Tag: Prostate Cancer

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 174,650 new cases of prostate cancer were diagnosed in 2019 and 31,620 men died of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second-generation, anti-androgen agents, which include, ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide), ERLEADA® (Apalutamide) and NUBEQA® (Darolutamide). Approximately 10-20% of patients with advanced prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis (mCRPC). Among those patients without metastases at CRPC diagnosis, 33% are likely to develop metastases within two years. The estimated mean survival of patients with CRPC is 9-36 months.
The skeletal system is the most common site for distant metastases among patients with prostate cancer and over 80% of patients with advanced prostate cancer develop bone metastases, which are osteoblastic (or sclerotic), characterized by deposition of new bone. Bone scan is the most common and cost effective modality for the diagnosis of bone metastases and Technetium (Tc) 99m-labeled methylene diphosphonate is the most widely used bone scanning agent. Bone scans are commonly used to both diagnose and monitor disease progression in the bone, among patients with advanced prostate cancer, with a sensitivity ranging from 60-90% but with lower specificity. Bone scan however is more sensitive and specific than plain films and CT scans, whereas MRI is superior in evaluating vertebral metastases. Bone scan provides information on osteoblastic activity and skeletal vascularity, with preferential uptake at sites of active bone formation, reflecting the metabolic reaction of bone to the disease activity, regardless of whether it is neoplastic, traumatic or inflammatory. It is for these reasons it has been well known that bone scans can be misleading in determining whether a patient with bone metastases is benefiting from a treatment, particularly endocrine therapy. The Prostate Cancer Working Group (PCWG) recommended that the assessment of disease progression in bone in the absence of other signs of progression, requires that new lesions detected on the first post-treatment scan be confirmed with the documentation of additional new lesions on the next follow-up scan, in the absence of other signs of disease progression. This is because the new lesions detected on the first post-treatment scan may either reflect true progression or can be the result of bone healing known as pseudoprogression (also known as bone scan flare) that can be misinterpreted as treatment failure, and lead to the premature discontinuation of an effective therapy. Even though the occurrence of pseudoprogression is well documented, its association with clinical outcomes in large prospective studies has not been evaluated.
The authors therefore conducted a post hoc retrospective analysis of the PREVAIL (A Safety and Efficacy Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer) and AFFIRM (Safety and Efficacy Study of MDV3100 in Patients With Castration-Resistant Prostate Cancer Who Have Been Previously Treated With Docetaxel-based Chemotherapy) studies to determine the association between new unconfirmed lesions detected on a follow up bone scan, and clinical outcomes in XTANDI® (Enzalutamide)-treated men with mCRPC. The PREVAIL and AFFIRM trials were both designed in accordance with the PCWG guidelines. This analysis included 643 patients from the PREVAIL study who had not received Docetaxel and 404 men from the AFFIRM study who had previously received Docetaxel. Eligible patients had stable disease or response to therapy based on non-bone disease criteria, including assessment of PSA and soft-tissue disease response. Pseudoprogression was defined as detection of one or more lesions on a first post-treatment bone scan (at week 9 in PREVAIL or 13 in AFFIRM) or a second bone scan (at week 17 in PREVAIL or 25 in AFFIRM), without subsequent new lesions detected at later assessments. The authors evaluated the association of the new lesions detected on the first and second bone scans, with radiographic Progression Free Survival (rPFS), Overall Survival (OS), PSA decline, Objective Response in soft tissue, and Quality of Life.
In the PREVAIL study, new unconfirmed bone lesions were detected on bone scans in 27.5% of Docetaxel-naive patients. The rPFS, OS and time to PSA progression among these patients was similar to those without new lesions, suggesting pseudoprogression. In the AFFIRM study, new, unconfirmed lesions were detected in 18.1% of Docetaxel-treated patients and the rPFS, and time to PSA progression among these patients was similar to those without new lesions on bone scans. However, the OS was significantly worse among these patients, compared with those without new lesions on bone scan, suggesting true disease progression. Most lesions were detected on the first follow up bone scan and investigators were unable to identify any pretreatment factor associated with the development of new, unconfirmed lesions in patients responding to XTANDI®, in either clinical setting.
It was concluded that new unconfirmed lesions detected on follow up bone scans within the first 4 months of treatment initiation may represent pseudoprogression in men with mCRPC and are indicative of a favorable treatment response to XTANDI®. However, new unconfirmed bone lesions in men with mCRPC who were previously treated with Docetaxel may reflect disease heterogeneity and true progression with associated worse Overall Survival. Treatment discontinuation can be considered in this patient group, taking into consideration other disease manifestations such as changes in PSA level, finding on soft tissue imaging, symptoms, and patient preferences. These findings reinforce the importance of functional imaging for diagnosing bone metastases. Association Between New Unconfirmed Bone Lesions and Outcomes in Men With Metastatic Castration-Resistant Prostate Cancer Treated With Enzalutamide: Secondary Analysis of the PREVAIL and AFFIRM Randomized Clinical Trials. Armstrong AJ, Al-Adhami M, Lin P, et al. JAMA Oncol. 2019 Dec 12. doi: 10.1001/jamaoncol.2019.4636. [Epub ahead of print]

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 174,650 new cases of Prostate cancer will be diagnosed in 2019 and 31,620 men will die of the disease. The etiology of Prostate cancer remains unclear, and North American Blacks are at the highest risk whereas risk is lowest in Asians, with the risk among Caucasians somewhere in between.

The Insulin-like Growth Factor (IGF) system has been reported to regulate normal and malignant cell growth, proliferation and differentiation, tissue homeostasis and cellular metabolism, and its relevance in carcinogenesis has been well established. The role of IGF system in Prostate cancer was initially recognized from epidemiological studies which showed that higher serum IGF-1 concentrations correlated with an increased risk of Prostate cancer. Testosterone in the circulation is bound primarily to Sex Hormone Binding Globulin (SHBG) while the unbound, or free testosterone, is the most bioavailable and active form.

The authors in this large prospective study investigated the association of circulating levels of IGF-I, free (biologically active testosterone) and total testosterone, and Sex Hormone Binding Globulin (SHBG) with Prostate cancer incidence and mortality, in a large cohort of patients. This study included 200,452 male participants who were free of cancer when they were enrolled in the study, and were not taking any hormone therapy. Baseline blood samples were obtained from these men and tested for levels of total testosterone and IGF-1. Free testosterone level was calculated from measured total testosterone and binding protein concentrations.

After a mean follow up of 6.9 years, 5412 men were diagnosed with Prostate cancer and 296 had died from the disease. It was noted that higher levels of circulating IGF-I was associated with an elevated risk of Prostate cancer diagnosis, as well as Prostate cancer mortality. Higher free testosterone level was associated with an elevated risk of incident Prostate cancer, whereas higher SHBG was associated with a lower risk, but neither was associated with Prostate cancer mortality. Total testosterone levels were not associated with Prostate cancer incidence or mortality. For every 5 nanomoles increase in the concentration of IGF-1 per liter of blood (5 nmol/L), men were 9% more likely to develop Prostate cancer. For every 50 picomoles increase of free testosterone per liter of blood (50 pmol/L), there was a 10% increase in Prostate cancer risk. The researchers added that their findings correspond to a 25% greater risk of Prostate cancer in men who have the highest levels of IGF-1, compared to those with the lowest, and men with the highest free testosterone levels have a 18% greater risk of Prostate cancer, compared to those with the lowest levels.

It was concluded from this study that circulating levels of IGF-I and free testosterone play a role in the development of Prostate cancer and these two hormones could be one of the several mechanisms that links diet, lifestyle, and body size with the risk of Prostate cancer, taking us one step closer to Prostate cancer prevention. Serum hormones and prostate cancer incidence and mortality in UK Biobank. Travis R, Watts E, Fensom G, et al. Presented at the 2019 NCRI Cancer Conference. Abstract#2904

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 174,650 new cases of Prostate cancer will be diagnosed in 2019 and 31,620 men will die of the disease. The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide). The first-generation Androgen Receptor (AR) inhibitors act by binding to the Androgen Receptor (AR) and prevent the activation of the AR and subsequent up-regulation of androgen responsive genes. They may also accelerate the degradation of the AR. These agents have a range of pharmacologic activity from being pure anti-androgens to androgen agonists. The second-generation, anti-androgen agents include, ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide) and ERLEADA® (Apalutamide). ZYTIGA® inhibits CYP17A1 enzyme and depletes adrenal and intratumoral androgens, thereby impairing AR signaling. XTANDI® and ERLEADA® compete with Testosterone and Dihydrotestosterone and avidly binds to the Androgen Receptor, thereby inhibiting AR signaling, and in addition inhibits translocation of the AR into the nucleus and thus inhibits the transcriptional activities of the AR.

Androgen Deprivation Therapy (ADT) is often recommended alone or as a part of multimodality therapy, as ADT reduces the likelihood of cancer progression and/or mortality, in high-risk localized, locally advanced, recurrent, or metastatic Prostate cancer. ADT however can be associated with side effects such as fatigue, loss of muscle mass, impotence, anemia, osteoporosis, depression, etc., which in turn can have a significant negative impact on an individual’s quality of life. ADT has also been associated with cognitive dysfunction and there has been conflicting evidence establishing an association between ADT use and diagnosis of Alzheimer disease or Dementia. It has been postulated that lower testosterone levels impair neuron growth and axonal regeneration, in addition to accumulation of abnormally folded β-amyloid protein. With the earlier introduction of ADT in the course of disease progression for patients with Prostate cancer, it is important to discuss the association between ADT and Dementia with patients, which in turn can improve shared decision making around the risks and benefits of ADT in Prostate cancer.

The present study was conducted to analyze the association between ADT exposure and diagnosis of Alzheimer disease or Dementia, among elderly men with Prostate cancer. The authors in this retrospective cohort study used data from the NCI’s Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, and the participants included 154,089 elderly men with newly diagnosed Prostate cancer, between 1996 and 2003. The analyses were conducted in 2018 and patients receiving ADT within 2 years of Prostate cancer diagnosis were identified. In this study, 62,330 men received ADT within 2 years of Prostate cancer diagnosis, and 91,759 men did not receive ADT. Mean follow up was 8.3 years, and survival analysis was used to determine association between ADT exposure and diagnosis of Alzheimer disease or Dementia.

The researchers noted that exposure to ADT, compared with no ADT exposure, was associated with a diagnosis of Alzheimer disease (13.1% vs 9.4%; HR=1.14; P<0.001) and Dementia (21.6% vs 15.8%; HR=1.20; P<0.001). There was a dose-response relationship and patients who received more than 8 doses of ADT were at a significantly higher hazard of diagnosis of both Alzheimer disease and Dementia, than those receiving fewer doses ADT.

The authors concluded that over a follow-up period of at least 10 years, ADT exposure among elderly patients with Prostate cancer was associated with subsequent diagnosis of Alzheimer disease or Dementia. They added that clinicians should carefully weigh the long-term risks and benefits of ADT, in patients with a prolonged life expectancy, and stratify patients based on Dementia risk, prior to ADT initiation. Association Between Androgen Deprivation Therapy Use and Diagnosis of Dementia in Men With Prostate Cancer. Jayadevappa R, Chhatre S, Malkowicz SB, et al. JAMA Netw Open. 2019;2(7):e196562. doi:10.1001/jamanetworkopen.2019.6562

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 174,650 new cases of Prostate cancer will be diagnosed in 2019 and 31,620 men will die of the disease. The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide). The median duration of response is approximately 1 year and majority of these patients progress to Castration Resistant Prostate Cancer (CRPC). The mechanism of resistance to Androgen Deprivation Therapy (ADT) include reactivation of Androgen Receptor signaling through persistent adrenal androgen production, modification of the biologic characteristics of Androgen Receptors, intratumoral testosterone production and parallel steroidogenic pathways. Progression to Castration Resistant Prostate Cancer (CRPC) often manifests itself with a rising PSA (Prostate Specific Antigen), and watchful waiting is recommended in men with non-metastatic CRPC. However, those with a rapidly rising PSA on ADT (doubling time of less than 8-10 months), are at significantly greater risk of developing metastases and death.

The Androgen-Receptor inhibitors ERLEADA® (Apalutamide) and XTANDI® (Enzalutamide) have recently been approved for the treatment of nonmetastatic CRPC. However, patients who may already be experiencing adverse effects from their ongoing ADT may experience additional toxicities from these agents. There is therefore an unmet need for therapies with improved safety and toxicity profiles.

Darolutamide is a nonsteroidal AR antagonist with a unique molecular structure that is distinct from other AR antagonists and exhibits tighter binding affinity to the AR than ERLEADA® and XTANDI®, resulting in strong androgen inhibitory activity. Darolutamide and its major metabolite are full antagonists and retain their activity against known AR mutations shown to enable resistance to first- and second-generation ADTs. Additionally, Darolutamide has low penetration of the blood-brain barrier and low binding affinity for Gamma AminoButyric Acid type A receptors, which in turn reduces the risk of CNS-related Adverse Events such as seizures, and results in less severe toxic effects than ERLEADA® and XTANDI®, in patients with CRPC. Darolutamide and its active metabolite have been shown to inhibit testosterone-induced translocation of AR to the nucleus, thus decreasing activation of genes required for the growth and survival of prostate tumor cells.

Based on the significant antitumor activity of Darolutamide in Phase I and II studies, as well as favorable side effect profile, the authors conducted a multinational, randomized, double-blind, placebo-controlled, Phase III trial (ARAMIS- Androgen Receptor Antagonizing Agent for Metastasis-free Survival), involving 1509 patients with nonmetastatic, Castration-Resistant Prostate Cancer (CRPC) and a Prostate Specific Antigen doubling time of 10 months or less and a baseline PSA level of at least 2 ng/ml. Patients were randomly assigned in a 2:1 ratio to receive Darolutamide 600 mg orally twice daily or placebo. Patients continued to receive ADT (Luteinizing Hormone Releasing Hormone agonist or antagonist) throughout the trial. The median patient age was 74 years, median time from initial diagnosis was 85 months and approximately 30% of patients were on a bone-sparing agent. The Primary end point was Metastasis-Free Survival, with the presence of metastasis determined by Independent Central Review of radiographic imaging, every 16 weeks. Secondary end points included Overall Survival, Time to pain progression, Time to first symptomatic skeletal event and Time to first cytotoxic chemotherapy. The median follow up was 17.9 months.

The median Metastasis-Free Survival was 40.4 months with Darolutamide, as compared with 18.4 months with placebo (Hazard Ratio for metastasis or death in the Darolutamide group=0.41; P<0.001). This treatment benefit with Darolutamide was consistently favorable across all prespecified subgroups, including in patients with PSA doubling times of 6 months or less or more than 6 months. Darolutamide was also associated with improved Overall Survival, with a lower risk of death (HR=0.71; P=0.045) and longer time to pain progression (40.3 months versus 25.4 months, HR=0.65; P<0.001), compared to the placebo group. The median time to PSA progression was 33.2 months with Darolutamide and 7.3 months with placebo (Hazard ratio for PSA progression or death=0.13; P<0.001). The time to first cytotoxic chemotherapy and time to first symptomatic skeletal event also favored Darolutamide. Adverse Events overall were reported by 83.2% of the patients who received Darolutamide and 76.9% of the patients who received placebo, and patient-reported quality of life was similar in the Darolutamide and placebo group.

It was concluded that among patients with nonmetastatic CRPC, Metastasis-Free Survival was significantly longer with Darolutamide compared with placebo, with similar incidence of Adverse Events and Quality of Life outcomes. Darolutamide in Nonmetastatic Castration-Resistant Prostate Cancer. Fizazi K, Shore N, Tammela TL, et al., for the ARAMIS Investigators. N Engl J Med 2019;380:1235-1246

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 174,650 new cases of Prostate cancer will be diagnosed in 2019 and 31,620 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention.

The intergroup trial developed by the NCIC Clinical Trials Group, in collaboration with the Medical Research Council and the National Cancer Institute US Cancer Therapy Evaluation Program, concluded that the addition of radiotherapy to Androgen Suppression significantly prolongs Overall and Disease Specific Survival, in patients with locally advanced prostate cancer. The optimal duration of Androgen Suppression along with radiotherapy, in the curative management of locally advanced prostate cancer however remains unclear. Neoadjuvant Androgen Suppression schedules have ranged in duration from 3-8 months and for those patients with high risk disease, post radiotherapy adjuvant androgen suppression therapy schedules have ranged from 6-36 months. The study published by Bolla, et al. (NEJM 2009;360:2516-2527) concluded that a combination of radiotherapy along with 6 months of Androgen Suppression provided inferior survival compared with radiotherapy plus 3 years of Androgen Suppression, in patients with locally advanced prostate cancer. This long duration of Androgen Suppression however can be associated with significant adverse events. The PCS IV trial (Nabid, et al. European Urology 2018;74: 432-441) compared 36 months of Androgen Suppression and radiotherapy with 18 months of Androgen Suppression and radiation therapy and concluded that there was no difference in survival between the two treatment groups, with the 18-month group experiencing a better quality of life. Zoledronic acid is effective in preventing Androgen Suppression-induced bone loss, but its role in preventing castration-sensitive bone metastases in locally advanced prostate cancer has been unclear. Randomized Androgen Deprivation And Radiotherapy trial (RADAR) was conducted to determine whether an intermediate duration of Androgen Suppression would be superior to short-term Androgen Suppression, without compromising quality of life. This study was also designed to evaluate whether bisphosphonate therapy would help reduce some of the adverse effects associated with Androgen Suppression and prevent bone disease progression. RADAR trial is randomized, Phase III, 2 × 2 factorial study, which was designed to assess whether the addition of 12 months of adjuvant Androgen Suppression, 18 months of zoledronic acid, or both, can improve outcomes in men with locally advanced prostate cancer, who receive 6 months of Androgen Suppression and radiotherapy to the prostate gland.

This trial enrolled 1071 men 18 years or older with locally advanced prostate cancer, defined as either T2b-4, N0 M0 tumors or T2a, N0 M0 tumors with a Gleason score was 7 or more, and baseline PSA of 10 μg/L or more. Patients were randomly assigned in a 1:1:1;1 ratio to four treatment groups, but all patients following randomization received 6 months of neoadjuvant Androgen Suppression with Leuprolide 22.5 mg IM every 3 months, and radiotherapy to the prostate and seminal vesicles five months after randomization. The four treatment groups were 1) STAS or Short-Term Androgen Suppression which was the control group (N=268), in which patients received 6 months of neoadjuvant Androgen Suppression with Leuprolide 22.5 mg IM every 3 months, and radiotherapy to the prostate and seminal vesicles 2) ITAS or Intermediate-Term Androgen Suppression (N=268), in which STAS was followed by an additional 12 months of adjuvant Androgen Suppression (total of 18 months) with Leuprolide 22.5 mg IM every 3 months 3) STAS plus 18 months of Zoledronic acid 4 mg IV every 3 months, starting at randomization (N=268) 4) ITAS plus Zoledronic acid (N=267). The Primary endpoint was prostate cancer-specific mortality. Secondary endpoints included PSA progression, local progression and distant progression. The median follow up was 10.4 years. Because no interactions were observed between Androgen Suppression and Zoledronic acid at this 10 year follow up, treatment groups were collapsed and 6 months of Androgen Suppression (STAS) plus radiotherapy was compared with 18 months of Androgen suppression (ITAS) plus radiotherapy and groups receiving or not receiving treatment with Zoledronic acid, were compared.

It was noted that the use of additional 12 months of adjuvant Androgen Suppression (total of 18 months) resulted in a significant improvement in prostate cancer specific mortality compared to 6 months of Androgen Suppression and radiotherapy (9.7% versus 13.3% respectively), representing an absolute difference of 3.7% (sub-HR=0.70, adjusted P=0.035). The addition of Zoledronic acid did not have an impact on prostate cancer-specific mortality.

The authors concluded that 18 months of Androgen Suppression plus radiotherapy is a more effective treatment option for locally advanced intermediate and high risk prostate cancer patients, than 6 months of Androgen Suppression plus radiotherapy. It was also concluded that the addition of Zoledronic acid to this treatment regimen does not improve outcomes. Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): 10-year results from a randomised, phase 3, factorial trial. Denham JW, Joseph D, Lamb DS, et al. Lancet Oncol 2019;20:267-281