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Therapeutics Prostate Cancer: Current Approach and Future Perspective in Castration-resistant Cancer Treatment Abstract Prostate carcinoma is one of the most commonly diagnosed solid tumours in males worldwide. Selection of the treatment method is strictly dependent upon disease stage and the patient’s age. Availability of diagnostic tests is constantly increasing in clinical practice, allowing early diagnosis and better chances for complete and permanent recovery. In the case of locally advanced prostate carcinoma, radical surgery or radiotherapy is considered as the most effective therapeutic approach, whereas in metastatic prostate carcinoma, hormone therapy or androgen deprivation therapy (ADT) is the primary therapeutic option. Moreover, increased use of chemotherapy with docetaxel and cabazitaxel in clinical practice has resulted in better prognosis for patients in this advanced stage of the disease. The biggest challenge for doctors and patients remains the treatment of hormone-resistant carcinoma (which very often is also metastatic). Concerns of today’s medicine regarding effective therapies for this type of disease have recently led to a significant increase in the number of papers/ studies on new-generation biological treatments. Background Prostate cancer is one of the most common types of cancer among men of all races and usually begins without symptoms. 2015, and the number of deaths will reach 27,540. One of the primary risk factors is age. Prostate carcinoma is usually diagnosed in patients aged over 65. According to the American Cancer Society, about six in 10 cases of prostate cancer are diagnosed in men over 65. Other risk factors include genetic burden and race (prostate cancer prevalence is highest among African and Caucasian men). Early prostate cancer may not cause any symptoms for years, therefore screening for prostate cancer is recommended, especially in high-risk populations. Recently, due to better availability of diagnostic tests, particularly determination of serum prostate specific antigen (PSA), the detection rate of prostate carcinoma has significantly improved. Blood PSA levels above 4 ng/ml may suggest the presence of carcinoma cells and indicate the need for further diagnostics. However, studies have indicated that PSA levels below 4 ng/ml are not definitely predictive of the absence of prostate carcinoma. Most cases of prostate carcinoma (90%) are adenocarcinomas, malignant tumours of the epithelial tissue. Histopathologic differentiation is based on the Gleason score3, a combined total of the two most prevalent patterns in the biopsy material (Table 1). Table 1. on Gleason score Gleason score Histopathological characteristics 15-year risk of death due to prostate carcinoma 2-4 4-7% 5 6-11% 6 18-30% 7 42-70% 8-10 60-87% The prevalence of prostate cancer in Europe was estimated at 416,700 cases in 20121. Prostate cancer has been recognised as the third leading cause of death in Europe. According to the International Agency for Research on Cancer, the biggest incidence of prostate cancer in 2012 was reported in northern European countries (Norway, Sweden, Ireland, Iceland and Switzerland). Reported mortality was also the highest in Scandinavian countries. Based on data analysed by the American Cancer Society, it is estimated that in the US about 220,800 new cases of prostate cancer will be diagnosed in 46 Journal for Clinical Studies Prostate carcinoma is most commonly located in the peripheral zone and typically multifocal. The term advanced prostate carcinoma is used to describe the stage of the disease in which the tumour has already spread beyond the organ and infiltrated the surrounding tissues and organs (locally advanced carcinoma) or has metastasised to bones or distant organs (disseminated, metastatic cancer). Early detection significantly increases the chances of Volume 7 Issue 5 Therapeutics Table 2. Prostate carcinoma treatment options Organ-limited prostate carcinoma Locally advanced prostate carcinoma Metastatic prostate carcinoma • radical prostatectomy • radical radiotherapy • radical brachytherapy • radical radiotherapy • hormone therapy • • • • • palliative hormone therapy palliative radiotherapy palliative brachytherapy chemotherapy novel drugs Table 3. Hormonal therapies in prostate carcinoma Gonadoliberin analogues Gonadoliberin antagonists Antiandrogens • Goserelin • Leuprorelin • Triptorelin • Degarelix • Flutamide • Bicalutamide • Table 4. - Response Evaluation Criteria in Solid Tumors Biochemical progression Radiographic progression Castrate level of blood Castrate level of blood testosterone testosterone (< 50 ng/dl or 1.7 nmol/l) (< 50 ng/dl or 1.7 nmol/l) + + Three consecutive PSA increments within 1 week by 50% from the lowest PSA level • development of min. 2 bone lesions • or development or growth of metastatic lesions in soft tissues, according to RECIST survival. In the United States, where screening tests are commonly used, over 90% of prostate cancer cases are diagnosed in the organ-limited or locally advanced stage, and five-year survival rate at this stage is nearly 100%2. According to the most recent data analysed by the American Cancer Society (including all stages of prostate cancer) the survival rates are as follows: • • The relative five-year survival rate is almost 100% The relative 10-year survival rate is 99% www.jforcs.com The relative 15-year survival rate is 94% Therapy – General Principles Prostate cancer growth is androgen-dependent, therefore androgen blockade is an effective anti-cancer therapy. It can be achieved with surgical castration, radiation therapy, or medical castration (hormone therapy). The choice of the therapy course largely depends on the stage of the disease. General therapeutic approaches in prostate carcinoma are outlined in Table 2. Radical surgery is indicated only in patients with prostatelimited carcinoma (cT1-2 N0 M0) whose life expectancy is above 10 years. Radical irradiation – teletherapy and/or brachytherapy is also indicated in patients with prostate-limited carcinoma (stage cT1-T3 N0 M0) and some cases of locally advanced carcinoma (T4 and N(+)). Hormonal therapy (HTH) or androgen deprivation therapy (ADT) is the primary therapy for advanced disease. The treatment eliminates the endogenous androgens in patients who are not eligible for radical therapy. Hormonal therapy is the first-line treatment for advanced prostate cancer. This course of treatment allows slowing down the cancer growth but it does not cure the disease itself. Traditional ADT (Table 3) includes a variety of approaches: • surgical castration – removal of the testes, thus blocking the secretion of androgens; • pharmacological castration – blocking the secretion of androgens at the pituitary level; • intracellular pharmacologic castration – blocking the Journal for Clinical Studies 47 Therapeutics effect of androgens on prostate cells with androgen receptor blocking drugs (so-called anti-androgens). Diagram 1. Therapeutic options for patients after biochemical progression (increase of PSA level) used in combination with hormonal therapy Asymptomatic disease Moderate symptoms without metastases to soft tissues: 1. Abiraterone or 2. Sipuleucel T or 3. Enzalutamide or 4. Docetaxel or 5. Cabazitaxel Performance status 0 or 1 No metastases to soft tissues Docetaxel or Alpharadin Metastases to soft tissues Docetaxel Combination of surgical and pharmacologic castration is known as total or maximal androgen blockade (MAB). Ablation therapy results in reducing testosterone levels to castration values, i.e. <50 ng/ml. Symptomatic disease mCRPC Symptomatic disease bone Alpharadin Asymptomatic patients Follow-up Hormone Resistance Unfortunately, in many cases, the prostate carcinoma progresses despite castration and very low blood testosterone levels. Despite the high efficacy of hormonal therapy, cancer cells become adapted to low (castrate) androgen levels after some time and castration-resistant prostate cancer (CRPC) develops4,5. The definition of CRPC is presented in Table 4. Performance status 2 Typically the skeletal system is the first area of metastasis for prostate carcinoma. Bone metastases are observed in 90% of patients with metastatic castration-resistant prostate carcinoma (mCRPC). This patient population requires particular and thorough therapy due to severe disease symptoms, dramatically affecting the quality of life. The objective of therapy is to improve quality of life, but also prolong time to progression and total survival. Further efforts are being made to modify early-stage treatment to obtain maximum improvement of time to development of hormoneresistance and metastases. How to proceed, if an aggressive type of disease is suspected, particularly in young patients with high histologic grade (Gleason 8 or above), remains one of the most challenging questions. Table 5. Selected phase 3 clinical trials in patients with known castration-resistant prostate carcinoma: PSA regression rate, pain, total survival, time to progression. EMP=estramustine; HC=hydrocortisone; 1p<0.000 compared to mitoxantrone; 2p=0.001 compared to mitoxantrone Clinical trial Regression of PSA level > 50% Pain regression Survival (months) Time to progression TAX 327 Mitoxantrone 12 mg/m2 body surface area every 3 weeks for 10 cycles 32.00% 22.00% 16.5 Docetaxel 75 mg/m2 body surface area every 3 weeks for 10 cycles 45.00% 35.00% 18.91 48.00% 31.00% 17.4 Docetaxel 30 mg/m2 body surface area 5 weeks, in a 6-week cycle, for 5 cycles SWOG 99-16 Mitoxantrone 12 mg/m2 body surface area every 3 weeks for 10 cycles 50.00% 15.6 3.2 months Docetaxel / EMP every 3 weeks 60 mg/m2; EMP 3 x 280 mg/dose 27.00% 17.52 6.3 months Despite insufficient knowledge of the precise mechanisms involved in the development of CRPC, difficulties and challenges related to CRPC therapy have led to the development and launch of several new drugs, improving patients’ prognosis. These new medicines include: abirateron, enzalutamide, sipuleucel, docetaxel (new in this indication), and cabazitaxel (Diagram 1). CALGB 9182 Hydrocortisone 38.00% 12.3 2.3 months Mitoxantrone / HC every 3 weeks 12 mg/m2 22.00% 12.6 3.7 months Prednisone 22.00% 12.00% 18 weeks Mitoxantrone every 3 weeks 12 mg/m2 / Prednisone 33.00% 29.00% 43 weeks TANNOCK ET AL. Chemotherapy For many years prostate cancer has been believed to be cytostatic-resistant. A significant step forward was made in 2004, with the publication of two large studies comparing TROPIC Cabazitaxel + prednisone 15.1 2.8 months Mitoxantrone + prednisone 12.7 1.4 months Table 6. Selected randomized phase 3 clinical trials in patients with known castration-resistant prostate cancer Author Year Study drug (sample size) Time to progression (months) Total survival Abiraterone Ryan 2013 Abiraterone + Prednisone (546) vs Placebo + Prednisone (542) 16.5 vs 8.5 Median not reached vs 27.2 months Fizazi 2012 Abiraterone + Prednisone (797) vs Placebo + Prednisone (398) 5.6 vs 3.6 15.8 vs 11.2 months (p<0.001) Enzalutamide Scher 2012 48 Journal for Clinical Studies Enzalutamide (800) 8.3 18.4 Volume 7 Issue 5 Therapeutics Table 7. Selected clinical trials of Sipuleucel-T Author Year Study drug (sample size) Time to progression (months) Total survival Sipuleucel-T Small 2010 Sipuleucel-T (341) vs placebo (171) 3.7 vs. 3.6 25.8 vs 21.7 months (p.03) 2006 Sipuleucel-T (82) vs Placebo (45) 11.7 vs. 10 25.9 vs 21.4 months (p.03) the efficacy of docetaxel and mitoxantrone plus prednisone chemotherapy, which was the standard therapy at that time. Docetaxel is an anti-cancer drug that works by binding to microtubules and stabilising them, which eventually leads to cell death. The safety and efficacy of docetaxel in combination with prednisone and prednisolone in patients with hormone-independent prostate carcinoma has also been studied in a multi-centre Phase III randomised trial TAX 327. This study recruited 1006 patients. The median (mean) survival time was 18.9 months compared to 16.6 months in the mitoxantrone group (HR=0.7695%, CI: 17.0-21.2) 9-12 The only drug which has shown an improvement of total survival in patients with progression following docetaxelbased chemotherapy was cabazitaxel. This semi-synthetic taxoid belongs to new generation antineoplastic drugs and is characterised by partial lack of cross-resistance to docetaxel. The TROPIC study comparing treatment with cabazitaxel and prednisone vs. mitoxantrone and prednisone has shown improvement of median survival time by more than two months (15.1 vs. 12.7 months, respectively) and a doubled median time to progression (2.8 vs. 1.4 months)13,14. Current Hormonal Therapy in Advanced Prostate Carcinoma Recently, two novel hormone therapies have been introduced based on abiraterone and enzalutamide. They act by blocking androgen receptor activation pathways, but their mechanism of action is different than in therapies used so far. Therapeutic benefits of abiraterone and enzalutamide have been evaluated following docetaxel chemotherapy, as well as prior to docetaxel therapy, as a first-line therapy in patients diagnosed with CRPC. Results of selected Phase III clinical trials are presented in Table 6. Abiraterone selectively inhibits CYP17 activity (17α-hydroxylase and C17,20-lipase activity). This enzyme is responsible for the biosynthesis of androgens in the testes, adrenal glands and prostate cancer tissue. Blocking its activity results in stopping testosterone production. In a prospective, placebo-controlled Phase III randomised clinical trial (COU-AA-301) abiraterone was used in combination with prednisone in patients with known castration-resistant prostate cancer, following a failure of docetaxel therapy. A statistically significant therapeutic benefit was shown – mean total survival in the non-abiraterone group was 11.2 months (95% CI 10.4-13.1 months) vs 15.8 months (95% CI 14.817.0 months) in the abiraterone arm. Median follow-up time was 20.2 months. The study also demonstrated increased www.jforcs.com median time to PSA progression of 8.5 months (95% CI 8.311.1) vs 6.6 months (95% CI 5.6-8.3); HR 0.63; p< 0.0001. In another prospective Phase III randomised clinical trial (COU-AA-302) abiraterone was used in combination with prednisone in docetaxel-naive patients with known castrationresistant prostate carcinoma. The study demonstrated an increased median of total survival by 4.8 months (35.3 vs 30.1 months; HR 0.79, p=0.0151). Abiraterone also reduced the risk of radiographic progression (rPFS, radiographic progression free survival) or death by 47% compared to placebo (HR=0.530; 95% CI: 0.451; 0.623; p<0.0001)6-8. Enzalutamide is indicated for the treatment of metastatic castration-resistant prostate cancer in patients with disease progression during or following docetaxel treatment. It is a potent inhibitor of the androgen receptor signalling pathway. It blocks several stages of the androgen receptor signalling pathway. The efficacy and safety of this drug have been evaluated e.g. in a randomised, placebo-controlled, multicentre Phase III clinical trial in patients with metastatic castration-resistant prostate carcinoma, following earlier docetaxel therapy. The patients received a concomitant gonadotropin-releasing hormone (GnRH) analogue or underwent surgical castration (orchyectomy). Progression free survival confirmed by radiologic evaluation determined with RECIST (Response Evaluation Criteria In Solid Tumors) v. 1.1 criteria was 8.3 months in the enzalutamide group and 2.9 months in the placebo group (HR = 0.404, 95% CI: [0.350; 0.466]); p < 0.0001). Combination therapies including both products (enzalutamide and abiraterone) are currently under investigation in mCRPC. These medicinal products with different targets given in parallel may demonstrate significantly higher efficacy than when used alone. Immunotherapy for Prostate Carcinoma The purpose of immunotherapy is to induce and stimulate immunologic mechanisms in order to destroy cancer cells. A breakthrough strategy in the treatment of CRPC turned out to be the use of autologous dendritic cells, professional antigen presenting cells. Sipuleucel-T is a vaccine for personalised treatment based on patient’s own cells obtained during leukapheresis. Immunotherapy and therapies targeting the receptors and signalling pathways in prostate carcinoma cells and endothelium provide a true opportunity for improving Journal for Clinical Studies 49 Therapeutics future prognosis in patients with CRPC. Further studies, both in the field of immunology and cancer molecular biology, should allow the identification of currently unknown therapeutic targets, and design new, promising systemic treatment strategies of early and advanced prostate cancer. Results of selected clinical trials are presented in Table 7. Sipuleucel-T was approved by the FDA in 2010 and shortly after the marketing authorization, the National Comprehensive Cancer Network added Sipuleucel-T as a category 1 recommendation for patients with castrationresistant prostate cancer. Summary and Conclusions Prostate cancer is one of the most common types of cancer and one of the leading causes of cancer death worldwide. The most difficult type of prostate cancer for effective therapy is metastatic castration-resistant prostate cancer. CRPC remains an incurable disease usually associated with poor prognosis and short survival time. A multidisciplinary approach is advised in the treatment of patients with a known castrationresistant stage of prostate carcinoma, but patient care remains a tremendous challenge for today’s medicine. Very high incidence of prostate cancer and lack of fully effective treatment methods of its advanced, castration-resistant forms have resulted in a dynamic progress of clinical trials of novel therapies. The primary purpose of novel therapies, including chemotherapies, is to reduce the patient’s pain, improve quality of life and above all improve survival rates. Positive and promising study results have been obtained for abiraterone, enzalutamide as well as for Sipuleucel-T. During the last years these products were granted marketing authorisation both in the United States (FDA) and throughout the European Union (EMA), however because of the high cost of novel therapies, patients’ access to advanced treatment is still limited in many countries. 5. 6. 7. 8. 9. 10. 11. 12. Schröder FH. Progress in understanding androgen-independent prostate cancer (AIPC): a review of potential endocrine-mediated mechanisms. Eur Urol 2008 Jun;53(6):1129-37.http://www.ncbi. nlm.nih.gov/pubmed/18262723 Ryan CJ, Smith MR, de Bono JS, et al. COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013 Jan;368(2):138Fizazi K, Scher HI, Molina A, et al. COU-AA-301 Investigators. Abiraterone acetate for treatment of metastatic castrationresistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2012 Oct;13(10):983-92.http://www.ncbi.nlm. nih.gov/pubmed/22995653 de Bono JS, Logothetis CJ, Molina A, et al. COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011 May;364(21):1995-2005.http://www.ncbi.nlm.nih. gov/pubmed/21612468 Tannock IF, de Wit R, Berry WR, et al. TAX 327 Investigators. Docetaxel plus prednisone ormitoxantrone plus prednisone for advanced prostate cancer. New Engl J Med 2004 Oct;351(15):150212.http://www.ncbi.nlm.nih.gov/pubmed/15470213 Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. New Engl J Med 2004 Oct;351(15):1513-20.http://www.ncbi.nlm.nih.gov/ pubmed/15470214 Kantoff PW, Halabi S, Conaway M, et al. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the Cancer and Leukemia Group B 9182 Study. J Clin Oncol 1999 Aug;17(8):2506-13.http://www.ncbi.nlm.nih.gov/ pubmed/10561316 Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 1996 Jun;14(6):1756-64. http://www.ncbi.nlm.nih.gov/pubmed/8656243 Bahl A, Oudard S, Tombal B, et al; TROPIC Investigators. Impact of cabazitaxel on 2-year survival and palliation of tumour-related pain in men with metastatic castration-resistant prostate cancer treated in the TROPIC trial. Ann Oncol 2013 Sep;24(9):2402-8.http://www. ncbi.nlm.nih.gov/pubmed/23723295 de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010 Oct;376(9747):1147-54. http://www.ncbi.nlm.nih. gov/pubmed/208889 Currently, the potential use of these hormonal drugs is also being studied in other clinical indications, e.g. the use of enzalutamide prior to radical prostatectomy. Therapies targeting the receptors and signalling pathways in prostate carcinoma cells and endothelium provide a true opportunity for improving future prognosis in patients with CRPC. Further studies both in the field of immunology and cancer molecular biology should allow the identification of currently unknown therapeutic targets, and design new, promising systemic treatment strategies of both early and advanced prostate cancer. 13. References 1. Ferlay J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer, 2013.49(6): p. 1374-1403. 2. Siegel R, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin, 2012.62(4):p. 220-241 3. Gleason DF. Classification of prostatic carcinomas. Cancer Bożena Sikora-Kupis is an experienced oncologist with over 10 years of practice in the clinical research area as an investigator and medical monitor. With the broad scientific background and high-level education gained with the medical doctor degree and additional postgraduate diploma of specialty of oncology she has comprehensive knowledge of the industry. She practiced in the department of diagnostic oncology in the Institute of Oncology, Warsaw, Poland, with a focus on prostate cancer. At KCR she currently supports Medical Affairs Team with her extensive hands-on experience in managing clinical studies in complex indications. Email: [email protected] 4. Chemother Rep, 1966. 50(3):p. 125-128 Chi KN, Bjartell A, Dearnaley D, et al. Castration-resistant prostate cancer: from new pathophysiology to new treatment targets. Eur Urol 2009 Oct;56(4):594-605.http://www.ncbi.nlm.nih.gov/ pubmed/19560857 50 Journal for Clinical Studies 14. Volume 7 Issue 5