Tag: Prostate Cancer

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 180,890 new cases of prostate cancer will be diagnosed in 2016 and over 26,000 men will die of the disease. The major source of PSA (Prostate Specific Antigen) is the prostate gland and the PSA levels are therefore undetectable within 6 weeks after Radical Prostatectomy. Similarly, following Radiation Therapy, there is a gradual decline in PSA before reaching a post treatment nadir. A detectable PSA level after Radical Prostatectomy, or a rising PSA level following Radiation Therapy, is considered PSA failure or biochemical recurrence. The American Urological Association suggested that a PSA of 0.2 ng/mL or higher after Radical Prostatectomy, defines PSA failure or relapse. A PSA rise 2 ng/ml or more above post Radiation Therapy nadir is considered PSA failure or relapse. Approximately 35% of the patients with prostate cancer will experience PSA only relapse within 10 years of their primary treatment and a third of these patients will develop documented metastatic disease within 8 years following PSA only relapse. Rising PSA is therefore a sign of recurrent 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 for Hormone Sensitive Prostate Cancer. The appropriate time (immediate versus delayed) to start Androgen Deprivation Therapy in patients with prostate cancer with rising PSA, as the only sign of relapse, has remained unclear. This has been partly due to lack of patient accruals and patient reluctance to be randomized, in these clinical trials.

The authors conducted a randomized, prospective, phase III trial, to determine if immediate intervention with Androgen Deprivation Therapy (ADT) would improve Overall Survival (OS), compared with delayed ADT, in prostate cancer patients with PSA relapse, following previous attempted curative therapy (radiotherapy or surgery with or without postoperative radiotherapy) or in those considered not suitable for curative treatment (because of age, comorbidity or locally advanced disease). This analysis combined prostate cancer patients with PSA relapse enrolled in two separate studies. Two hundred and ninety three (N=293) eligible patients were randomly assigned 1:1 to immediate Androgen Deprivation Therapy (N= 142) or delayed ADT (N=151). The primary endpoint was Overall Survival. Secondary endpoints included Cancer-Specific Survival and Time to Clinical Progression. The median follow up was 5 years.

There was a statistically significant improvement in the Overall Survival, with a 45% reduction in the risk for death, for those receiving immediate ADT compared with the delayed treatment group (HR=0.55; P=0.05). Further, with immediate ADT, there was a statistically significant delay in the time to first local progression (HR= 0.51; P=0.001).

The authors concluded that immediate Androgen Deprivation Therapy significantly improved Overall Survival and Time to Clinical Progression for prostate cancer patients with PSA relapse, following immediate intervention with Androgen Deprivation Therapy. This benefit however must be weighed against the risks associated with long term Androgen Deprivation Therapy. Immediate ADT may be appropriate for patients with high risk features at the time of initial diagnosis, who present with early biochemical relapse after initial treatment and have a rapid PSA doubling time (less than 6 months). Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial. Duchesne GM, Woo HH, Bassett JK, et al. Lancet Oncol 2016;17:727-737

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 180,890 new cases of prostate cancer will be diagnosed in 2016 and over 26,000 men will die of the disease. The widespread use of PSA testing in the recent years has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer. The management of clinically localized prostate cancer that is detected based on Prostate Specific Antigen (PSA) levels remains controversial and management strategies for these patients have included Surgery, Radiotherapy or Active Monitoring. However, it has been proposed that given the indolent nature of prostate cancer in general, majority of the patients do not benefit from treatment intervention and many patients die of competing causes. Further, treatment intervention can result in adverse effects on sexual, urinary, or bowel function. The U.S. Preventive Services Task Force (USPSTF) has recommended that population screening for prostate cancer should not be adopted as a public health policy, because the risks appeared to outweigh benefits, from detecting and treating PSA-detected prostate cancer. Previously published trials evaluated the effectiveness of treatment, but they did not compare Surgery, Radiotherapy and Active Monitoring.

Prostate Testing for Cancer and Treatment (ProtecT) study is a prospective, randomized trial, which compared Active Monitoring, Radical Prostatectomy, and External Beam Radiotherapy, for the treatment of PSA-detected clinically localized prostate cancer. A total of 1,643 patients were randomly assigned to Radical Prostatectomy (N=553), Radiotherapy (N=545) or Active Monitoring (N=545). Patients in the Active Monitoring group were evaluated every 3 months for the first year, then every 6-12 months thereafter and radical treatment with curative intent was offered, based on changes in PSA levels. This is different from “watchful waiting”, which has no planned curative radical treatment on disease progression. The median age in this study was 62 yrs, the median PSA level was 4.6 ng/ml, 77% had tumors with a Gleason score of 6 and 76% had Stage T1c disease. The primary end point was prostate cancer mortality at a median of 10 years of follow-up, with prostate cancer-related deaths defined as deaths that were definitely or probably due to prostate cancer or its treatment. Secondary end points included all-cause mortality and the rates of metastases, clinical progression, primary treatment failure, and treatment complications.

At a median follow up of 10 years, prostate cancer-specific mortality was low at approximately 1% irrespective of treatment and all-cause mortality was also low at approximately 10%. However, higher rates of disease progression were seen in the Active Monitoring group (22.9 events per 1000 person-years) compared to the Surgery group (8.9 events per 1000 person-years) or the Radiotherapy group (9.0 events per 1000 person-years). This meant that patients assigned to Active Monitoring were significantly more likely to have metastatic disease than those assigned to treatment (P<0.001 for the overall comparison).

The authors in a companion article (N Engl J Med. DOI: 10.1056/NEJMoa1606221) focused on the patient-reported outcomes after Monitoring, Surgery and Radiotherapy over 6 years of follow up. Prostatectomy had the greatest negative effect on urinary continence and sexual function, whereas Radiotherapy plus neoadjuvant androgen-deprivation therapy had more of a negative effect on bowel function, urinary voiding and nocturia, although patients recovered some function over time. Approximately 44% of the patient’s who were assigned to Active Monitoring, did not receive radical curative treatment and were able to avoid these toxicities.

It was concluded that at a median follow up of 10 yrs, prostate cancer-specific mortality was low, irrespective of the treatment given, with similar efficacy outcomes but with a variable impact on quality of life. However, it should be noted that patients assigned to Active Monitoring were significantly more likely to have metastatic disease than those assigned to treatment. This in turn would warrant salvage treatment, which could result in toxicities as well. Further follow up, evaluating long term survival and the accompanying risk/benefits, will allow patients to make informed decisions, with regards to the treatment options, for clinically localized prostate cancer. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. Hamdy FC, Donovan JL, Lane JA, et al. for the ProtecT Study Group. September 14, 2016DOI: 10.1056/NEJMoa1606220

SUMMARY: The FDA on May 27, 2016 approved AXUMIN® (Fluciclovine F18), a novel molecular radiopharmaceutical diagnostic agent, for Positron Emission Tomography (PET) imaging in men with suspected prostate cancer recurrence, based on elevated Prostate Specific Antigen (PSA) levels, following prior treatment. Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 180,890 new cases of prostate cancer will be diagnosed in 2016 and over 26,000 men will die of the disease.

The major source of PSA (Prostate Specific Antigen) is the prostate gland and the PSA levels are therefore undetectable within 6 weeks after Radical Prostatectomy. Similarly, following Radiation Therapy, there is a gradual decline in PSA before reaching a post treatment nadir. A detectable PSA level after Radical Prostatectomy, or a rising PSA level following Radiation Therapy, is considered PSA failure or biochemical recurrence. Approximately 35% of the patients with prostate cancer will experience PSA only relapse within 10 years of their primary treatment and a third of these patients will develop documented metastatic disease within 8 years following PSA only relapse.

Rising PSA is therefore a sign of recurrent disease and identifying the site of recurrence can be of immense value for the clinician and can help determine the best course of therapy. The diagnostic accuracy of standard imaging tests, for the identification of sites of recurrence in patients with biochemical recurrence, is low. Almost 90% of the standard imaging tests such as CT/MRI and Bone Scan may be negative. More accurate non-invasive imaging techniques for the detection of recurrent tumor is an unmet need. Prostascint, a Single Photon Emission Computerized Tomography (SPECT) radiopharmaceutical agent, was approved in 1999 for the diagnostic imaging of post-prostatectomy patients with a rising PSA. PET scans have largely superseded this study. FluDeoxyGlucose F18 (FDG), a glucose analogue is the most widely used PET radiotracer, but is not generally used as an imaging agent in prostate cancer. This is because good and reliable quality images are not feasible due to indolent growth of prostate cancers and the high urinary excretion of FDG. The other PET radiotracer that is available, Choline C11, has been shown to improve cancer detection in men with biochemical recurrent prostate cancer, but this agent has a short half life of 20 minutes, requires greater patient preparation including 6 hours of fasting prior to administration of Choline C11, delivers higher radiation dose to patients and image quality is poor.

AXUMIN® (Fluciclovine), a diagnostic radiopharmaceutical, is a synthetic amino acid that is preferentially transported into prostate cancer cells by amino acid transporters such as LAT-1 and ASCT2, which are upregulated in prostate cancer cells. This agent is neither metabolized nor incorporated into newly synthesized proteins. The visualization of the increased amino acid transport is facilitated by labeling AXUMIN® with F18 for PET imaging. The FDA approval of AXUMIN® was based on two retrospective trials (Trial 1 and Trial 2) which evaluated the safety and efficacy of AXUMIN® for imaging prostate cancer, in patients with recurrent disease. Trial 1 compared 105 (N=105) AXUMIN® scans in men with suspected prostate cancer, to the histopathology (study of tissue changes caused by disease) obtained by prostate biopsy and by biopsies of suspicious imaged lesions. PET/CT imaging generally included both abdomen and pelvic regions. Local radiologist read the scans initially and subsequently, three independent radiologists read the same scans in a blinded study. Trial 2 evaluated the concordance between 96 (N=96) AXUMIN® and Choline C11 scans, in patients with median PSA values of 1.44 ng/mL. Local radiologist read the Choline C11 scans, and the same three independent radiologists from Trial 1 read the scans, in this second blinded study.

The FDA reported that results of the independent scan readings were generally consistent and confirmed the local scan reading results, and both studies supported the safety and efficacy of AXUMIN® for imaging prostate cancer in men with elevated PSA levels, following prior treatment. It should be noted that a negative study does not rule out the presence of recurrent prostate cancer and a positive image does not confirm the presence of recurrent prostate cancer. Clinical correlation, which may include histopathological evaluation of the suspected recurrence site, is recommended. The most commonly reported adverse events in patients were injection site pain, redness and a metallic taste in the mouth.

It was concluded that AXUMIN® can determine the location of the recurrent prostate cancer in patients with low PSA levels. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208054Orig1s000TOC.cfm

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 180,890 new cases of prostate cancer will be diagnosed in 2016 and over 26,000 men will die of the disease. The development and progression of prostate cancer is driven by androgens (primarily testosterone) and androgen signaling pathways. Androgen Deprivation Therapy (ADT) has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention for hormone sensitive prostate cancer. This is accomplished by either surgical castration (bilateral orchiectomy) or medical castration using LHRH (GnRH- Gonadotropin-Releasing Hormone) agonists, given along with 2 weeks of first generation anti-androgen agents such as CASODEX® (Bicalutamide), with the anti-androgen agents given to prevent testosterone flare. There is evidence to suggest that prostate cancer cells continue to depend on androgen receptor (AR) signaling even in an androgen-deprived environment. Therefore, targeting AR and AR signaling pathways remains a rational approach in the treatment of Castration Resistant Prostate Cancer (CRPC).

The first generation anti-androgen agents such as EULEXIN® (Flutamide), CASODEX® (Bicalutamide) and NILANDRON® (Nilutamide) 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. CASODEX® is a nonsteroidal oral anti-androgen, that is often prescribed along with LHRH (GnRH- Gonadotropin-Releasing Hormone) agonists for metastatic disease or as a single agent second line hormonal therapy for those who had progressed on LHRH agonists. XTANDI® (Enzalutamide) is a second-generation anti-androgen with no reported agonistic effects. It competitively inhibits androgens and AR binding to androgens as well as AR nuclear translocation and interaction with DNA. It thus inhibits several steps in the AR signaling pathway.

TERRAIN is a double-blind, randomized phase II trial, in which 375 asymptomatic or minimally symptomatic prostate cancer patients, who had progressed following treatment with an LHRH agonists or following surgical castration, were enrolled. The objective of the TERRAIN study was to compare the efficacy and safety of XTANDI® with CASODEX®, in patients with metastatic Castration Resistant Prostate Cancer. Patients were randomly assigned in a 1:1 ratio to receive XTANDI® 160 mg daily (N=184) or CASODEX® 50 mg daily (N=191), both taken orally, in addition to Androgen Deprivation Therapy, until disease progression. Bone targeted agents, ie. Bisphosphonates and RANKL inhibitors were allowed. The primary endpoint was Progression Free Survival and secondary endpoints included PSA response and time to PSA progression. Median time on treatment for the XTANDI® group was 11.7 months and 5.8 months for the CASODEX® group.

It was noted that patients in the XTANDI® group had a significantly improved median Progression Free Survival (15.7 months) compared with 5.8 months in the CASODEX® group (HR=0.44; P<0.0001). Adverse events in the two treatment groups were different as anticipated. The most common adverse events with XTANDI® were fatigue, back pain and hot flashes whereas CASODEX® was more often associated nausea, constipation and arthralgia. Serious adverse events were experienced by 31% of the patients in the XTANDI® group and 23% of the patients in the CASODEX® group.

The authors concluded that XTANDI® increased Progression Free Survival (PFS) by nearly 10 months compared with CASODEX®, in patients with metastatic Castration Resistant Prostate Cancer (CRPC). In the PREVAIL study, XTANDI® significantly improved Overall Survival and radiographic PFS, in patients with chemotherapy-naive mCRPC and demonstrated that it can significantly delay the need for chemotherapeutic intervention. With this abundant data in favor of XTANDI®, CASODEX® may not have a significant role to play in patients with mCRPC. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Shore ND, Chowdhury S, Villers A, et al. The Lancet Oncology 2016; 17:153-163

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 220,800 new cases of prostate cancer will be diagnosed in 2015 and over 27,000 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 for hormone sensitive prostate cancer. Prostate cancer in general is a disease of the elderly and is a leading cause of cancer mortality in men, second only to lung cancer. Elderly patients however are often under-represented in clinical trials. This is in spite of data published in previous studies showing that an average 75 yr old male in the United States has an additional life expectancy of 11 years. Further in clinical practice, elderly patients are less likely to receive either Surgery or Radiation Therapy (RT) and this is also true in men with high risk prostate cancer. This mind set has been further reinforced by recent recommendations against PSA screening and role of close surveillance for patients with low risk prostate cancer.

It is generally perceived that clinically localized prostate cancer is an indolent tumor. Patients with clinically localized prostate cancer can present with either locally advanced prostate cancer or prostate cancer detected by PSA screening. Patients with locally advanced disease have clinical stage T3 disease with tumor extending beyond the confines of the prostate gland. The 10 yr mortality in this patient group is as high as 25%. Patients with PSA screening-detected prostate cancer may have earlier stage disease with a much better prognosis. However, in this subgroup, those with poorly differentiated or undifferentiated clinical stage T1c tumors, with a Gleason score of 8-10, have a significantly higher mortality rate. It is now well established that the addition of Radiation Therapy (RT) to Androgen Deprivation Therapy (ADT) improves Overall Survival compared to ADT alone, in patients with locally advanced prostate cancer. However, these studies did not include patients over 75 years of age or those with PSA screen detected high risk prostate cancer.

With this age-biased background, the authors conducted a non-randomized observational study to assess, whether the survival advantage of ADT plus RT over ADT alone, reported in clinical trials, could be replicated in real world clinical practice, to two subgroups of patients poorly represented in the clinical trials such as, men older than 75 years, with locally advanced prostate cancer and men age 65 years or older, with PSA screen detected high risk prostate cancer. Utilizing the SEER-Medicare data set, the authors reviewed the effectiveness of ADT plus RT compared to ADT alone in three groups of patients diagnosed with localized prostate cancer between 1995 and 2007 and observed through 2009. These three groups included 1) The Randomized Clinical Trial (RCT) cohort, which included men age 65 to 75 years, a profile consistent with participants in the randomized trials 2) The elderly cohort, which included men over 75 years of age, with locally advanced prostate cancer 3) PSA screen-detected cohort, which included men 65 years or older with PSA screen-detected high risk prostate cancer. The cause-specific and all-cause mortality was determined in these patient groups.

It was noted that in the RCT cohort, ADT plus RT was associated with reduced cause-specific and all-cause mortality compared to ADT alone and these finding were not significantly different from published randomized trials data. Interestingly, similar Overall Survival benefit was noted in the elderly and PSA screen-detected cohorts, with ADT plus RT. The authors in this thought provoking study concluded that older men with locally advanced or PSA screen-detected high-risk prostate cancer should also be offered ADT plus Radiation Therapy, as this therapeutic modality can improve Overall Survival. Effectiveness of Androgen-Deprivation Therapy and Radiotherapy for Older Men with Locally Advanced Prostate Cancer. Bekelman JE, Mitra N, Handorf EA, et al. J Clin Oncol 2015;33:716-722

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 220,800 new cases of prostate cancer will be diagnosed in 2015 and over 27,000 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 for hormone sensitive prostate cancer. Chemotherapy is usually considered for patients who progress on hormone therapy (Castrate Resistant Prostate Cancer-CRPC) and TAXOTERE® (Docetaxel) has been shown to improve Overall Survival (OS) of metastatic prostate cancer patients, who had progressed on Androgen Deprivation Therapy. Tumors in patients with CRPC are not androgen independent and continue to rely on Androgen Receptor signaling and two oral agents are presently available for metastatic CRPC. They include ZYTIGA® (Abiraterone) and XTANDI® (Enzalutamide). ZYTIGA® inhibits CYP 17A1 enzyme thus decreasing androgen biosynthesis and depletes adrenal and intratumoral androgens. XTANDI® competes with Testosterone and Dihydrotestosterone and avidly binds to the Androgen Receptor (AR), thereby inhibiting AR signaling and in addition inhibits translocation of the AR into the nucleus and thus inhibits the transcriptional activities of the AR. There is presently very little guidance with regards to the sequencing of these two oral agents after progression on TAXOTERE®, in patients with metastatic CRPC. ZYTIGA® was approved initially by the FDA in April 2011, for use in combination with prednisone for the treatment of patients with metastatic CRPC, who had received prior chemotherapy containing TAXOTERE®. Treatment with ZYTIGA® resulted in a 35% reduction in the risk of death and a 36% increase in median Overall Survival (OS) compared with placebo. Subsequently, XTANDI® was approved by the FDA on August 31, 2012 for the treatment of patients with metastatic CRPC who had previously received TAXOTERE®. XTANDI® improved median OS and reduced the risk of death by 37% when compared to placebo. Even though these two anti-androgen therapies improved OS in metastatic CRPC patients previously treated with TAXOTERE®, the proper sequence of administration of these two agents after TAXOTERE® failure, has remained unclear. At least 2 published studies have shown that the use of ZYTIGA® as third line therapy after progression on TAXOTERE® and XTANDI® resulted in inferior outcomes.

The purpose of this study was to evaluate the role of XTANDI® as third line therapy, in patients with metastatic CRPC, following progression on TAXOTERE® and ZYTIGA®. The authors searched large, established medical databases and selected 10 publications out of 1264 articles, in which metastatic CRPC patients were treated with XTANDI® as third line therapy, following progression on TAXOTERE® and ZYTIGA®. The study included 536 patients. The primary outcomes were PSA Response Rate of more than 50%, activity of XTANDI® based on previous response to ZYTIGA® and median Progression Free Survival (PFS) or Time To Progression. The secondary outcomes included safety and the median Duration of Response. The pooled Response Rate in this patient population with XTANDI® was 22.9%. However, in patients previously sensitive to ZYTIGA®, the Response Rate with XTANDI® was higher at 35%. The median PFS was 3.1 months and the median OS was 8.3 months. This pooled analysis gives some perspective on the initial choice of anti-androgen therapy in metastatic CRPC patients who progress on TAXOTERE®, with XTANDI® benefitting the most, in patients who respond to second line treatment with ZYTIGA®. It remains to be seen if this sequencing strategy can be confirmed in prospective trials. Enzalutamide After Docetaxel and Abiraterone Acetate Treatment in Prostate Cancer: A Pooled Analysis of 10 Case Series. Petrelli F, Coinu A, Borgonovo K, et al. Clinical Genitourinary Cancer 2015;13:193-198

SUMMARY:Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 220,800 new cases of prostate cancer will be diagnosed in 2015 and over 27,000 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 for hormone sensitive prostate cancer. This is accomplished by either surgical castration (bilateral orchiectomy) or medical castration using LHRH (GnRH- Gonadotropin-Releasing Hormone) agonists given along with 2 weeks of first generation anti-androgen agents such as EULEXIN® (Flutamide), CASODEX® (Bicalutamide) or NILANDRON® (Nilutamide), with the anti-androgen agents given to prevent testosterone flare. This large intergroup trial which was developed by the NCIC Clinical Trials Group in collaboration with the Medical Research Council and the National Cancer Institute US Cancer Therapy Evaluation Program, evaluated the benefits of adding Radiation Therapy (RT) to ADT, when compared to ADT alone, in patients with locally advanced prostate cancer. In this study, 1205 patients were randomly assigned to receive either ADT alone (N=602) or ADT plus RT (N=603). Eligible patients included those with T1-2 disease with either Prostate Specific Antigen (PSA) of more than 40 μg/L or PSA of 20-40 μg/L plus Gleason score of 8-10 or patients with T3-4, N0/NX, M0 prostate cancer. ADT consisted of either bilateral orchiectomy or LHRH agonists (plus 2 weeks of oral anti-androgen therapy to prevent testosterone flare), based on patient and physician preference, and ADT was continued for life. RT consisted of a dose of 64-69 Gy given in 35-39 fractions to the prostate gland and pelvis or prostate gland alone. The median age was 70 years and the median follow up was 8 years. Eighty seven percent of patients had T3-4 disease, 63% of patients had a PSA more than 20 μg/L and 18% had a Gleason score of more than 8. The Primary Endpoint was Overall Survival (OS), defined as the time from randomization to death from any cause. Secondary Endpoints included Time To Progression (TTP), improvement in Disease Specific Survival, quality of life and toxicity. The authors had previously reported the interim analysis findings of this intergroup trial and they noted that the addition of RT to ADT significantly improved overall survival, at a median follow up of 6 years (HR= 0.77; P=0.033). In this final analysis, at a median follow up of 8 years, the interim analysis findings were confirmed and the patients assigned to ADT plus RT had significantly improved Overall Survival compared to those who received ADT alone (HR=0.70; P<0.001), with a 30% reduction in the risk of death. Disease Specific Survival was also superior with ADT plus RT compared to ADT alone, with a 54% reduction in deaths from prostate cancer (HR=0.46; P <0 .001). There was a higher incidence of grade 1 and 2 bowel toxicities in patients who received ADT plus RT, but grade 3 bowel toxicities were rare and short term. The authors concluded that this long term follow up data suggests that the addition of Radiation Therapy to Androgen Deprivation Therapy significantly prolongs Overall and Disease Specific Survival, in patients with locally advanced prostate cancer. Final Report of the Intergroup Randomized Study of Combined Androgen-Deprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy Alone in Locally Advanced Prostate Cancer. Mason MD, Parulekar WR, Sydes MR, et al. J Clin Oncol 2015; 33:2143-2150