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LUGPA President, Neal Shore, MD opens up the 2017 Annual Large Urology Group Practice Association (LUGPA) meeting which focuses on the theme, “Updates for Optimizing GU Oncology Cancer Clinics of Excellence”.
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Optimal sequencing strategies for approved agents in metastatic castration-resistant prostate cancer (mCRPC) are unclear. Retrospective clinical studies suggest cross-resistance between specific therapies. This review assesses treatment decisions for mCRPC. Increased use of chemohormonal therapy in castration-sensitive disease may affect subsequent treatment decisions in mCRPC. Initial abiraterone or enzalutamide treatment may result in cross-resistance for subsequent androgen receptor-targeted therapy. Clinical responses may be seen in both docetaxel- and cabazitaxel-treated patients progressing after treatment with abiraterone or enzalutamide. These observations are supported by proposed resistance mechanisms. In conclusion, small, retrospective studies suggest cross-resistance between specific therapies in mCRPC. Larger prospective studies are required.
Although curative treatment for men with metastatic castration-resistant prostate cancer (mCRPC) has not yet been achieved, multiple therapeutic advances for CRPC patients have been realized. In 2004, a taxane-based chemotherapy, docetaxel, was established as the first therapeutic to prolong survival in patients with mCRPC1,2; in the phase 3 trial TAX 327, 3-weekly docetaxel plus prednisone improved the median overall survival (OS) by 2.4 months in patients with mCRPC compared with mitoxantrone plus prednisone.2 Since 2010, additional mCRPC treatments that prolong survival have been approved by the U.S. Food and Drug Administration (FDA): taxane chemotherapy (cabazitaxel), androgen receptor (AR)-directed therapies (abiraterone and enzalutamide), immunotherapy (sipuleucel-T), and bone-targeting radiotherapy (radium-223), completely altering the treatment paradigm.3,4,5,6 Recently, the use of docetaxel plus androgen deprivation therapy (ADT) for high-volume castration-sensitive metastatic disease has demonstrated a significant survival benefit.7,8
Optimal sequencing of therapies used to treat advanced prostate cancer remains controversial. Therapies targeting AR signaling may be recommended before chemotherapy in mCRPC because of their relative safety and tolerability profiles and ease of administration.9,10 Hence, patients often undergo chemotherapy only after progressing on AR-targeted oral therapies, and thus presumably have a more advanced disease, possibly a concomitant decreased performance status, and may therefore be less suitable for, or tolerant of, chemotherapy. Selecting the optimal treatment strategy for sequencing or combining therapies to provide maximal OS and quality-of-life benefit is a significant challenge in the management of advanced prostate cancer. For example, early use of chemotherapy might be a better option for patients with specific disease characteristics, for example, visceral metastases or low prostate-specific antigen (PSA) and extensive tumor burden, suggestive of anaplastic or possible neuroendocrine features. Nonetheless, existing clinical data describing the relative benefits of different treatment strategies are usually retrospective and originate from a single institution.
In addition to concerns about ease of administration and patient tolerability, selecting the right treatment, at the right time, will avoid exposure to a clinically nonbeneficial therapy. Hence, can we improve precision therapeutic selection? Is there evidence for cross-resistance between or among treatments? Does resistance develop first at the molecular level, then at the clinical level? Can clinical factors and biomarkers predict resistance? These questions are pertinent to all clinicians managing advanced prostate cancer, especially to urologists specializing in advanced prostate cancer care. This article reviews data evaluating response and resistance to therapeutics currently used to treat mCRPC, and assays under investigation that may identify specific patient resistance patterns that may better inform therapeutic selection.
We searched MEDLINE and PubMed for literature to include in this review. Terms combined in our searches included, “prostate cancer,” “chemotherapy,” “docetaxel,” “cabazitaxel,” “abiraterone,” “enzalutamide,” “sipuleucel-T,” “radium-223,” “resistance,” “sequencing,” and “biomarker.” Identified publications were manually filtered for articles focusing on treatment sequencing, treatment resistance, and biomarkers in metastatic prostate cancer.
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Cutting-edge trials: treatments for newly diagnosed mHSPC patients
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As posted on October 5th by www.clinical-genitourinary-cancer.com. With Dr. Neal Shore.
Introduction
Prostate cancer is the second most common malignancy in men worldwide, with an estimated 1.1 million men across the world diagnosed in 2012, and the fifth leading cause of cancer-related death in men, with 307,000 deaths reported worldwide in 2012.1 Prostate cancer is an androgen-dependent disease that initially responds to androgen-deprivation therapy (ie, chemical or surgical castration). However, most men will become resistant to androgen deprivation therapy over time, developing nonmetastatic castration-resistant prostate cancer (CRPC), in which a rise in prostate-specific antigen is often the first detectable sign.2, 3, 4 For some men, nonmetastatic CRPC will progress to metastatic CRPC, which is still uniformly incurable, although several new treatment options have been shown to significantly improve survival, including traditional taxane chemotherapy (docetaxel), new androgen receptor pathway antagonists (enzalutamide, abiraterone), novel taxanes (cabazitaxel), immunotherapy (sipuleucel-T), and targeted alpha therapy (radium-223).5, 6
A large majority of men with metastatic CRPC (90%) will develop bone metastases, which are often initially asymptomatic.6, 7 Although a small proportion of patients are de novo diagnosed with metastatic disease, most bone metastases develop in patients who have failed local treatment and progress under androgen-deprivation therapy. Bone metastases are strongly associated with increased mortality in men with metastatic CRPC, and the risk of death is even higher in men with skeletal-related events.8, 9 In addition to increased mortality, bone metastases are a major cause of disability, bone pain, impaired quality of life (QoL), and excessive treatment costs.6, 10 Pain is the most common symptom, occurring in 75% of symptomatic patients with metastatic prostate cancer,7 while spinal cord compression occurs in up to 12% of patients and may be the first sign of bone metastases.11
To better understand the symptoms associated with advanced prostate cancer (aPC) and the impact of symptoms on the lives of patients and their caregivers, an international survey was commissioned by the International Prostate Cancer Coalition. The goals of the survey were to describe the disease burden, highlight barriers that prevent men from discussing symptoms, explore the patient-caregiver dynamic, and raise awareness of the importance of discussing symptoms with healthcare providers.
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Antiandrogen’s role may extend to non-metastatic castration-resistant prostate cancer (CRPC).
As posted on October 4th by Urology Times. With Dr. Neal Shore.
by Cheryl Guttman Krader
Top-line results from the phase III PROSPER trial support a potential role for enzalutamide (XTANDI) as treatment for non-metastatic castration-resistant prostate cancer (CRPC).
The efficacy analysis showed that the study met its primary endpoint by demonstrating that the combination of enzalutamide plus androgen deprivation therapy (ADT) was associated with a statistically significant improvement in metastasis-free survival (radiographically detected metastasis). Thus, enzalutamide becomes the first androgen receptor inhibitor to show in a randomized, controlled trial improvement in metastasis-free survival in men with non-metastatic CRPC.
Read: Immune content linked to aggressive PCa outcomes
“When the full PROSPER results are available, they will hopefully confirm metastasis-free survival is significantly improved for men who received enzalutamide plus ADT compared to men receiving ADT alone. While there are currently no FDA-approved treatments for men who have non-metastatic CRPC, we may have an agent in the future that will allow us to treat these men earlier, rather than waiting for them to develop confirmed radiographic metastatic disease,” said PROSPER investigator and steering committee member Neal Shore, MD, of Carolina Urologic Research Center, Myrtle Beach, SC.
“A delay in the development of metastatic cancer is important in the journey of a prostate cancer patient. To have the option to prescribe a once-a-day therapy that can be taken with or without food, and without stringent laboratory requirements, would provide flexibility for the provider and the patient.”
A preliminary analysis of adverse event data collected in PROSPER identified no new safety signals associated with enzalutamide. According to the findings, enzalutamide’s safety profile was consistent with that reported in previous clinical trials.
“When the final analysis is done, I do not anticipate seeing any difference in the safety profile of enzalutamide compared to what has been seen in earlier trials in which it was evaluated in men with metastatic CRPC,” Dr. Shore said.
“We didn’t see any new safety signals for enzalutamide in the phase II TERRAIN trial that enrolled asymptomatic or minimally symptomatic men with disease progression on ADT, and we found that the treatment arm of enzalutamide was superior to the comparator bicalutamide [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][Casodex] arm in terms of disease progression for this metastatic castrate-resistant prostate cancer population.”
Also see: Research reveals possible predictor of PCa germline mutation
PROSPER has a randomized, double-blind, placebo-controlled design and is being conducted at study sites in the United States, Canada, Europe, South America, and the Asia Pacific region. It enrolled approximately 1,400 patients who were randomized to treatment with enzalutamide, 160 mg once daily plus ADT, or ADT plus placebo.
Eligible patients were on ongoing ADT with a gonadotropin-releasing hormone agonist/antagonist or prior bilateral orchiectomy (medical or surgical castration). They were to have PSA ≥2.0 ng/mL, PSA doubling time ≤10 months, Eastern Cooperative Oncology Group performance status of 0 or 1, and estimated life expectancy ≥12 months. Men who had received prior cytotoxic chemotherapy were excluded as were those who used hormonal therapy or biologic for prostate cancer (other than approved bone targeting agents and gonadotropin-releasing hormone agonist/antagonist therapy) or use of an investigational agent within 4 weeks of randomization.
An amendment to the PROSPER protocol in June 2017 revised the plan for the analyses of the primary and several secondary endpoints, which allowed for a reduction in the target sample size and accelerated completion of the clinical trial by 2 years.
Dr. Shore is a consultant and researcher for Amgen, Astellas, Bayer, Dendreon, Janssen, Pfizer, and Sanofi.
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