Brian E. Lewis

Current clinical challenges in prostate cancer

Prostate cancer is the most common malignancy and the second leading cause of cancer death in men in the United States. Close to

Exceptional Duration of Radium-223 in Prostate Cancer With a BRCA2 Mutation

12 billion are spent annually on the treatment of prostate cancer in the US alone. Yet still there remain tremendous controversies and challenges that exist in all facets of the disease. This review and discussion will focus on issues and challenges for clinicians and patients diagnosed with the disease. Appropriate risk stratification for men with newly diagnosed prostate cancer is an appropriate first step for all patients. Once risk-stratified, for those with low-risk of death, it is increasingly recognized that overtreatment creates an unnecessary burden for many patients. This is particularly evident when put in the context of competing comorbidities in an elderly population. For those with advanced or high-risk localized disease, under-treatment remains too common. For those with a high-risk of recurrence or failure following primary treatment, adjuvant or salvage therapies are an option, but how and when to best deploy these treatments are controversial. Recently, tremendous progress has been made for those with advanced disease, in particular those with metastatic castrate-resistant prostate cancer (mCRPC). Within the last 4 years, five novel FDA approved agents, acting through distinct mechanisms have been FDA approved for mCRPC. With the introduction of these new agents a host of new challenges have arisen. Timing, sequencing and combinations of these novel agents are welcomed challenges when compared with the lack of available therapies just a few years ago. In this summary of current clinical challenges in prostate cancer we review critical recent studies that have created or shifted the current paradigms of treatment for prostate cancer. We will also highlight ongoing issues that continue to challenge our field.

Management of Docetaxel Failures in Metastatic Castrate- Resistant Prostate Cancer

Clinical Practice PointsIt is now recognized that patients with prostate cancer have a higher rate of DNA repair gene mutations than previously appreciated.The prevalence of germline alterations in DNA repair genes may be as high as 11.8% in patients with metastatic prostate cancer.Several targeted agents for DNA repair defects (poly ADP ribose polymerase inhibitors and platinums) have shown increased sensitivity in the setting of biallelic breast cancer susceptibility gene 2 (BRCA2) loss.The mechanism of action of Radium‐223, a bone‐targeted radiopharmaceutical, raises the possibility of clinical exploitation among patients with a BRCA2 mutation.We hypothesize that the extraordinary duration of disease control with Radium‐223 described herein is owing to the presence of a unique sensitivity in patients with a BRCA2 mutation.

Radiation-based approaches for therapy and palliation of advanced prostate cancer.

The treatment of metastatic castration-resistant prostate cancer has evolved since the approval of docetaxel-based therapy. Since docetaxel approval, three new agents have gained approval for this indication: sipuleucel-T, cabazitaxel, and abiraterone. Recent Phase III trials have also demonstrated survival benefits for MDV-3100 and radium-223 though regulatory approval ispending. Practicing physicians face the challenge of determining the optimal sequencing of these new agents. This dilemma is particularly relevant to the post-docetaxel setting, in which the indication for several of these agents overlaps. This article details the efficacy and safety of these agents to provide a framework for their clinical use.

Prostate-specific Antigen Response and Eradication of Androgen Receptor Amplification with High-dose Testosterone in Prostate Cancer

Purpose of review Randomized clinical trials of palliative radiation therapy and radiopharmaceuticals are emphasized, and new concepts in targeted alpha-emitter therapy are introduced. Recent findings Radiation therapy has a proven palliative role in the treatment of patients with advanced prostate cancer. Findings from 223radium clinical trials emphasize the importance of alpha particles as a new therapeutic modality in patients with bone metastatic castrate-resistant prostate cancer. We introduce the concept of alpha-emitting particles from both a basic and clinical perspective in the realm of bone-targeted radiopharmaceuticals and discuss how these agents compare and contrast with conventional beta-emitting radioisotopes. The physics, radiobiology, and survival data with 223radium are unique compared with previously used radiopharmaceuticals. Summary Targeted alpha-emitting therapies such as 223radium have the capacity to change the way we treat patients with bone-metastatic prostate cancer.

Laboratory‐Based Biomarkers and Liver Metastases in Metastatic Castration‐Resistant Prostate Cancer

Metastatic castrate-resistant prostate cancer (CRPC) has been studied from a tissue-based molecular perspective [1] and much has been learned. Alterations in the androgen receptor (AR) are common, as are a multiplicity of other genetic changes. More recent studies indicate that plasma cell-free DNA (cfDNA) may be used to assess the molecular genetics of tumors, and potentially direct therapy [2]. Resistance to newer hormonal agents such as abiraterone and enzalutamide can be predicted by cfDNA changes, including both AR amplification and select AR mutations [3,4]. Here we describe a case involving a heavily pretreated patient for whom

Beyond Just Androgen Deprivation Therapy: Novel Therapies Combined With Radiation

BACKGROUND Metastatic castrate-resistant prostate cancer (mCRPC) patients with liver metastases have a poor prognosis. No large studies have investigated the clinical and biochemical parameters associated with liver metastases in this population. MATERIALS AND METHODS Patient data made available via Project Data Sphere were collected from 1,281 men with mCRPC who were enrolled on to three phase III clinical trials for the treatment of their disease. Multiple logistic regression was performed on eight clinical and biochemical baseline variables to test their association with the presence of liver metastases on baseline radiographic imaging. Variables of interest included prior docetaxel exposure, Eastern Cooperative Oncology Group performance status, albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase (AST), hemoglobin (HGB), lactate dehydrogenase (LDH), prostate-specific antigen, and total bilirubin. Final models were compared when treating the variables as either continuous or categorized. RESULTS Multiple variable analysis demonstrated that an increasing serum AST or LDH or a decreasing HGB was associated with an increased probability of having documented radiographic liver metastases (p < .0001). The area under the curve for the continuous model was 0.6842 and 0.6890 for the categorical one, with the latter model containing a dichotomized AST and LDH based on the upper limit of normal and tertile ranges of HGB based on the distribution of the outcome. CONCLUSION Our analysis demonstrated a significant association between the presence of liver metastases and laboratory levels of AST, LDH, and HGB. These have implications for patient management. More research is needed to validate these biomarkers and prospectively determine their application in the clinical setting. IMPLICATIONS FOR PRACTICE The purpose of this study was to evaluate biochemical and clinical biomarkers associated with the presence of liver metastases in men diagnosed with metastatic castrate-resistant prostate cancer. The results indicate that quantitative assessments of aspartate transaminase, lactate dehydrogenase, and hemoglobin are significantly associated with an increased probability of having documented radiographic liver metastases. Analysis of these simple variables can alert clinicians to those at high risk for prostate cancer that has spread to the liver, a finding of clear importance for clinical management.

Extreme Prostate‐Specific Antigen Response to Infusional 5‐Flourouracil in Castrate‐Resistant Prostate Cancer

External beam radiation therapy (EBRT) combined with androgen deprivation are standard of care for selected patients with prostate cancer. In recent years, multiple therapies have been experimentally combined with EBRT either concomitantly or adjuvantly. These therapies include chemotherapies, immunotherapies, and novel hormones. In addition to EBRT, clinical trials with radiopharmaceuticals are planned or have been performed with concomitant chemotherapy, immunotherapies, novel hormones, and inhibitors of DNA damage repair. Herein we cover the therapeutic landscape of radiation, both EBRT and radiopharmaceuticals, and various novel therapies. Today, these therapies have yet to change the standard of care, but in the future, these combinations may improve upon currently available therapies. Clinical trials with radiation and novel forms of therapy are the key to progress, and newer adaptive clinical trial designs may allow such progress to occur faster.

Sequencing of treatments in metastatic CRPC for patients who have completed all therapeutic interventions.

Prostate cancer that has progressed after androgen deprivation, abiraterone, and taxane therapy is challenging to treat successfully. Herein we report a dramatic response to continuous-infusion 5-fluorouracil (5-FU) at a dose of 200 mg/m2 in a patient with rapidly progressive, heavily pretreated, metastatic castrate-resistant prostate cancer. Baseline prostate-specific antigen values declined from 1,890 ng/mL to <1 ng/mL after 5-FU therapy. We hypothesized that prostate-specific membrane antigen overexpression may result in cancer cells uniquely susceptible to antifolate therapies.

Radium-223 and Other Radiopharmaceuticals in Prostate Cancer

339 Background: The current treatment paradigm for metastatic, castrate-resistant prostate cancer (mCRPC) has rapidly changed and six therapies [abiraterone (Abi), enzalutamide (Enza), docetaxel (Doc), cabazitaxel (Cab), radium-223 (Ra-223), and sipuleucel-T (Sip-T)] have now been proven to prolong overall survival. Though sequential therapy is the norm, few studies have reported on the variety and prevalence of these agents over the course of patients lifetime. Herein, we sought to describe the temporal frequencies of mCRPC therapies in patients who completed all of their therapies. Methods: Retrospective chart reviews were conducted on 119 patients who died from mCRPC at Tulane Cancer Center from 2008-2015 (thus completing all possible therapies). Many patients were not treated with multiple life-prolonging therapies given the timing of their death. Post-mCRPC therapies were longitudinally sequenced and a frequency table was generated for first, second, third, etc. line of therapies. Results: Median du...