enrolled. A prognostic nomogram based on the risk factors was developed using the Cox proportional hazards regression model and clinically important factors. The discriminatory ability of the nomogram was assessed according to the concordance index (C-index). A 5-fold cross-validation was repeated 2000 times to estimate the C-index, and the means of the estimated C-index for the training and validation sets were determined. A calculator based on this nomogram was then developed.ResultsThe median overall survival (OS) was 24.7 months. Multivariate analysis showed that the time to CRPC, pre-chemotherapy, baseline prostate-specific antigen, baseline alkaline phosphatase, and baseline lactate dehydrogenase levels were independent risk factors for OS (hazard ratio [HR]: 0.521, 1.681, 1.439, 1.827, and 12.123, p = 0.001, 0.001, < 0.001, 0.019, and < 0.001, respectively). The C-index was 0.72 in the training cohort and 0.71 in the validation cohort.ConclusionsWe developed a nomogram and calculator to predict OS in Japanese patients with mCRPC who received ABI and/or ENZ. Reproducible prognostic prediction calculators for mCRPC will facilitate greater accessibility for clinical use.

Prostate-specific antigen response after Abiraterone treatment in mCRPC: PSA as a predictor of overall survival

Abiraterone Acetate (AA) is an important agent in the treatment of advanced prostate cancer. It was primarily approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) after failure of androgen deprivation therapy. There is still no available strong data regarding the impact of early decline of prostate-specific antigen (PSA) in the overall survival. The aim of this study was to evaluate the clinical efficacy of an early prostate-specific antigen response as a predictor of overall survival (OS) in metastatic castration-resistant prostate cancer when treated with Abiraterone Acetate. A dual center, retrospective, cohort study on patients diagnosed with mCRPC treated with abiraterone between 2013 and 2020 was performed. Primary end-point was to demonstrate the efficacy of AA, with the analysis of PSA decline, and the correlation with overall survival. The cohort analysis consisted of 84 patients with a median age of 71 ± 9 years. A PSA response of > 30% and > 50% at 60 and 90 days was associated with improved OS. Multivariate analysis revealed that a 60 day PSA decline of > 30% was predictive of overall survival. Median OS of diag-nosed mCRPC patients was 28 months. Docetaxel pre-treatment was not associated with longer OS. The median duration of drug exposure for patients submitted to AA was found to be 14 months. Early PSA response rate can offer clinically meaningful information and can be considered a surrogate of longer OS. A > 30% or > 50% prostate-specific antigen decline at 60 and 90 days provided an important low-cost clinical tool to predict subsequent events in mCRPC patients treated with abiraterone.