Current capabilities in treatment of non-metastatic castration-resistant prostate cancer: effectiveness, safety, and quality of life of patients taking darolutamide

Prostate cancer is an important disease in current oncological urology. Radical treatment of patients with localized and locally advanced prostate cancer, including surgical and radiological treatments, often does not cure patients from this pathology, especially in the group with high risk of disease progression; the risk of biochemical recurrence in this patient group can be up to 40-60 %. Widespread application of radical treatment allowed to significantly increase survival of patients from this group. However, in case of biochemical recurrence, the majority of patients require longterm androgen-depriving therapy for suppression of natural testosterone level. In some of these patients during longterm castration therapy, non-metastatic castration-resistant prostate cancer develops (CRPC) in the absence of signs of radiological disease progression. Results of large randomized trials show the necessity of stratification of these patients in the group with high risk of progression considering short doubling period of prostate-specific antigen and realization of distant metastases. The main therapy concept for this patient group is use of new-generation inhibitors of androgen signal to increase time to CRPC metastases and overall life expectancy. The article presents results of large trials performed in patients with non-metastatic CRPC and characterizes the role of one of the most effective drugs, darolutamide, used for treatment in this patient cohort.

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ZRSR2 overexpression is a frequent and early event in castration-resistant prostate cancer development

Prostate Cancer and Prostatic Diseases ◽

10.1038/s41391-021-00322-7 ◽

2021 ◽

Author(s):

Haiqing He ◽

Jun Hao ◽

Xin Dong ◽

Yu Wang ◽

Hui Xue ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Cycle Progression ◽

Locally Advanced ◽

Patient Treatment ◽

Early Event ◽

Driver Gene ◽

Castration Resistant Prostate Cancer ◽

Driver Genes ◽

Castration Resistant ◽

Pdx Models

Abstract Background Androgen deprivation therapy (ADT) remains the leading systemic therapy for locally advanced and metastatic prostate cancers (PCa). While a majority of PCa patients initially respond to ADT, the durability of response is variable and most patients will eventually develop incurable castration-resistant prostate cancer (CRPC). Our research objective is to identify potential early driver genes responsible for CRPC development. Methods We have developed a unique panel of hormone-naïve PCa (HNPC) patient-derived xenograft (PDX) models at the Living Tumor Laboratory. The PDXs provide a unique platform for driver gene discovery as they allow for the analysis of differentially expressed genes via transcriptomic profiling at various time points after mouse host castration. In the present study, we focused on genes with expression changes shortly after castration but before CRPC has fully developed. These are likely to be potential early drivers of CRPC development. Such genes were further validated for their clinical relevance using data from PCa patient databases. ZRSR2 was identified as a top gene candidate and selected for further functional studies. Results ZRSR2 is significantly upregulated in our PDX models during the early phases of CRPC development after mouse host castration and remains consistently high in fully developed CRPC PDX models. Moreover, high ZRSR2 expression is also observed in clinical CRPC samples. Importantly, elevated ZRSR2 in PCa samples is correlated with poor patient treatment outcomes. ZRSR2 knockdown reduced PCa cell proliferation and delayed cell cycle progression at least partially through inhibition of the Cyclin D1 (CCND1) pathway. Conclusion Using our unique HNPC PDX models that develop into CRPC after host castration, we identified ZRSR2 as a potential early driver of CRPC development.

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MP07-09 ALDO-KETO-REDUCTASE 1C3 EXPRESSION IS AN INDEPENDENT RISK FACTOR FOR OCCURRENCE OF CASTRATION RESISTANT PROSTATE CANCER IN HIGH RISK PROSTATE CANCER TREATED WITH NEOADJUVANT THERAPY AND PROSTATECTOMY

The Journal of Urology ◽

10.1016/j.juro.2016.02.2212 ◽

2016 ◽

Vol 195 (4S) ◽

Author(s):

Yasuhiro Hashimoto ◽

Hiromichi Iwamura ◽

Atsushi Imai ◽

Shingo Hatakeyama ◽

Takahiro Yoneyama ◽

...

Keyword(s):

Prostate Cancer ◽

Risk Factor ◽

High Risk ◽

Neoadjuvant Therapy ◽

Independent Risk Factor ◽

Castration Resistant Prostate Cancer ◽

High Risk Prostate Cancer ◽

Castration Resistant ◽

Risk Prostate Cancer

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Resolution of the Expert Council on the New Approach to Drug Therapy for Non-Metastatic Castration-Resistant Prostate Cancer

Oncologia i radiologia Kazakhstana ◽

10.52532/2521-6414-2021-1-59-8-11 ◽

2021 ◽

Vol 59 (1) ◽

pp. 8-11

Author(s):

Dilyara Kaidarova ◽

Oxana Shatkovskaya ◽

Zaure Dushimova ◽

Bakytzhan Ongarbayev

Keyword(s):

Prostate Cancer ◽

High Risk ◽

Treatment Efficacy ◽

Doubling Time ◽

Distant Metastases ◽

Diagnostic Methods ◽

Efficacy And Safety ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Psa Doubling Time

Relevance: Prostate cancer (PC) is one of the most common malignant neoplasms in the male population. The widespread introduction of modern diagnostic methods and the determination of prostate-specific antigen (PSA) levels have increased the number of detected cases of localized and locally advanced PC forms. However, in some patients treated with radical methods and long-term androgen deprivation therapy (ADT), the disease continues to progress in the form of an increase in PSA levels with castration testosterone values and with no distant metastases. Such a course of the disease is referred to as non-metastatic castration-resistant prostate cancer (nmCRPC). Purpose: The article reports the results of a meeting of the Expert Council arranged by the Kazakh Research Institute of Oncology and Radiology on December 25, 2020, on non-metastatic castration-resistant prostate cancer diagnostics and treatment. Results: Large clinical studies highlight the critical importance of controlling the PSA doubling time as the main prognostic factor for an unfavorable outcome to increase patient survival and prevent the development of distant metastases. Based on the results of large randomized studies, experts recommended using new-generation androgen receptor antagonists in combination with ongoing ADT to improve the clinical outcomes in nmCRPC patients at high risk of metastatic progression. The Expert Council was presented with the data of a registration clinical study on darolutamide efficacy and safety. The advantages of introducing this drug into clinical practice to expand the choice of therapeutic options were identified. Personalized adjustment of a treatment regimen will increase the treatment efficacy and ensure higher survival in this category of patients. Conclusion: Increasing survival as the main objective in treating nmCRPC patients requires improved diagnostics through regular controlling of testosterone and PSA levels, calculation of PSA doubling time, and the use of radiological diagnostic methods to rule out distant metastases. The choice of therapy in patients at high risk of metastasis shall consider the patient’s status and the treatment efficacy and safety balance.

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ENZA-p: A randomized phase II trial using PSMA as a therapeutic agent and prognostic indicator in men with metastatic castration-resistant prostate cancer treated with enzalutamide (ANZUP 1901).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.tps177 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. TPS177-TPS177

Author(s):

Louise Emmett ◽

Shalini Subramaniam ◽

Alison Yan Zhang ◽

Andrew James Martin ◽

Sonia Yip ◽

...

Keyword(s):

Prostate Cancer ◽

High Risk ◽

Fdg Pet ◽

Predictive Biomarkers ◽

Receptor Expression ◽

Receptor Blockade ◽

Castration Resistant Prostate Cancer ◽

Concurrent Administration ◽

Castration Resistant ◽

Psma Pet

TPS177 Background: 177Lu‐PSMA‐617 (LuPSMA) is a novel radionuclide with promising activity and tolerability in metastatic, castration-resistant prostate cancer (mCRPC). Pre-clinical studies have shown that androgen receptor blockade with enzalutamide upregulates PSMA-receptor expression, and that PSMA-receptor blockade increases treatment response to enzalutamide. We hypothesise that concurrent administration of LuPSMA and enzalutamide will be synergistic in mCRPC. The aims of ENZA-p are to determine the activity and safety of LuPSMA and enzalutamide in men with mCRPC at high-risk of early progression on enzalutamide alone; and to identify potential prognostic and predictive biomarkers from imaging, blood, and tissue. Methods: This open-label, randomised, multicentre, phase 2 trial will recruit 160 men with mCRPC. Key eligibility criteria include progression on androgen deprivation therapy, 2 or more high-risk features for early (LDH ≥ULN; ALP ≥ULN; albumin <35 g/L; M1 disease at diagnosis; <3 years from initial diagnosis to randomisation; >5 bone metastases; visceral metastases; PSA doubling time <84 days; pain requiring opiates >14 days; prior abiraterone), no prior treatment with a novel androgen signalling inhibitor (except abiraterone), no prior chemotherapy for mCRPC, and PSMA-avid disease on positron emission tomography (PET) with 68Ga-PSMA. Participants are randomly assigned (1:1) enzalutamide 160 mg daily or enzalutamide 160 mg daily plus LuPSMA 7.5 GBq on days 15 and 57. Two subsequent doses of Lu-PSMA will be administered if the 68Ga-PSMA PET on day 92 shows persistent PSMA expression in the tumour. Imaging assessments include CT and technetium bone scan at baseline, day 99, then every 12 weeks; 68Ga-PSMA-11 PET at baseline, days 15, 92, and first progression; and 18F FDG PET at baseline and first progression. Translational samples including circulating tumour cells (CTCs), circulating tumour DNA (ctDNA) and biopsies (optional) will be collected at baseline, day 92, and first progression. The primary endpoint is PSA progression-free survival (PSA-PFS). Secondary endpoints include radiological-PFS, PSA-response rate, pain response and PFS, clinical-PFS, overall survival, health related quality of life, adverse events, and cost-effectiveness. Correlative studies include identification of prognostic and predictive biomarkers from 68Ga-PSMA, 18F FDG PET/CT, CTCs, and ctDNA. A sample size of 160 provides 80% power with a 2-sided type 1-error rate of 5% to detect a HR of 0.625 assuming a median PSA-PFS of 5 months with enzalutamide alone. Accrual was 5 on 13 October 2020. ENZA-p is an investigator-initiated, academic trial led by ANZUP in collaboration with the NHMRC Clinical Trials Centre, University of Sydney. Clinical trial information: NCT04419402.

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