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Treatment resistant mCRPC

Silvana Giacinti, Paolo Carlini, Michela Roberto, Maria Bassanelli, Lidia Strigari, Francesco Pavese, Anna M Aschelter, Alessandra Felici, Maurizio Valeriani, Francesco Cognetti, Paolo Marchetti
Abiraterone acetate (AA) demonstrated its efficacy in the treatment of patients with metastatic castration resistance prostate cancer (mCRPC) in predocetaxel and postdocetaxel setting. However, we learn from pivotal studies that forms of primary and acquired resistance to this drug exist. Patient selection becomes so crucial to optimize treatment results. Potential predictive biomarkers have been identified but are not yet validated. In this scenario, clinical features and disease characteristics may still be of value in selecting patients for different treatments...
October 19, 2016: Anti-cancer Drugs
Claire Levrier, Martin C Sadowski, Anja Rockstroh, Brian Gabrielli, Maria Kavallaris, Melanie Lehman, Rohan A Davis, Colleen C Nelson
The lack of a cure for metastatic castrate-resistant prostate cancer (mCRPC) highlights the urgent need for more efficient drugs to fight this disease. Here, we report the mechanism of action of the natural product 6α-acetoxyanopterine (6-AA) in prostate cancer cells. At low nanomolar doses, this potent cytotoxic alkaloid from the Australian endemic tree Anopterus macleayanus induced a strong accumulation of LNCaP and PC-3 (prostate cancer) cells as well as HeLa (cervical cancer) cells in mitosis, severe mitotic spindle defects and asymmetric cell divisions, ultimately leading to mitotic catastrophe accompanied by cell death through apoptosis...
October 19, 2016: Molecular Cancer Therapeutics
Shabbir M H Alibhai, Salman Aziz, Tharsika Manokumar, Narhari Timilshina, Henriette Breunis
OBJECTIVE: Since the benefits of chemotherapy in treating older men with metastatic castration-resistant prostate cancer (mCRPC) are modest, validated tools that predict the risk of treatment toxicity may aid clinical decision-making. Whether these tools are better than oncologist judgment remains unclear. We compared the Cancer and Aging Research Group (CARG) tool, the Vulnerable Elders Survey-13 (VES-13), and oncologist judgment in predicting toxicity in men with mCRPC undergoing chemotherapy...
October 15, 2016: Journal of Geriatric Oncology
Yoko Yamada, Nobuaki Matsubara, Ken-Ichi Tabata, Takefumi Satoh, Naoto Kamiya, Hiroyoshi Suzuki, Takashi Kawahara, Hiroji Uemura, Akihiro Yano, Satoru Kawakami
BACKGROUND: Both abiraterone acetate (AA) and enzalutamide are promising agents for patients with pre- and post-chemotherapy metastatic castration-resistant prostate cancer (mCRPC). Several retrospective analysis suggested clinical cross-resistance between these agents in patients previously treated with docetaxel. However, data on the antitumor activity of AA as a second androgen receptor-targeting new agent after the failure of enzalutamide in chemotherapy-naive mCRPC patients is unavailable...
October 18, 2016: BMC Research Notes
Zachery R Reichert, Maha Hussain
The development of metastatic castration-resistant prostate cancer (mCRPC) signals the terminal disease phase. The preceding hormone-dependent disease setting is effectively managed with androgen deprivation therapy. This foundation of treatment has a high rate of biochemical and clinical response and meaningful clinical benefit but is finite in duration as most cancers will progress to castration resistance. Historically, treatment for mCRPC entailed androgen receptor (AR) inhibitors (nilutamide, flutamide, bicalutamide), nonspecific steroidal biosynthesis inhibitors (ketoconazole, itraconazole), steroids (prednisone, diethylstilbesterol, dexamethasone), or palliative chemotherapy (mitoxantrone, estramustine), but none of these strategies impacted survival...
September 2016: Cancer Journal
Che-Kai Tsao, John Sfakianos, Bobby Liaw, Kiev Gimpel-Tetra, Margaret Kemeny, Linda Bulone, Mohammad Shahin, William Kyu Oh, Matthew David Galsky
LESSONS LEARNED: The safety and activity findings of abiraterone acetate plus prednisone treatment in black men with mCRPC were similar to results from previously conducted studies with largely white populations.Poor trial accrual continues to be a challenge in black men with mCRPC and further efforts are needed to address such underrepresentation. BACKGROUND: Self-identified black men have higher incidence and mortality from prostate cancer in the United States compared with white men but are dramatically underrepresented in clinical trials exploring novel therapies for metastatic castration-resistant prostate cancer (mCRPC)...
October 14, 2016: Oncologist
Jesse Aidan Dinh, Danial Baker, Manpreet Chahal
OBJECTIVE: To provide an overview of the efficacy, tolerability, drug interactions, dosing, and administration issues associated with enzalutamide, abiraterone, and radium-223 for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). DATA SOURCES: MEDLINE and Web of Science were used to search for relevant articles using a key-word search (enzalutamide, abiraterone, radium-223, and phase 3). No restriction was placed on the date of publication...
2016: Consultant Pharmacist: the Journal of the American Society of Consultant Pharmacists
Pradeep S Jadhavar, Sreekanth A Ramachandran, Eduardo Riquelme, Ashu Gupta, Kevin P Quinn, Devleena Shivakumar, Soumya Ray, Dnyaneshwar Zende, Anjan K Nayak, Sandeep K Miglani, Balaji D Sathe, Mohd Raja, Olivia Farias, Ivan Alfaro, Sebastián Belmar, Javier Guerrero, Sebastián Bernales, Sarvajit Chakravarty, David T Hung, Jeffrey N Lindquist, Roopa Rai
While enzalutamide and abiraterone are approved for treatment of metastatic castration-resistant prostate cancer (mCRPC), approximately 20-40% of patients have no response to these agents. It has been stipulated that the lack of response and the development of secondary resistance to these drugs may be due to the presence of AR splice variants. HDAC6 has a role in regulating the androgen receptor (AR) by modulating heat shock protein 90 (Hsp90) acetylation, which controls the nuclear localization and activation of the AR in androgen-dependent and independent scenarios...
October 4, 2016: Bioorganic & Medicinal Chemistry Letters
Sebastien J Hotte
Despite the significant survival benefit of taxane therapy in metastatic castration-resistant prostate cancer (mCRPC), all patients inevitably develop treatment resistance. An understanding of resistance mechanisms has led to new therapies for prostate cancer (cabazitaxel, abiraterone and enzalutamide), all of which have improved survival following first-line docetaxel. Another treatment, currently in development, targets the prosurvival molecule clusterin. Custirsen, an antisense molecule that inhibits clusterin production, has shown promise in combination with docetaxel in mCRPC patients at risk for poor outcomes...
October 7, 2016: Future Oncology
Harshad R Kulkarni, Aviral Singh, Christiane Schuchardt, Karin Niepsch, Manal Sayeg, Yevgeniy Leshch, Hans-Juergen Wester, Richard P Baum
A potential milestone in personalized nuclear medicine is theranostics of metastatic castration-resistant prostate cancer (mCRPC) based on molecular imaging using PET/CT with (68)Ga-labeled prostate-specific membrane antigen (PSMA) ligands and molecular radiotherapy using PSMA-targeted radioligand therapy (PRLT) with (177)Lu-PSMA ligands. (68)Ga-PSMA PET/CT enables accurate detection of mCRPC lesions with high diagnostic sensitivity and specificity and provides quantitative and reproducible data that can be used to select patients for PRLT and therapeutic monitoring...
October 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Per Kongsted, Inge Marie Svane, Henriette Lindberg, Lisa Sengeløv
BACKGROUND: We investigated the impact of the number of docetaxel cycles administered in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with first-line chemotherapy. PATIENTS AND METHODS: Charts from 421 consecutive patients who initiated standard treatment with docetaxel-based chemotherapy (75 mg/m(2) every 3 weeks) between 2007 and 2013 were reviewed. Patients who received < 6 cycles of docetaxel were excluded from the analysis...
September 8, 2016: Clinical Genitourinary Cancer
Wolfgang P Fendler, Svenja Reinhardt, Harun Ilhan, Andreas Delker, Guido Böning, Franz J Gildehaus, Christian Stief, Peter Bartenstein, Christian Gratzke, Sebastian Lehner, Axel Rominger
Prostate cancer can be targeted by ligands to the prostate-specific membrane antigen (PSMA). We aimed to evaluate dosimetry, safety and efficacy of 177Lu-PSMA-617 radioligand therapy (RLT) in patients with metastatic castration-resistant prostate cancer (mCRPC).Fifteen patients each received two cycles of 3.7 GBq (n = 5) or 6.0 GBq (n = 10) 177Lu-PSMA-617 at an eight to ten weeks interval. For safety monitoring, each treatment was followed by dosimetry with serial quantitative SPECT as well as inpatient and outpatient recording of adverse events...
September 24, 2016: Oncotarget
K Miller, J Gschwend, J-M Wolff
At present, abiraterone acetate and enzalutamide are the most commonly used substances in the first-line treatment of asymptomatic or mildly symptomatic metastatic castration-resistant prostate carcinoma (mCRPC). Since the relevant pivotal trials have demonstrated comparable clinical efficacy for both substances, further factors should be considered for the choice of treatment. As mCRPC patients usually receive several lines of treatment, different adaptation and resistance mechanisms leading to treatment failure could be important...
September 2016: Aktuelle Urologie
Fable Zustovich, Davide Pastorelli
Bone metastases affect the majority of patients with castration-resistant prostate cancer (CRPC), resulting in significant morbidity and mortality. This review describes the current therapies available for the management of CRPC patients with bone metastases. Areas covered: Studies on the use of currently available therapeutic approaches for palliating pain, delaying skeletal-related events (SREs) and prolonging survival in CRPC patients with bone metastases have been examined. PubMed database was searched in May 2016 starting with the following keywords: ('castration-resistant prostate cancer' OR 'CRPC') AND 'bone metastases', and approximately 270 results were retrieved...
October 6, 2016: Expert Review of Anticancer Therapy
Carlo Buonerba, Giuseppe Di Lorenzo, Guru Sonpavde
Currently, clinical factors related to the malignancy and patient-related factors such as performance status and comorbidities are employed to select agents to treat metastatic castration resistant prostate cancer (mCRPC). Areas covered: This paper covers emerging molecular panels that may be used in the clinic as prognostic or predictive biomarkers to treat mCRPC. Expert commentary: The expression of androgen receptor variant (AR-V)-7 in circulating tumor cells appears especially promising to select patients for taxane chemotherapy versus androgen inhibitors, abiraterone and enzalutamide...
October 2016: Expert Review of Molecular Diagnostics
Yohann Loriot, Karim Fizazi, Johann S de Bono, David Forer, Mohammad Hirmand, Howard I Scher
BACKGROUND: Patients with metastatic castration-resistant prostate cancer (mCRPC) and visceral metastases have a worse prognosis than those with nonvisceral metastases. Treatment with the androgen receptor inhibitor enzalutamide in the phase 3 AFFIRM trial led to significant improvements in outcomes for patients with mCRPC. For the current report, the authors analyzed the efficacy of enzalutamide among patients from the AFFIRM trial who had visceral disease. METHODS: Patients who had liver and/or lung metastases at baseline were selected for prespecified overall survival (OS) and exploratory post hoc analyses, including prostate-specific antigen (PSA) response and the time to PSA and radiographic progression...
September 20, 2016: Cancer
Giulia Baciarello, Cora N Sternberg
Prostate cancer is initially responsive to androgen deprivation therapy, but most patients eventually develop castration-resistant disease. Enzalutamide is an androgen receptor (AR) inhibitor that targets several steps in the AR signaling pathway and has shown significant efficacy in the treatment of metastatic castration-resistant prostate cancer in patients with or without prior chemotherapy. To provide optimal treatment, it is important to understand the implications of enzalutamide use in the context of other therapies, as recent findings have suggested cross-resistance occurs between and within drug classes...
October 2016: Critical Reviews in Oncology/hematology
Ke Li, Yunhua Mao, Li Lu, Cheng Hu, Dejuan Wang, Jie Si-Tu, Minhua Lu, Shubin Peng, Jianguang Qiu, Xin Gao
The role of cell division cycle 20 (CDC20) was investigated in chemoresistance to decetaxel and the underlying mechanisms in metastatic castration-resistant prostate cancer (mCRPC). MTT assays were performed to determine effects of siRNA-mediated CDC20 knockdown on cell proliferation and anticancer activity of docetaxel. Western blot analyses were conducted to detect changes of Akt and Wnt signaling. Furthermore, in vivo growth of PCa was examined in nude mice treated with siCDC20 or docetaxel alone or in combination...
October 2016: International Journal of Oncology
Andrew K Kwegyir-Afful, Robert D Bruno, Puranik Purushottamachar, Francis N Murigi, Vincent C O Njar
Metastatic castration-resistant prostate cancer (mCRPC) accounts for a high percentage of prostate cancer mortality. The proprietary compound galeterone (gal) was designed to inhibit proliferation of androgen/androgen receptor (AR)-dependent prostate cancer cell in vitro and in vivo and is currently in phase III clinical development. Additionally, clinical studies with gal revealed its superb efficacy in four different cohorts of patients with mCRPC, including those expressing splice variant AR-V7. Preclinical studies with gal show that it also exhibits strong antiproliferative activities against AR-negative prostate cancer cells and tumors through a mechanism involving phosphorylation of eIF2α, which forms an integral component of the eukaryotic mRNA translation complex...
September 12, 2016: FEBS Journal
Yujiro Ueda, Nobuaki Matsubara, Ken-Ichi Tabata, Takefumi Satoh, Naoto Kamiya, Hiroyoshi Suzuki, Takashi Kawahara, Hiroji Uemura
BACKGROUND: Prostate-specific antigen (PSA) flare is a well-known phenomenon in patients with prostate cancer treated with luteinizing hormone-releasing hormone agonist and chemotherapy. However, its incidence and the significance for the clinical outcomes of patients treated with abiraterone acetate (AA) are uncertain. PATIENTS AND METHODS: A multicenter retrospective analysis of chemotherapy-naive patients treated with AA for metastatic castration-resistant prostate cancer (mCRPC) was conducted...
August 8, 2016: Clinical Genitourinary Cancer
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