Treatment Of Castration-resistant Prostate Cancer Research Articles

Lu-177 PSMA vs Comparator Treatments and Survival in Metastatic Castration-Resistant Prostate Cancer

Observed treatment effects on overall survival (OS) differed substantially in the first 2 randomized clinical trials of lutetium Lu 177 vipivotide tetraxetan (Lu-177) prostate-specific membrane antigen (PSMA) in metastatic castration-resistant prostate cancer. To investigate factors associated with the observed difference in treatment effects on OS, including differences in the risk of crossover from randomized treatment after disease progression. This comparative effectiveness study used individual participant data from 2 randomized clinical trials, TheraP (A Randomised Phase 2 Trial of 177Lu-PSMA617 Theranostic Versus Cabazitaxel in Progressive Metastatic Castration Resistant Prostate Cancer [ANZUP Protocol 1603]) (n = 200), recruited from February 2018 to September 2019 in Australia, and published data from VISION (An International, Prospective, Open Label, Multicenter, Randomized Phase 3 Study of 177Lu-PSMA-617 in the Treatment of Patients With Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer) (n = 831), recruited from June 2018 to October 2019 in North America and Europe. Individual participant data for OS were reconstructed from VISION using the published survival curves. Data were analyzed February 6, 2018, to December 31, 2021, for TheraP and June 4, 2018, to January 27, 2021, for VISION. TheraP randomized participants to receive treatment with Lu-177 PSMA or cabazitaxel. VISION randomized participants to receive treatment with or without Lu-177 PSMA in addition to physicians' choice of protocol-permitted treatments (PPT; approved hormonal treatments [such as abiraterone and enzalutamide], bisphosphonates, radiotherapy, denosumab, or glucocorticoids), excluding cabazitaxel. Patient characteristics, treatment protocols, and OS outcomes of the 2 trials were compared. Estimates of the effect on OS from TheraP were adjusted for crossover from randomly assigned treatment using a rank-preserving structural failure time model (RPSFTM) and inverse probability of censoring weights (IPCW) methods. The 200 participants in TheraP and 831 participants in VISION were similar in age (median [range], 72 [49-86] vs 71 [40-94] years). Improved OS was observed in the comparator treatment group (cabazitaxel) in TheraP compared with VISION (PPT) (hazard ratio [HR], 0.53 [95% CI, 0.39-0.71]). The Lu-177 PSMA treatment groups in TheraP and VISION had similar OS (HR, 0.92 [95% CI, 0.70-1.19]). In TheraP, 20 of 101 participants in the cabazitaxel group crossed over to Lu-177 PSMA, while 32 of 99 participants in the Lu-177 PSMA arm crossed over to cabazitaxel. No statistically significant differences in OS between the Lu-177 PSMA and cabazitaxel groups of TheraP were observed after controlling for crossover to cabazitaxel: RPSFTM HR, 0.97 (95% CI, 0.60-1.58); IPCW HR, 0.92 (95% CI, 0.65-1.32); RPSFTM HR, 0.97 (95% CI, 0.60-1.58) and IPCW HR, 0.82 (95% CI, 0.54-1.24) for crossover to Lu-177 PSMA; RPSFTM HR, 0.96 (95% CI, 0.53-1.74) and IPCW HR, 0.82 (95% CI, 0.53-1.27) for crossover to either Lu-177 PSMA or cabazitaxel. Findings of this secondary analysis of the TheraP and VISION randomized clinical trials suggest that the choice of comparator treatments (ie, cabazitaxel vs PPT) may explain the difference in the observed effect of Lu-177 PSMA on OS between the 2 trials. Causal inference methods such as RPSFTM and IPCW may help rule out crossover as a plausible explanation.

Budget Impact Analysis of Olaparib for the Management of Patients with Homologous Recombination Repair (HRR)-Mutated Castration-Resistant Metastatic Prostate Cancer in Argentina.

The aim of this study was to perform a budget impact analysis (BIA) of introducing olaparib treatment for adult patients with metastatic castration-resistant prostate cancer in Argentina. A BIA model was used to estimate the cost difference between the current scenario (without olaparib) and the new scenario (incorporation of olaparib) for a third-party payer over a 5-year time horizon. The budgetary impact is estimated at the national health system level and by healthcare sectors in Argentina. Input parameters were obtained from the literature and validated by local expert opinion. Direct medical costs were obtained from both the Institute for Clinical Effectiveness and Health Policy (IECS) unit cost database and public data in Argentina. The microcosting estimation was used for key variables of the analysis. All costs are reported in US dollars (US$) as for October 2022 (1 US$ = 152.59 Argentine pesos). One-way sensitivity analyses and scenario analyses were conducted to evaluate the model robustness. The incorporation of olaparib, with a wholesale price per pack of US$3176, was associated with a weighted average of the budget impact per member per month (PMPM) of US$0.0191 for the national health system, being slightly higher than the estimated budgeted high impact threshold (US$0.0153). The PMPM budget impact for a 5-year average ranged between US$0.007 (public sector) and US$0.033 (private sector). The duration of treatment with olaparib was the most influential parameter in the budget impact results. The introduction of olaparib for the treatment of metastatic castration-resistant prostate cancer has a high budget impact for Argentina's health system. These findings are informative to support policy decisions aimed to expand the current treatment landscape for prostate cancer.

Neuroendocrine Prostate Cancer Drivers SOX2 and BRN2 Confer Differential Responses to Imipridones ONC201, ONC206, and ONC212 in Prostate Cancer Cell Lines.

Prostate cancer (PCa) is the leading cause death from cancer in men worldwide. Approximately 30% of castrate-resistant PCa's become refractory to therapy due to neuroendocrine differentiation (NED) that is present in <1% of androgen-sensitive tumors. First-in-class imipridone ONC201/TIC10 has shown clinical activity against midline gliomas, neuroendocrine tumors and PCa. We explored the question of whether NED promotes sensitivity to imipridones ONC201 and ONC206 by inducible overexpression of SOX2 and BRN2, well-known neuroendocrine drivers, in human PCa cell lines DU145 or LNCaP. Slight protection from ONC201 or ONC206 with SOX2 and BRN2 overexpression was observed in the inducible LNCaP cells but not in the DU145 cells. At 2 months, there was an apparent increase in CLpP expression in LNCaP SOX2-overexpressing cells but this did not confer enhanced sensitivity to ONC201. DU145 SOX2-overexpressing cells had a significantly reduced ONC201 sensitivity than DU145 control cells. The results support the idea that treatment of castrate-resistant prostate cancer by imipridones may not be significantly impacted by neuroendocrine differentiation as a therapy-resistance mechanism. The results support further testing of imipridones across subtypes of androgen-sensitive and castrate-resistant prostate cancer.

Androgen deprivation as initial and backbone therapy for prostate carcinoma cancer : Aretrospective data analysis from urological practices in Germany

The aim of this study was to determine the proportion of patients with prostate cancer (PCa) who remained on primary androgen deprivation therapy (ADT) after starting treatment for castration-resistant prostate cancer (CRPC) and to describe their treatment patterns. The study comprises aretrospective analysis of 609,308patients in urological practices in Germany from 2011 to 2020 based on anonymized secondary data from the UROscience webserver. PCa patients were eligible for inclusion if they received ADT after a6-month prescription-free pre-index period. Atotal of 3,112patients (mean age 75.5 [±8.0]years) were included. Most patients received gonadotropin-releasing hormone (GnRH) agonists (72.3%), followed by antiandrogens (24.9%). The median duration of ADT treatment was 25.9months. The estimated probabilities of continuing ADT 3, 6, and 8years after starting treatment were 40.7%, 20.1%, and 12.7%, respectively. Interruption across all ADTs occurred in 42.7% of patients, switching of primary ADT in 52.2% and discontinuation in 82.2% of patients. After starting ADT, 14.6% of patients received treatment for CRPC, of whom 76.4% continued primary ADT. The median duration of CRPC treatment was 11.0months. The estimated probabilities of developing CRPC 3, 6, and 8years after starting ADT were 11.1%, 20.1%, and 25.9%, respectively. This study has shown that arelevant proportion of patients discontinued primary ADT after starting treatment for CRPC, although guidelines recommend continuing ADT if the disease progresses.

Androgen Receptor Inhibitors in Patients With Nonmetastatic Castration-Resistant Prostate Cancer

Novel androgen receptor inhibitors (ARIs; darolutamide, enzalutamide, and apalutamide) are standard-of-care treatments for nonmetastatic castration-resistant prostate cancer (nmCRPC). However, there are sparse data comparing their clinical use and tolerability. To compare clinical use and outcomes for darolutamide, enzalutamide, and apalutamide in patients with nmCRPC. This retrospective cohort study reviewed electronic medical records from the Precision Point Specialty network of US urology practices. Eligible patients had nmCRPC and no prior novel hormonal therapy and initiated novel ARI treatment between August 1, 2019, and March 31, 2022. Data were analyzed from February 1, 2019, to December 31, 2022. Patients were prescribed darolutamide, enzalutamide, or apalutamide as their first novel ARI for nmCRPC. The main outcome was a composite of 2 end points, treatment discontinuation and progression to metastatic CRPC (mCRPC), whichever occurred first. Both end points were also assessed separately. All 870 patients meeting eligibility criteria were included (362 receiving darolutamide [41.6%]; 382, enzalutamide [43.9%]; 126, apalutamide [14.5%]); mean (SD) age was 78.8 (8.7) years. Self-reported race was Black or African American in 187 patients (21.5%), White in 585 (67.2%), and other or unknown in 98 (11.3%). The darolutamide cohort had lower proportions of patients with a composite end point event (134 [37.0%] vs 201 [52.6%] for enzalutamide and 66 [52.4%] for apalutamide), discontinuation (110 [30.4%] for darolutamide vs 156 [40.8%] for enzalutamide and 58 [46.0%] for apalutamide), and progression to mCRPC (64 [17.7%] for darolutamide vs 108 [28.3%] for enzalutamide and 35 [27.8%] for apalutamide) during the study period. After adjusting for baseline covariates, patients receiving darolutamide had a lower risk of a composite end point event compared with enzalutamide (risk reduction, 33.8%; hazard ratio [HR], 0.66 [95% CI, 0.53-0.84]) and apalutamide (risk reduction, 35.1%; HR, 0.65 [95% CI, 0.48-0.88]). Similarly, patients receiving darolutamide had a lower risk of discontinuation compared with enzalutamide (risk reduction, 27.4%; HR, 0.73 [95% CI, 0.56-0.94]) and apalutamide (risk reduction, 39.1%; HR, 0.61 [95% CI, 0.44-0.85]) and a lower risk of progression to mCRPC compared with enzalutamide (risk reduction, 40.6%; HR, 0.59 [95% CI, 0.43-0.82]) and apalutamide (risk reduction, 35.3%; HR, 0.65 [95% CI, 0.42-0.99]). There was no difference between enzalutamide and apalutamide treatment across outcomes. In this large cohort study of patients with nmCRPC treated with novel ARIs, results suggest better tolerability for darolutamide compared with enzalutamide and apalutamide, which may be associated with a clinical effectiveness advantage. Comparative clinical studies are needed to guide treatment decisions in the absence of head-to-head clinical trials.

Falls in older adults during treatment for metastatic castration-resistant prostate cancer (mCRPC)

Falls in older adults during treatment for metastatic castration-resistant prostate cancer (mCRPC)

Real-World Clinical Outcomes and Treatment Patterns Among Black and Non-Black Patients With Prostate Cancer Initiated on Apalutamide in a Urology Setting

Background: The use of androgen receptor signaling inhibitors, including apalutamide, in combination with androgen deprivation therapy is recommended for the treatment of metastatic castration-sensitive prostate cancer (mCSPC) and non-metastatic castration-resistant prostate cancer (nmCRPC). Objective: To describe real-world treatment patterns and clinical outcomes among patients with mCSPC or nmCRPC who initiated apalutamide in the United States. Methods: A retrospective cohort study of patients with mCSPC or nmCRPC who initiated apalutamide was conducted using electronic medical record data from US community-based urology practices (Feb. 1, 2017–April 1, 2022). Persistence with apalutamide was reported at 6-, 12-, and 18-months post treatment initiation. Clinical outcomes described up to 24 months after apalutamide initiation using Kaplan-Meier analyses included progression to castration resistance, castration resistance-free survival (CRFS), and metastasis-free survival (MFS). Outcomes were reported separately based on mCSPC or nmCRPC status and race (ie, Black or non-Black). Results: This study included 589 patients with mCSPC (mean age, 75.9 years) and 406 patients with nmCRPC (mean age, 78.8 years). Using a treatment gap of &gt;90 days, persistence with apalutamide at 12 months remained high for both the mCSPC (94.9%) and nmCRPC (92.7%) cohorts, and results were descriptively similar among Black and non-Black patients, and when a treatment gap of &gt;60 days was considered. In patients with mCSPC, overall progression to castration resistance rates at 12 and 24 months were 20.9% and 33.5%, and overall CRFS rates were 76.2% and 62.0%, respectively. In patients with nmCRPC, overall MFS rates at 12 and 24 months were 89.7% and 75.4%, respectively. Rates of these clinical outcomes were descriptively similar between Black and non-Black patients. Discussion: While clinical trials have demonstrated the efficacy and safety of apalutamide, there is limited real-world data describing treatment persistence and clinical outcomes among patients with mCSPC and nmCRPC who initiated apalutamide. Conclusions: In this real-world study of patients with mCSPC or nmCRPC initiated on apalutamide, treatment persistence was high and apalutamide demonstrated robust real-world effectiveness with respect to progression to castration resistance, CRFS, and MFS, overall and among Black and non-Black patients.

Real-World Clinical Outcomes and Treatment Patterns Among Black and Non-Black Patients With Prostate Cancer Initiated on Apalutamide in a Urology Setting.

Background: The use of androgen receptor signaling inhibitors, including apalutamide, in combination with androgen deprivation therapy is recommended for the treatment of metastatic castration-sensitive prostate cancer (mCSPC) and non-metastatic castration-resistant prostate cancer (nmCRPC). Objective: To describe real-world treatment patterns and clinical outcomes among patients with mCSPC or nmCRPC who initiated apalutamide in the United States. Methods: A retrospective cohort study of patients with mCSPC or nmCRPC who initiated apalutamide was conducted using electronic medical record data from US community-based urology practices (Feb.1, 2017-April 1, 2022). Persistence with apalutamide was reported at 6-, 12-, and 18-months post treatment initiation. Clinical outcomes described up to 24 months after apalutamide initiation using Kaplan-Meier analyses included progression to castration resistance, castration resistance-free survival (CRFS), and metastasis-free survival (MFS). Outcomes were reported separately based on mCSPC or nmCRPC status and race (ie, Black or non-Black). Results: This study included 589 patients with mCSPC (mean age, 75.9 years) and 406 patients with nmCRPC (mean age, 78.8 years). Using a treatment gap of >90 days, persistence with apalutamide at 12 months remained high for both the mCSPC (94.9%) and nmCRPC (92.7%) cohorts, and results were descriptively similar among Black and non-Black patients, and when a treatment gap of >60 days was considered. In patients with mCSPC, overall progression to castration resistance rates at 12 and 24 months were 20.9% and 33.5%, and overall CRFS rates were 76.2% and 62.0%, respectively. In patients with nmCRPC, overall MFS rates at 12 and 24 months were 89.7% and 75.4%, respectively. Rates of these clinical outcomes were descriptively similar between Black and non-Black patients. Discussion: While clinical trials have demonstrated the efficacy and safety of apalutamide, there is limited real-world data describing treatment persistence and clinical outcomes among patients with mCSPC and nmCRPC who initiated apalutamide. Conclusions: In this real-world study of patients with mCSPC or nmCRPC initiated on apalutamide, treatment persistence was high and apalutamide demonstrated robust real-world effectiveness with respect to progression to castration resistance, CRFS, and MFS, overall and among Black and non-Black patients.

Multicenter non-interventional study of prevalence of homologous recombination gene mutations and approaches to treatment of metastatic castration-resistant prostate cancer in Russia (ADAM)

Multicenter non-interventional study of prevalence of homologous recombination gene mutations and approaches to treatment of metastatic castration-resistant prostate cancer in Russia (ADAM)

Gösta Jönsson (1909-1978): A pioneer in the hormonal treatment of prostate cancer in Sweden.

Treatment of castration-resistant prostate cancer is and has been a challenge. In 1957, the chemist Imre Könyves came to Sweden as a refugee from Hungary and started to work at AB Leo, a pharmaceutical company in Helsingborg. In 1961, he started to synthesize compounds where the oestrogens were linked to a mustard group by a carbamate. This resulted in estramustine phosphate, which was initially tested against mammary cancer with disappointing results. He then started a cooperation with urology professor Gösta Jönsson, Head of the Department of Urology at the Lund University Hospital, to test estramustine phosphate against prostate cancer. Jönsson started clinical estramustine phosphate tests in 1966. His studies were one-armed and consecutive, with a "favourable response" in 83% of previously untreated patients. These favourable results could not be reproduced in later randomized controlled studies suggesting that estramustine phosphate as primary treatment was not better than conventional estrogenic treatment. Conclusions: Even if the results of Gösta Jönsson's studies could not be confirmed, the subsequent randomized studies of estramustine phosphate may hide the desired action of estramustine phosphate in a subgroup of patients. It has still not been elucidated whether estramustine phosphate has effects in this subgroup of patients with ostrogen-resistant prostate cancer.

PROTACs as Therapeutic Modalities for Drug Discovery in Castration-Resistant Prostate Cancer.

Castration-resistant prostate cancer (CRPC) presents significant challenges in clinical management due to its resistance to conventional androgen receptor (AR)-targeting therapies. The advent of proteolysis targeting chimeras (PROTACs) has revolutionized cancer therapy by enabling the targeted degradation of key molecular players implicated in CRPC progression. In this review we discuss the developments of PROTACs for CRPC treatment, focusing on AR and other CRPC-associated regulators. We provide an overview of the strategic trends in AR PROTAC development from the aspect of targeting site selection and preclinical antitumor evaluation, as well as updates on AR degraders in clinical applications. Additionally, we briefly address the current status of selective AR degrader development. Furthermore, we review new developments in PROTACs as potential CRPC treatment paradigms, highlighting those targeting chromatin modulators BRD4, EZH2, and SWI/SNF; transcription regulator SMAD3; and kinases CDK9 and PIM1. Given the molecular targets shared between CRPC and neuroendocrine prostate cancer (NEPC), we also discuss the potential of PROTACs in addressing NEPC.

Symptom burden among men treated for castration-resistant prostate cancer: a longitudinal study

ObjectivesDespite rapid expansion of treatments for metastatic castration-resistant prostate cancer (mCRPC) and the importance of symptom management for enhancing quality of life, few studies have focused on men’s experiences of...

Prediction of PSA Response after Dexamethasone Switch during Abiraterone Acetate + Prednisolone Treatment of Metastatic Castration-Resistant Prostate Cancer Patients.

The aim was to elaborate a predictive model to find responders for the corticosteroid switch (from prednisolone to dexamethasone) at the first prostate-specific antigen (PSA) progression (≥25% increase) during abiraterone acetate (AA) treatment of metastatic castration-resistant prostate cancer (mCRPC) patients. If PSA has decreased (≥25%) after switch, patients were considered responders. Logistic regression of 19 dichotomized parameters from routine laboratory and patients' history was used to find the best model in a cohort of 67 patients. The model was validated in another cohort of 42 patients. The model provided 92.5% and 90.5% accuracy in the testing and the validation cohorts, respectively. Overall the accuracy was 91.7%. The AUC of ROC curve was 0.92 (95% CI 0.85-0.96). After a median follow-up of 27.9 (26.3-84) months, the median AA+dexamethasone treatment duration (TD) in non-responders and responders was 4.7 (3.1-6.5) and 11.1 (8.5-12.9) months and the median overall survival (OS) was 23.2 (15.6-25.8) and 33.5 (26.1-38) months, respectively. Multivariate Cox regression revealed that responsiveness was an independent marker of TD and OS. A high accuracy model was developed for mCRPC patients in predicting cases which might benefit from the switch. For non-responders, induction of the next systemic treatment is indicated.

Prostate-Specific Membrane Antigen PET/CT-Guided, Metastasis-Directed Radiotherapy for Oligometastatic Castration-Resistant Prostate Cancer.

Systemic treatments for metastatic castration-resistant prostate cancer (mCRPC) include androgen deprivation therapy, androgen receptor pathway inhibitors, chemotherapy, and radiopharmaceuticals, all of which have associated toxicity. Prostate-specific membrane antigen (PSMA) PET/CT allows for higher sensitivity in detecting metastatic disease than is possible with conventional imaging. We hypothesized that PSMA PET/CT-guided, metastasis-directed radiotherapy may offer durable disease control with low toxicity rates in patients with mCRPC who have a limited number of metastases. Methods: We retrospectively screened 5 prospective PSMA PET/CT studies for patients with mCRPC who had up to 5 sites of oligorecurrent or oligoprogressive disease on PSMA PET/CT and subsequently received definitive-intent, metastasis-directed radiotherapy to all new or progressing sites with concurrent androgen deprivation therapy. Progression-free survival, freedom from new lines of systemic therapy, and overall survival (OS) were calculated from the start of metastasis-directed radiotherapy using Kaplan-Meier analysis. Biochemical response was defined as at least a 50% decrease in prostate-specific antigen 6 mo after the start of treatment. Toxicity was graded using the Common Terminology Criteria for Adverse Events, version 5. Results: Twenty-four patients met the inclusion criteria with a median follow-up of 33.8 mo (interquartile range, 27.6-45.1 mo). Between October 2017 and April 2023, 11 patients (45.8%) had 1 treated site, 10 patients (41.7%) had 2, and 3 patients (12.5%) had 3. Five sites were prostate or prostate bed, 15 were nodal, 19 were osseous, and 1 was visceral. Seventeen patients (70.8%) continued their preexisting systemic therapy, whereas 7 (29.2%) started a new systemic therapy. Median progression-free survival was 16.4 mo (95% CI, 9.8-23.0 mo). The biochemical response rate was 66.7%. Median freedom from a new line of systemic therapy was 29.0 mo (95% CI, 7.6-50.4 mo). Median OS was not reached. The 2- and 4-y OS rates were 91.1% (95% CI, 79.3%-100%) and 68.8% (95% CI, 45.1%-92.5%), respectively. Grade 2 and grade 3 or higher toxicity rates were 4.2% and 0%, respectively. Conclusion: PSMA PET/CT-guided, metastasis-directed radiotherapy appears to offer durable disease control with low toxicity rates for oligometastatic castration-resistant prostate cancer. Further prospective studies are needed to compare metastasis-directed radiotherapy with systemic therapy versus systemic therapy alone and PSMA PET/CT-guided versus conventional imaging-guided radiotherapy.

GSFM: A genome-scale functional module transformation to represent drug efficacy for in silico drug discovery

Pharmacotranscriptomic profiles, which capture drug-induced changes in gene expression, offer vast potential for computational drug discovery and are widely used in modern medicine. However, current computational approaches neglected the associations within gene‒gene functional networks and unrevealed the systematic relationship between drug efficacy and the reversal effect. Here, we developed a new genome-scale functional module (GSFM) transformation framework to quantitatively evaluate drug efficacy for in silico drug discovery. GSFM employs four biologically interpretable quantifiers: GSFM_Up, GSFM_Down, GSFM_ssGSEA, and GSFM_TF to comprehensively evaluate the multi-dimension activities of each functional module (FM) at gene-level, pathway-level, and transcriptional regulatory network-level. Through a data transformation strategy, GSFM effectively converts noisy and potentially unreliable gene expression data into a more dependable FM active matrix, significantly outperforming other methods in terms of both robustness and accuracy. Besides, we found a positive correlation between RSGSFM and drug efficacy, suggesting that RSGSFM could serve as representative measure of drug efficacy. Furthermore, we identified WYE-354, perhexiline, and NTNCB as candidate therapeutic agents for the treatment of breast-invasive carcinoma, lung adenocarcinoma, and castration-resistant prostate cancer, respectively. The results from in vitro and in vivo experiments have validated that all identified compounds exhibit potent anti-tumor effects, providing proof-of-concept for our computational approach.

Abiraterone or Enzalutamide for Patients With Metastatic Castration-Resistant Prostate Cancer

Abiraterone acetate and enzalutamide are recommended as preferred treatments for metastatic castration-resistant prostate cancer (mCRPC), but differences in their relative efficacy are unclear due to a lack of head-to-head clinical trials. Clear guidance is needed for making informed mCRPC therapeutic choices. To compare clinical outcomes in patients with mCRPC treated with abiraterone acetate or enzalutamide. This retrospective, multicenter cohort study included patients with mCRPC in the US Department of Veterans Affairs health care system who initiated treatment with abiraterone acetate or enzalutamide between January 1, 2014, and October 30, 2022. Abiraterone acetate or enzalutamide. The study used inverse probability of treatment weighting to balance baseline characteristics between patients initiating abiraterone acetate or enzalutamide and evaluated restricted mean survival time (RMST) differences in overall survival (OS), prostate cancer-specific survival (PCS), time to next treatment switching or death (TTS), and time to prostate-specific antigen (PSA) response (TTR) at different time points after treatment initiation. The study included 5779 patients (median age, 74.42 years [IQR, 68.94-82.14 years]). Median follow-up was between 38 and 60 months. Patients initiating enzalutamide on average had longer OS than those initiating abiraterone acetate, with RMSTs of 24.29 months (95% CI, 23.58-24.99 months) and 23.38 months (95% CI, 22.85-23.92 months), respectively, and a difference in RMST of 0.90 months (95% CI, 0.02-1.79 months) at 4 years. Similarly, TTS and TTR were improved in patients initiating enzalutamide, with an RMST at 4 years of 1.95 months (95% CI, 0.92-2.99 months) longer for TTS and 3.57 months (95% CI, 1.76-5.38 months) shorter for TTR. For PCS, the RMST at 2 years was 0.48 months (95% CI, 0.01-0.95 months) longer. An examination of subgroups identified that enzalutamide initiation was associated with longer RMST in OS among patients without prior docetaxel treatment (1.14 months; 95% CI, 0.19-2.10 months) and in those with PSA doubling time of 3 months or longer (2.23 months; 95% CI, 0.81-3.66 months) but not among patients with prior docetaxel (-0.25 months; 95% CI, -2.59 to 2.09 months) or with PSA doubling time of less than 3 months (0.05 months; 95% CI, -1.05 to 1.15 months). In this cohort study of patients with mCRPC, initiation of enzalutamide was associated with small but statistically significant improvements in OS, PCS, TTS, and TTR compared with initiation of abiraterone acetate. The improvements were more prominent in short-term outcomes, including TTS and TTR, and in patient subgroups without prior docetaxel or with PSA doubling time longer than 3 months.

Interlesional response heterogeneity is associated with the prognosis of abiraterone treatment in metastatic castration-resistant prostate cancer.

Interlesional response heterogeneity (ILRH) poses challenges to the treatment of metastatic castration-resistant prostate cancer (mCRPC). Currently, there are no prospective clinical trials exploring the prognostic significance of ILRH on paired positron emission tomography/computed tomography (PET/CT) in the context of abiraterone therapy. In this prospective study, we enrolled patients with mCRPC treated with abiraterone (ClinicalTrials.gov: NCT05188911; ChiCTR.org.cn: ChiCTR2000034708). 68Ga-prostate-specific membrane antigen (PSMA)+18F-fluorodeoxyglucose (FDG) PET/CT and circulating tumor DNA (ctDNA) monitoring were performed at baseline and week 13. Patients were grouped by their early ILRH measurement. The primary endpoint was to evaluate the predictive role of ILRH for conventional progression-free survival (PFS) through the concordance index (C-index) assessment. Conventional PFS was defined as the time from medication to conventional radiographic progression, clinical progression, or death. Ultimately, 33 patients were included with a median follow-up of 28.7months. Baseline+week 13 PSMA PET/CT revealed that 33.3% of patients showed ILRH. Those patients with hetero-responding disease had significantly different PFS compared to the responding and non-responding groups (hazard ratio: responding group= reference, hetero-responding group= 4.0, non-responding group= 5.8; p<0.0001). The C-index of ILRH on paired PSMA PET/CT (0.742 vs. 0.660) and FDG PET/CT (0.736 vs. 0.668) for conventional PFS was higher than that of PSA response. In an exploratory analysis, PSMA-/FDG+ lesions at week 13 were identified as a strong surrogate for poor conventional PFS (p= 0.039). ILRH on both baseline+week 13 PSMA and FDG PET/CT strongly associated with conventional PFS. This study was funded by the Ministry of Science and Technology of China and Shanghai.

Investigating miR-6880-5p in extracellular vesicle from plasma as a prognostic biomarker in endocrine therapy-treated castration-resistant prostate cancer

BackgroundAdvancements in the diagnosis, treatment, and surveillance of castration-resistant prostate cancer (CRPC) have progressed considerably, but a new biomarker that combines existing clinical and pathological data could be useful for a more precise diagnosis and prognosis. Some investigations have found that extracellular vesicle (EV)-derived miRNAs play crucial roles in various types of malignant tumors. The objective of this study was to explore EV miRNA and identify its biologic function as a biomarker for the diagnosis and prognosis of CRPC.MethodsPlasma samples were collected from five healthy donors (Control, CT) and 17 CRPC patients, categorizing into two groups based on their endocrine treatment response: partial response (PR; n = 10) and progressive disease (PD; n = 7). Candidate extracellular vesicle (EV) miRNAs were identified using miRNA microarray and RT-qPCR. The biological functions of the selected miRNAs were evaluated using the MTT assay, wound healing assay, trans-well assay, and RNA sequencing in CRPC cells after transient miRNA expression.ResultsMicroarray analysis revealed a significant downregulation of EV-miR-6880-5p in the PD samples compared to both CT and PR samples (p < 0.01). The expression of EV-miR-6880-5p in CRPC patients was decreased compared with that CT group (p = 0.0336) using RT-qPCR. In the PR group, EV-miR-6880-5p was increased at follow-up compared with the baseline (p = 0.2803), while in the PD group, it decreased at follow-up compared with the baseline samples (p = 0.4356). Furthermore, overexpression of miR-6880-5p hampered cell proliferation, migration, and invasion, downregulated pathways associated with tumor progression, and simultaneously upregulated pathways associated with cell growth and apoptosis in CRPC cells.ConclusionsEV-miR-6880-5p shows promise as a prognostic biomarker in patients with CRPC. Further, prospective validations are necessary to evaluate the potential of these candidate miRNAs.

A Review of Abiraterone Acetate for the Treatment of Metastatic Castration-Resistant Prostate Cancer

A Review of Abiraterone Acetate for the Treatment of Metastatic Castration-Resistant Prostate Cancer

Real-life Data on First- and Second-Line Treatment of Metastatic Castration-Resistant Prostate Cancer With Abiraterone, Enzalutamide and Cabazitaxel – A multicentric Study From Portugal

Introduction and objectivesNew drugs for metastatic castrate resistant prostate cancer (mCRPC) were approved, first in the pos-docetaxel and then in the pre-docetaxel setting. We aim to assess the real daily practice benefit of abiraterone (Abi), enzalutamide (Enz) and cabazitaxel (Cab) in patients with mCRPC, compare it with RCT results and compare Abi vs Enz. Materials and methodsWe retrospectively collected the data of all consecutive mCRPC patients treated with Abi, Enz or Cab in the six major oncological hospitals in the north of Portugal until December 2020. ResultsA total of 470 treatments pre-docetaxel (163 Abi and 307 Enz) and 373 pos-docetaxel (160 Abi, 148 Enz and 59 Cab) were included, with median follow-up time of 35 months. Mean age was 73.1, 84.4% had ECOG status < 2, ISUP grade was ≥ 4 in 59% and 28.0% had oligometastatic disease. In first line, for Abi and for Enz respectively, the proportion of patients with PSA reduction > 50% was 64.4% and 80.4% (P < .001), the mean duration of treatment (DT) was 10 and 14 months (P = .037) and the median overall survival (OS) was 25 months and 30 months (P = .17). In second line the results for Abi, Enz and Cab were respectively: proportion of patients with PSA reduction > 50% was 40.4%, 57.4% and 24.6% (p for Abi vs Enz=0.004); DT was 7, 8, and 3 months (p for Abi vs Enz = 0.27); OS was 17, 22 and 10 months (p for Abi vs. Enz = 0,07). ConclusionThese drugs have good efficacy in real-world evidence, similar to those reported in randomized clinical trials, with the expected exception of lower OS due to the inclusion of a broader sample of patients. Our results add to the evidence that Enz might have better efficacy in this setting compared with Abi.