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
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.
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
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 of 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. 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 (ADT) in patients with prostate cancer with rising Prostate-Specific Antigen (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.
Both these agents have been shown to improve survival in metastatic CRPC. ZYTIGA® inhibits CYP 17A1 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 these newer agents and even those who respond will invariably develop resistance to these drugs. This again has been attributed to persistent AR signaling by variant forms of Androgen Receptor, generated through somatic mutation or aberrant RNA splicing. Androgen Receptor Variant AR-V7 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 effected by androgen depleting agents including ZYTIGA®. With this background, the authors hypothesized that detection of Androgen Receptor variant AR-V7 in circulating tumor cells from men with metastatic prostate cancer would be associated with resistance to both ZYTIGA® and XTANDI®. In a previously published prospective study, data involving 62 patients showed that detection of AR-V7 in Circulating Tumor Cells (CTCs) in men with mCRPC was indeed associated with primary resistance to both ZYTIGA® and XTANDI®. AR-V7–positive patients had inferior overall survival with both XTANDI® (HR = 6.9; P =0.002) and ZYTIGA® (HR = 12.7; P =0.006). AR-V7 was therefore shown to have a prognostic value for outcomes in mCRPC with ZYTIGA® and XTANDI®. In this present publication, the authors studied to determine if AR-V7-positive patients would retain sensitivity to Taxane chemotherapy. The researchers in this small prospective study enrolled 37 patients with metastatic CRPC who were starting Taxane chemotherapy with Cabazitaxel (JEVTANA®) or Docetaxel (TAXOTERE®). Presence or lack of AR-V7 in circulating tumor cells (CTCs), was determined by the qRT-PCR assay. Of the enrolled patients, 46% had detectable AR-V7 in CTCs. The primary endpoint was associations between AR-V7 status and PSA response rates and secondary endpoints included Progression Free Survival (PFS). They noted that the PSA responses were achieved in both AR-V7- positive and AR-V7-negative men and the difference was non-significant (41% versus 65%, P=0.19). Likewise there was no significant difference in the median PFS in AR-V7-positive and AR-V7-negative men (5.1 versus 6.9 months (HR= 2.65; P=0.11). The researchers then combined the data from their previously published study with 62 patients and they noted that, in AR-V7-positive men, PSA responses were higher in Taxane treated versus ZYTIGA®/XTANDI® treated men (41% versus 0%, P<0.001) and PFS were longer in the Taxane treated men as well (HR for PFS = 0.21, P=0.003). The outcomes however did not differ by treatment type in AR-V7-negative men and were comparable. The authors concluded that detection of AR-V7 in CTCs from men with mCRPC is not associated with primary resistance to Taxane chemotherapy, and such patients may retain sensitivity to Taxanes. In AR-V7-positive men however, Taxanes appear to be more efficacious than ZYTIGA® or XTANDI®. AR-V7 once available commercially, may become a biomarker for treatment selection, in metastatic Castrate Resistant Prostate Cancer. AR splice variant 7 (AR-V7) and response to taxanes in men with metastatic castration-resistant prostate cancer (mCRPC). Antonarakis ES, Lu C, Chen Y, et al. J Clin Oncol 33, 2015 (suppl 7; abstr 138)
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. COU-AA-302 trial is a placebo controlled, double-blind, randomized, phase III study and at the interim analyses showed that ZYTIGA® plus Prednisone significantly improved radiographic Progression Free Survival compared with placebo plus Prednisone, in men with chemotherapy-naive CRPC. The authors in this publication provided additional data on the pre-specified final analysis of the trial, which included the effect of ZYTIGA® plus Prednisone on Overall Survival, time to opiate use, and use of other subsequent therapies. In this study which included 1088 chemotherapy-naïve, asymptomatic or mildly symptomatic CRPC patients, 546 patients received ZYTIGA® 1000 mg PO plus Prednisone 5 mg PO twice daily and 542 patients received placebo plus Prednisone. The co-primary endpoints were radiographic Progression Free Survival and Overall Survival. In the final analysis, at a median follow up of 49•2 months, the median Overall Survival was 34.7 months in the ZYTIGA® group vs 30.3 months in the placebo control group (HR = 0.81, P = 0.0033). This benefit was seen across all prespecified subgroups, as well as adjusting for crossover from placebo to ZYTIGA® (HR = 0.79, P = 0.0013). The median time to opiate use for cancer-related pain was significantly prolonged in the ZYTIGA® group compared to the placebo group (33.4 vs 23.4 months, HR = 0.72, P < 0.0001). The most common grade 3 or 4 adverse events of special interest in the ZYTIGA® vs placebo group were cardiac disorders (8% vs 4%), increased ALT (6% vs < 1%), and hypertension (5% vs 3%). The authors concluded that with a median follow up of more than 4 years, treatment with ZYTIGA® in patients with chemotherapy-naive metastatic CRPC, significantly improved Overall Survival compared with Prednisone alone, with favorable toxicities. Ryan CJ, Smith MR, Fizazi K, et al. for the COU-AA-302 Investigators .The Lancet Oncology 2015; 16:152-160
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 and TAXOTERE® (Docetaxel) has been shown to improve Overall Survival (OS) of metastatic prostate cancer patients, who had progressed on androgen deprivation therapy. It is not clear however, whether ADT is more effective with or without TAXOTERE®, when treating patients with metastatic prostate cancer. To address this further, a randomized phase III trial (E3805) was conducted to assess the benefit of upfront treatment with a combination of chemotherapy and hormonal therapy, in patients with metastatic hormone sensitive prostate cancer. Seven hundred and ninety (N=790) patients with newly diagnosed metastatic prostate cancer were randomly assigned to receive either Androgen Deprivation Therapy alone (N=393) or ADT plus TAXOTERE® (N=397). Androgen Deprivation Therapy consisted of either Luteinizing Hormone Releasing Hormone (LHRH) agonist therapy, LHRH antagonist therapy, or surgical castration. Chemotherapy consisted of TAXOTERE®, started within 4 months of starting ADT, dosed at 75 mg/m2 given every 3 weeks for a maximum of six cycles. The median age of patients was 63 years and approximately two-thirds of patients had high-volume disease, with either extensive liver or bone metastases. The primary endpoint of this study was Overall Survival. At a median follow up of 29 months, the median Overall Survival was 42.3 months in the ADT group and 52.7 months in the ADT plus TAXOTERE® group (HR=0.63; P<0.0006). This benefit was even more significant in patients with high volume disease (32.2 vs 49.2 months for ADT and ADT plus TAXOTERE® respectively, HR=0.62; P<0.0012). At 12 months, the proportion of patients with PSA levels less than 0.2 ng/mL was 9.4% in the ADT alone group vs 19.7% in the ADT plus TAXOTERE® group (P < 0.0001). The median time to clinical progression was 19.8 months in the ADT alone group vs 32.7 months in the ADT plus TAXOTERE® group (P < 0.0001). The authors concluded that this is the first study to demonstrate survival benefit in patients with newly diagnosed metastatic prostate cancer. This survival benefit with Androgen Deprivation Therapy and TAXOTERE® is even more so, in patients with high volume disease and should be considered standard treatment for those patients who are fit to receive TAXOTERE® based therapy. Sweeney C, Chen Y, Carducci MA, et al. 2014 ASCO Annual Meeting; LBA2
Upon progression {described as Castrate Resistant Prostate Cancer (CRPC), as these tumors are not androgen independent and continue to rely on Androgen Receptor signaling} two agents are presently available for metastatic CRPC. They include ZYTIGA® (Abiraterone) and XTANDI® (Enzalutamide). Both these agents have been shown to improve survival in metastatic CRPC. ZYTIGA® inhibits CYP 17A1 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 these newer agents and even those who respond will invariably develop resistance to these drugs. This again has been attributed to persistent AR signaling by variant forms of Androgen Receptor, generated through somatic mutation or aberrant RNA splicing. Androgen Receptor Variant AR-V7 can be detected in the 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 effected by androgen depleting agents including ZYTIGA®. With this background, the authors hypothesized that detection of Androgen Receptor variant AR-V7 in circulating tumor cells from men with metastatic prostate cancer would be associated with resistance to both ZYTIGA® and XTANDI®. In this prospective study which enrolled patients with Castrate Resistant Prostate Cancer (CRPC), 31 patients received treatment with ZYTIGA® and 31 patients received treatment with XTANDI®. Levels of AR-V7 in circulating tumor cells of these patients were analyzed using quantitative Reverse Transcriptase – Polymerase Chain Reaction assay. The primary endpoint was association between AR-V7 status (positive versus negative) and Prostate Specific Antigen (PSA) response rates and secondary endpoints included freedom from PSA progression (PSA Progression Free Survival), clinical or radiographic Progression Free Survival, and Overall Survival. The authors noted that patients with detectable AR-V7 in circulating tumor cells had no response to ZYTIGA® or XTANDI® as measured by serum PSA level reduction of 50% or more and also had a shorter Progression Free Survival and Overall Survival. Also of interest, the prevalence of detectable AR-V7 in circulating tumor cells before treatment with ZYTIGA® and XTANDI® was 9-15% whereas it increased to approximately 50% after disease progressed during treatment with either of these two drugs. This suggested a common mechanism of resistance to both drugs. The authors concluded that detection of AR-V7 in circulating tumor cells from patients with Castration Resistant Prostate Cancer, may be associated with resistance to ZYTIGA® and XTANDI® and if further validated, could be used as a biomarker. Antonarakis ES, Lu C, Wang H, et al. N Engl J Med 2014; 371:1028-1038