scholarly journals Future therapeutic strategies for metastatic prostate cancer

2019 ◽  
Vol 9 (6-7) ◽  
pp. 117-130 ◽  
Author(s):  
Minke Smits ◽  
Winald Gerritsen ◽  
Niven Mehra
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Predictive Biomarkers ◽  
Parp Inhibition ◽  
Oncological Patient ◽  
Damage Repair ◽  
Repair Deficiency ◽  
Disease Stabilization ◽  
Combination Regimens

Abstract During the last decade several new therapies have been investigated and approved for metastatic prostate cancer that greatly impacts patients’ quality of life and outcome. Nevertheless, optimal sequencing algorithms are still lacking, as are combinatory strategies that deliver long-term disease stabilization. Precision medicine, utilizing molecular profiles from tissue biopsies, will help us deliver optimal patient care by identifying patients that may benefit from targeted- and immunotherapy, and help guide treatment decisions by use of predictive biomarkers. Here, we present an overview of predictive biomarkers in prostate cancer, including mismatch repair and DNA damage repair deficiency, and promising novel targeted- and immunotherapies regimens, such as PSMA-radioligand therapy, PARP inhibition and PD-1/PD-L1 and CTLA‑4 checkpoint therapy. We anticipate that these agents in monotherapy and in combination regimens will alter uro-oncological patient management within the next ten years.

PSMA heterogeneity and DNA repair defects in prostate cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5002-5002 ◽  
Author(s):  
Alec Paschalis ◽  
Beshara Sheehan ◽  
Ruth Riisnaes ◽  
Daniel Nava Rodrigues ◽  
Bora Gurel ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genomic Analysis ◽  
Predictive Biomarkers ◽  
Parp Inhibition ◽  
Gleason Grade ◽  
Castration Resistant Prostate Cancer ◽  
Damage Repair ◽  
Promising Target ◽  
Molecular Aberrations ◽  
Next Generation Sequencing Ngs

5002 Background: Prostate-specific membrane antigen (PSMA) is a promising target for theranostics in metastatic castration resistant prostate cancer (mCRPC). Methods: Membranous PSMA (mPSMA) expression was immunohistochemically evaluated in castration sensitive (CSPC) (n = 38) and mCRPC (n = 60) tissue biopsies, and associations with molecular aberrations (next-generation sequencing; NGS) and clinical outcome were determined. Results: mPSMA expression was significantly higher (p = 0.005) in mCRPC biopsies (median H-score [interquartile range]; 55.0 [2.8-117.5]) compared to CSPC biopsies (17.5 [0.0-60.0]). Furthermore, patients with higher mPSMA expression ( > median H-score) at diagnosis had higher Gleason Grade (p = 0.04) and shorter OS (p = 0.006). Critically, 42% (16/38) of CSPC biopsies and 27% (16/60) of mCRPC biopsies were completely negative for mPSMA expression. In addition, CSPC and mCRPC biopsies expressing mPSMA demonstrated marked intra-tumor heterogeneity in expression levels, commonly exhibiting areas without detectable PSMA (CSPC – 100%; mCRPC – 84%), while heterogeneous mPSMA expression between metastases from the same patient was also observed. Subsequent genomic analysis showed that mCRPC patients with deleterious DNA damage repair (DDR) aberrations have higher (p = 0.016) mPSMA expression (87.5 [25.0-247.5]) than those without these (20 [0.3-98.8]). Furthermore, 9 of the 11 patients (82%) responding to PARP inhibition had a mPSMA H-Score above the median. The association between mPSMA expression and DDR aberrations was validated in an independent cohort with known DDR aberrations. Tumors with DDR aberrations had significantly higher mPSMA (ATM 212.5 [136.3-300] p = 0.005; BRCA2 300 [165-300] p = < 0.001) than unselected mCRPC biopsies (55.0 [2.75-117.5]). Finally, analyses of 122 mCRPC biopsy transcriptomes confirmed a negative correlation between PSMA and BRCA2 mRNA expression (p = 1.5x10-5). Conclusions: mPSMA expression in CSPC and mCRPC exhibits marked intra- and inter-patient heterogeneity, limiting the clinical utility of PSMA-targeted theranostics. We show for the first time that DDR gene aberrations associate with high mPSMA expression and may serve as predictive biomarkers for PSMA-targeted therapies.

Efficacy of radium-223 in bone-metastatic prostate cancer patients with and without homologous repair deficiency (HRD) mutations.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. e17023-e17023 ◽  
Author(s):  
Pedro Henrique Isaacsson Velho ◽  
Fahad Qazi ◽  
Sayeedul Hasan ◽  
Michael Anthony Carducci ◽  
Mario A. Eisenberger ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Metastatic Prostate Cancer ◽  
Radium 223 ◽  
Repair Deficiency

Prevalence of overweight and prediabetes in men receiving systemic therapies for metastatic prostate cancer.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 289-289 ◽  
Author(s):  
Warner Finstad ◽  
Raimundas Galiauskas ◽  
James Cook ◽  
Kate Murphy ◽  
Derbrenn O'Connor ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Deprivation Therapy ◽  
Steroid Therapy ◽  
Metastatic Prostate Cancer ◽  
American Diabetes Association ◽  
Androgen Deprivation ◽  
Treatment Type ◽  
The Impact ◽  
Systemic Therapies

289 Background: Patients with metastatic prostate cancer receive several therapies which may be associated with a tendency to overweight and impaired glucose tolerance. These include androgen deprivation therapy and long term steroid therapy. We set out to assess the prevalence of overweight and diabetes/prediabetes in a cohort of patients attending an oncology day ward for a variety of systemic therapies. Methods: We performed a retrospective review of the medical records of men attending an oncology day ward for prostate cancer treatment. As part of their usual care, these men had regular height and weight checks and also had periodic hemoglobin A1C (HbA1C) measurements performed. The prevalence of prediabetes and diabetes in this patient population was assessed from the HbA1C results using the American Diabetes Association 2016 definitions. Information on patient steroid use (and type), and treatment type were also recorded. Results: Among 34 men with metastatic prostate cancer, the mean age was 74 (range 57-88). Therapies received included androgen deprivation therapy in all cases, with chemotherapy or novel androgen receptor pathway inhibitors such as abiraterone and enzalutamide. Only 12% had a pre-existing diagnosis of diabetes mellitus (all type 2). The majority (79%) are overweight or obese. 59% have pre-diabetes as per the American Diabetes Association 2016 Guidelines, while a further 24% meet criteria for diabetes. Only 18% have HbA1c in the normal range. 56% are on continuous long term steroid therapy, usually as part of their prostate cancer therapy. A further 23% receive intermittent steroids. Only 21% had received no steroids in the 6 months prior to first HbA1C check. 18% had castrate-sensitive disease and 82% had castrate resistant disease. Even among patients with castrate sensitive disease, 2/3 had abnormal HbA1c values. Conclusions: Overweight and prediabetes are very prevalent in men receiving systemic therapies for metastatic prostate cancer. A large percentage of men are on long-term steroid therapy which may be contributing to their risk of these conditions. Intervention is required for this group of patients to reduce the impact of therapy on cardiovascular and overall health.

scholarly journals Metronomic Treatment with Low-Dose Trofosfamide Leads to a Long-Term Remission in a Patient with Docetaxel-Refractory Advanced Metastatic Prostate Cancer

2010 ◽  
Vol 2010 ◽  
pp. 1-4 ◽  
Author(s):  
Jochen Greiner ◽  
Rainer Küfer ◽  
Sven N. Reske ◽  
Volker Martin ◽  
Hartmut Döhner ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Low Dose ◽  
Bone Lesions ◽  
Distant Failure ◽  
New Therapeutic Approaches ◽  
Positron Emission ◽  
Pet Ct ◽  
Androgen Withdrawal

The treatment of metastatic prostate cancer patients refractory to androgen withdrawal and docetaxel therapy is currently discouraging and new therapeutic approaches are vastly needed. Here, we report a long-term remission over one year in a 68-year-old patient with metastatic docetaxel-refractory prostate cancer employing low-dose trofosfamide. The patient suffered from distant failure with several bone lesions and lymph node metastases depicted by a (11) C-Choline positron emission tomography/computerized tomography (PET/CT). After initiation of trofosfamide 100 mg taken orally once a day we observed a steadily decreasing PSA value from initial 46.6 down to 2.1 . The Choline-PET/CT was repeated after 10 months of continuous therapy and demonstrated a partial remission of the bone lesions and a regression of all involved lymph nodes but one. Taken together we found an astonishing and durable activity of the alkylating agent trofosfamide given in a metronomic fashion. We rate the side effects as low and state an excellent therapeutic ratio of this drug in our patient.

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