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 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

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.

Prostate cancer is driven by Androgen Receptor (AR) and its signaling pathways. Initial treatment strategies for patients with metastatic prostate cancer include lowering the levels of circulating androgens with medical or surgical castration or blocking the binding of androgens to the Androgen Receptor (AR). Upon progression, (described as Castrate Resistant Prostate Cancer-CRPC, as these tumors are not androgen independent and continue to rely on Androgen Receptor), therapies directed at the Androgen Receptor , such as ZYTIGA® (Abiraterone acetate) and XTANDI® (Enzalutamide), and Taxanes such as TAXOTERE® (Docetaxel) and JEVTANA® (Cabazitaxel) are the most widely used drug classes in the United States. ZYTIGA® inhibits CYP17A1 enzyme and depletes adrenal and intratumoral androgens, thereby impairing AR signaling. XTANDI® competes 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. About 20-40% of the patients do not respond to therapies directed at the AR, and even those who respond will invariably develop resistance to these drugs.

ZYTIGA® and XTANDI® are often the preferred choice for the first-line treatment of metastatic CRPC (mCRPC). In clinical practice, the majority of patients with mCRPC who progress on one of these agents receive the alternative agent, as there are no formal guidelines on how best to sequence these agents after progression on first-line AR signaling inhibition. Resistance to ZYTIGA® and XTANDI® has been attributed to persistent AR signaling by variant forms of Androgen Receptor, generated through somatic mutation or aberrant RNA splicing. Androgen Receptor splice Variant 7 (AR-V7) is the most widely studied and can be detected in the CTCs (Circulating Tumor Cells). AR-V7 does not have the domain to bind androgens and may be associated with resistance to XTANDI®. Further AR-V7 is constitutively active and can independently activate transcription factors and therefore is not affected by androgen depleting agents including ZYTIGA®. A critical unmet need is an assay that can detect AR-V7 protein in the peripheral blood (liquid biopsy), and accurately identify patients who are resistant to AR targeted therapies and who should instead switch to chemotherapy.

PROPHECY is a multicenter, prospective-blinded study, which evaluated the ability of baseline/pretreatment AR-V7 status in CTCs, to predict treatment outcomes with ZYTIGA® or XTANDI®. The researchers enrolled 118 men with high-risk mCRPC starting ZYTIGA® or XTANDI® treatment, from five academic medical centers. Prior exposure to XTANDI® or ZYTIGA® was permitted for men who were planning to receive the alternative agent. Among the study patients, 55 were treated with ZYTIGA®, 58 were treated with XTANDI®, and five received both therapies concurrently. The median age was 73 years, 58% had a Gleason score sum of 8-10 and the median number of high-risk features was six.

Peripheral blood samples were obtained for CTCs analysis at baseline, and at the time of clinical, radiographic, or biochemical progression, and analyzed at two central laboratories, each blinded to the results of the other. AR-V7 in CTCs was detected using two blood-based assays, including the Epic Sciences CTC nuclear-specific AR-V7 protein assay and The Johns Hopkins University (JHU) modified-AdnaTest CTC AR-V7 mRNA assay. One of the unique aspects of this multicenter study was that laboratory investigators were blinded to the clinical results, and clinicians were blinded to the laboratory results, and the definitions of a positive test for AR-V7 were defined in advance, and thus prospectively validated. In this study, approximately 10-24% of men with high-risk mCRPC were AR-V7 positive at baseline, depending on the assay used. The Primary endpoint was Progression Free Survival (PFS) on the basis of radiographic or clinical progression and Secondary clinical end points included 50% or greater decline in PSA and Overall Survival (OS). The Primary objective was to validate the prognostic significance of baseline CTC AR-V7 on the basis of radiographic or clinical progression free-survival (PFS). The median follow up was 19.6 months.

It was noted that AR-V7 detection in CTCs by either of two different assays was independently associated with shorter PFS and OS, after adjusting for CTC number and clinical prognostic factors. There was very little evidence of clinical benefit from ZYTIGA® or XTANDI® in AR-V7 positive patients, with a very low probability of confirmed PSA decline (0-11%) or soft tissue responses (0-6%). The concordance between the two AR-V7 assays utilized in this study was 82%.

The authors concluded that among patients with high-risk mCRPC , detection of AR-V7 in Circulating Tumor Cells (CTCs) by two blood-based assays is independently associated with shorter PFS and OS, when treated with ZYTIGA® or XTANDI®. These high risk patients who test positive for AR-V7 should be offered alternative, more effective treatments, such as Taxane chemotherapy or a clinical trial of an investigational therapy. Testing for AR-V7 can be undertaken utilizing either modified-AdnaTest CTC AR-V7 mRNA assay or Epic Sciences CTC nuclear-specific AR-V7 protein assay. The later assay is commercially available as Oncotype DX® AR-V7 Nucleus Detect® test, and is covered by Medicare. Prospective Multicenter Validation of Androgen Receptor Splice Variant 7 and Hormone Therapy Resistance in High-Risk Castration-Resistant Prostate Cancer: The PROPHECY Study. Armstrong AJ, Halabi S, Luo J, et al. Published online March 13, 2019. DOI: 10.1200/JCO.18.01731 Journal of Clinical Oncology

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 ASCO clinical practice guideline published in 2018, recommended the addition of either TAXOTERE® (Docetaxel) or ZYTIGA® (Abiraterone acetate) to ADT, based on CHAARTED trial and STAMPEDE/LATITUDE trials respectively, for men with newly diagnosed metastatic Prostate cancer, based on the Overall Survival benefit with these combinations, when compared with the use of ADT alone. It is also 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. Patients with metastatic Prostate cancer however are often treated with systemic therapy alone without any local intervention such as Radiation Therapy to the Prostate gland.

The Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial is an ongoing phase III study and uses a novel multi-arm, multi-stage (MAMS) platform design, to test whether the addition of further treatments to ADT improves Overall Survival, when used in first-line setting, for patients with hormone sensitive, locally advanced or metastatic Prostate cancer. This group previously reported that there was a significantly improved Overall Survival with the addition of TAXOTERE® to initial ADT and also concluded that ZYTIGA® and prednisolone along with ADT results in significantly higher rates of Overall Survival as well as Failure-Free Survival, compared with ADT alone, among men with hormone sensitive, locally advanced or metastatic Prostate cancer.

The authors in this study had hypothesized based on studies in animal models that local treatment of the Prostate might not only improve local control but also slow progression of metastatic disease and improve Overall Survival in men presenting with metastatic Prostate cancer, and that survival benefit would be greater in men with lower metastatic burden. The accompanying results are from a preplanned analysis of one group in the multi-arm, multi-stage STAMPEDE study.

The study included 2,061 patients with newly diagnosed metastatic Prostate cancer who were randomized 1:1 to Standard of Care treatment consisting of lifelong Androgen Deprivation Therapy with or without early TAXOTERE® or the same Standard of Care plus Radiation Therapy to the Prostate. Radiotherapy was administered in two different schedules – either daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in 6 fractions for 6 weeks) based on investigator’s choice. The median age was 68 years, the median PSA level was 97 ng/mL and 18% received early TAXOTERE® treatment at the investigator’s discretion. Metastatic disease burden was characterized as Low in 40% and High in 54% and 6% was unknown. A High Prostate cancer disease burden was defined as 4 or more bone metastases, with at least 1 metastasis outside the axial skeleton and/or visceral metastases. The rest of the patients were characterized as having Low disease burden. The Primary outcome measure was Overall Survival and Secondary outcomes included Failure-Free Survival (FFS), and toxicity.

It was noted that Radiation Therapy to the Prostate improved FFS (HR=0.76; P<0.001) but not Overall Survival. However subgroup analysis showed that Radiation Therapy to the Prostate improved Overall Survival by 32% in the 819 men with lower metastatic disease burden (HR=0.68) and the 3 year Overall Survival rates were 81% in the Radiation Therapy arm versus 73% for Standard of Care, suggesting an absolute benefit of 8% and this was statistically significant (P =0 .007). By contrast, the 1120 men with higher metastatic disease burden did not benefit from Radiation Therapy. The Radiation Therapy schedule did not have any impact on outcomes. Radiation Therapy to the Prostate was well tolerated, with 5% of patients experiencing grade 3 or 4 adverse events during treatment and 4%, after treatment.

It was concluded that Prostate Radiotherapy in addition to systemic drug therapy improves the Overall Survival of men with newly diagnosed metastatic Prostate cancer who have a low metastatic disease burden, and should now be a standard treatment option. The authors added that this study did not include patients with pelvic node-positive nonmetastatic disease (N1, M0), where the addition of Radiotherapy to systemic drug therapy could be curative. Radiotherapy (RT) to the primary tumour for men with newly diagnosed metastatic prostate cancer (PCa): survival results from STAMPEDE (NCT00268476). Parker CC, James ND, Brawley C, et al. Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA5.

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. Over 90% of the patients with metastatic prostate cancer have bone metastases, and the tumor burden, is an independent predictor of death in this patient population. Agents such as ZOMETA® (Zoledronic acid) and XGEVA® (Denosumab) can prevent or delay Skeletal Related Events (SRE’s) and External Beam Radiation Therapy (EBRT) is often utilized to treat symptomatic SRE’s. EBRT can however damage the bone marrow in the radiated field, resulting in cytopenias, and consequently can potentially preclude patients from receiving cytotoxic chemotherapy.

Radium Ra 223 dichloride (XOFIGO®) is a bone seeking alpha particle emitter and by virtue of its chemical similarity to calcium is preferentially taken up by the bone and forms complexes with bone mineral, hydroxyapatite, in areas where there is increased bone turnover, such as bone metastases. XOFIGO® induces double stranded DNA breaks resulting in antitumor effects and has a very short range in tissues (around 2 and 10 cells), quickly losing energy, compared to beta or gamma radiation. The end result is less damage to the adjacent healthy tissues. Further, unlike Ra-226 which was first isolated by Madame Curie, XOFIGO® has a short half life of 11.4 days and rapidly decays, preventing significant radiation exposure.

XOFIGO® in a randomized, double-blind, Phase III trial (ALSYMPCA study) improved overall survival in patients with CRPC (Castrate Resistant Prostate Cancer) with bone metastases. Abiraterone acetate (ZYTIGA®) is a novel, targeted, oral androgen biosynthesis inhibitor that decreases androgen production in the adrenal glands, testes and prostate cancer cells by inhibiting a steroidal enzyme CYP17A. ZYTIGA® along with Prednisone in a double-blind, randomized, Phase III study (COU-AA-302 trial) significantly improved Overall Survival compared with Prednisone alone, in patients with chemotherapy-naive metastatic CRPC. This formed the basis for this present study.

ERA 223 is a randomized, double-blind, placebo controlled, Phase III trial in which 806 patients with asymptomatic or mildly symptomatic chemotherapy-naïve metastatic Castration Resistant Prostate Cancer with at least 2 bone metastases were randomly assigned in a 1:1 to ZYTIGA® plus concurrent XOFIGO® (N=401) versus ZYTIGA® plus matching placebo (N=405). Bone Health Agents (BHAs) (Bisphosphonates or XGEVA®) were only allowed in patients receiving them at baseline, and 39% of patients in the ZYTIGA® plus XOFIGO® and 42% in the ZYTIGA® plus placebo arms were receiving BHAs at baseline. The median age was 71 years in both treatment groups. The Primary endpoint was Symptomatic Skeletal Event-Free Survival (SSE-FS), defined as freedom from the use of External Beam Radiation to relieve symptomatic skeletal events, new symptomatic pathologic bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, or death. Secondary endpoints included Overall Survival, radiological Progression Free Survival (rPFS), time to cytotoxic chemotherapy, and time to opiate use for cancer pain. This study was unblinded prematurely due to more fractures and deaths in the ZYTIGA® plus XOFIGO® group. All patients had completed study-specified XOFIGO® /placebo treatment prior to unblinding. The treatment was however continued, and the protocol was amended to allow BHAs in patients who were not taking them at baseline.

At the primary analysis, it was noted that there was no significant difference between the two treatment arms for the Primary endpoint of Symptomatic Skeletal Event-Free Survival. The median Symptomatic Skeletal Event-Free Survival was 22.3 months in the ZYTIGA® plus XOFIGO® group versus 26 months in the ZYTIGA® plus placebo group (P=0.263). The Secondary endpoint of Overall Survival (OS) was 30.7 months with ZYTIGA® plus XOFIGO® and 33.3 months with ZYTIGA® plus placebo (P=0.128) and this was not significantly different. Fractures occurred in 29% of patients in the ZYTIGA® plus XOFIGO® group and 11% of patients in the ZYTIGA® plus placebo group respectively. Patients who were taking BHAs still sustained more fractures in the XOFIGO® containing arm. Baseline use of BHAs however was associated with lower fracture rates in both treatment groups. In patients receiving BHAs, 15% and 7% experienced a fracture in the ZYTIGA® plus XOFIGO® and ZYTIGA® plus placebo arms respectively, versus 37% and 15% without BHAs.

It was concluded that concurrent ZYTIGA® plus XOFIGO® treatment did not improve Symptomatic Skeletal Event-Free Survival or Overall Survival but on the contrary led to a higher fracture rate. Based on these results, the authors recommended against the use of XOFIGO® in combination with ZYTIGA®. ERA 223: A phase 3 trial of radium-223 (Ra-223) in combination with abiraterone acetate and prednisone/prednisolone for the treatment of asymptomatic or mildly symptomatic chemotherapy-naïve patients (pts) with bone-predominant metastatic castration-resistant prostate cancer (mCRPC). Smith MR, Parker CC, Saad F, et al. Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA30.

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 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. 

In the Prostate Testing for Cancer and Treatment (ProtecT) study which is a prospective, randomized trial, management with Active Monitoring, Radical Prostatectomy, and External Beam Radiotherapy were compared, among patients with PSA-detected clinically localized prostate cancer. This study at a median follow up of 10 yrs concluded that prostate cancer-specific mortality was low, irrespective of the treatment given, with similar efficacy outcomes, but with a variable impact on quality of life. In this study, it was 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. Long term survival results are not mature. In the Prostate Cancer Intervention versus Observation Trial (PIVOT), at 19 years of follow up, the relative risk of death from prostate cancer was 0.65 (65% lower with intervention) but the absolute difference in risk was only 4%. However, long term follow up results are not mature. These data suggested that Radical Prostatectomy reduces mortality among men with clinically detected localized prostate cancer, but evidence from long-term follow-up is lacking.

The Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) is a randomized trial in which 695 men with localized prostate cancer were randomly assigned to the Radical Prostatectomy group (N=347) and to the watchful-waiting group (N=348), between 1989 and 1999. This trial opened before the era of Prostate Specific Antigen (PSA) testing. Enrolled patients were younger than 75 years of age and had localized tumor Stage T1, or T2. Tumors had to be well differentiated to moderately well differentiated according to the WHO classification, and were required to have a serum PSA level of less than 50 ng/ml and a negative bone scan. The baseline characteristics were similar in both groups. The mean age was 65 years, the mean PSA level was approximately 13 ng/ml, and only 12% of the patients had nonpalpable stage T1c tumors. Patients were followed up every 6 months for the first 2 years and then annually. The Primary end points were death from any cause, death from prostate cancer, and the risk of metastases. Secondary end points included the initiation of Androgen Deprivation Therapy. The median follow up time was 23.6 years.

The cumulative incidence of death from prostate cancer at 23 years was 19.6% in the Radical Prostatectomy group and 31.3% in the watchful-waiting group (difference of 11.7%) and the relative risk for the complete follow up period was 0.55, meaning 55% lower risk of death with Radical Prostatectomy (P<0.001). The mean years of life gained, in the Radical Prostatectomy group at 23 years of follow up was 2.9 years. The cumulative incidence of distant metastases at 23 years was 26.6% in the Radical Prostatectomy group and 43.3% in the watchful-waiting group (difference of 16.7%) and the relative risk based on data from the complete follow up period was 0.54, meaning 54% lower risk of distant metastases (P<0.001). Among those who underwent Radical Prostatectomy, extracapsular extension was associated with a risk of death from prostate cancer that was 5 times as high as that among men without extracapsular extension. A Gleason score higher than 7 was associated with a risk, that was 10 times as high as that with a score of 6 or lower.

It was concluded that among men with clinically detected localized prostate cancer, Radical Prostatectomy resulted in a mean gain of almost 3 years of life after 23 years of follow up, and a high Gleason score and the presence of extracapsular extension in the Radical Prostatectomy specimens were highly predictive of death from prostate cancer. In the current day clinical practice however, with widespread PSA testing and PSA-detected tumors utilizing multiparametric Magnetic Resonance Imaging with targeted biopsies, the lead time induced by screening and definition of risk groups becomes increasing relevant when recommending treatment. Radical Prostatectomy or Watchful Waiting in Prostate Cancer – 29-Year Follow-up. Bill-Axelson A, Holmberg L, Garmo H, et al. N Engl J Med 2018; 379:2319-2329