Ct in pc
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1) Chemotherapy options for advanced prostate cancer have expanded significantly since the 1980s, with docetaxel and cabazitaxel approved based on trials showing improved survival. 2) Landmark trials in 2004 established docetaxel as providing a survival benefit over mitoxantrone for castration-resistant prostate cancer (CRPC). Subsequent trials tested docetaxel combinations without additional benefit. 3) New hormone therapies like abiraterone and enzalutamide provide alternatives or additions to chemotherapy for metastatic CRPC, but optimal sequencing remains unclear given new options.
![1984-1989
TREATMENT OPTIONS FOR
PROSTATE CANCER HAVE
SNOWBALLED AFTER A 6-YR
HIATUS
4
However, this rapid change has left many unanswered questions,
including the optimal selection and sequence of therapy
1. The Leuprolide Study Group. N Engl J Med. 1984;311:1281-1286. 2. Crawford ED, et al. N Engl J Med. 1989;321:419-424. 3. Tannock IF, et al. J Clin Oncol. 1996;14:1756-1764. 4. Saad F, et al. J Natl Cancer
Inst. 2002;94:1458-1468. 5. Petrylak DP, et al. N Engl J Med. 2004;351:1513-1520. 6. Tannock IF, et al. N Engl J Med. 2004;351:1502-1512. 7. de Bono JS, et al. Lancet. 2010;376:1147-1154. 8. Kantoff PW, et al.
N Engl J Med. 2010;363:411-422. 9. Fizazi K, et al. Lancet. 2011;377:813-822. 10. de Bono JS, et al. N Engl J Med. 2011;364:1995-2005. 11. Scher HI, et al. ASCO GU 2012. Abstract LBA1.
12. Parker C, et al. ASCO GU 2012. Abstract 8.
1996 2002 2004 .... 2010 2011
Mitoxantrone[3] Docetaxel*[5,6]
Sipuleucel-T*[8]
LHRH agonists*[1,2]
Abiraterone*[10]
Reversible AR
blockers[1,2]
Cabazitaxel*[7]
Denosumab[9]
Zoledronic Acid[4]
ENZALUTAMIDE [11]
Radium-223[12]
* Approved agent for PCa
Still not available in
market](https://image.slidesharecdn.com/ctinpc-150826042353-lva1-app6891/85/Ct-in-pc-4-320.jpg)
Ct in pc
- 1. EVOLVING APPROACHES FOR CHEMOTHERAPY FOR ADVANCED PROSTATE CANCER
- 2. PROSTATE CANCER ..GROWING PRESENCE! Incidence (ASR) Mortality (ASR) 5-yr prevalence Lung Ca 23.4% 20.7% 32.4% Prostate Ca 9.4% 3.8% 37.8% Incidence (ASR) Mortality (ASR) 5-yr prevalence Lung Ca 6.9% 6.3% 3.7% Prostate Ca 4.2% 2.7% 14.1% ASIA INDIA GLOBOCAN 2012 (IARC) Section of Cancer Information (29/8/2013) 2
- 3. TumorVolume M0 Diagnosis Primary PSA failure Second PSA failure = CRPC Androgen Deprivation Therapy CASTRATION-RESISTANT PROSTATE CANCER ..HETEROGENEOUS PROGRESSIVE DISEASE M1 173,000 100,000 64,000 Localized PCa Advanced PCa CRPC 3
- 4. 1984-1989 TREATMENT OPTIONS FOR PROSTATE CANCER HAVE SNOWBALLED AFTER A 6-YR HIATUS 4 However, this rapid change has left many unanswered questions, including the optimal selection and sequence of therapy 1. The Leuprolide Study Group. N Engl J Med. 1984;311:1281-1286. 2. Crawford ED, et al. N Engl J Med. 1989;321:419-424. 3. Tannock IF, et al. J Clin Oncol. 1996;14:1756-1764. 4. Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468. 5. Petrylak DP, et al. N Engl J Med. 2004;351:1513-1520. 6. Tannock IF, et al. N Engl J Med. 2004;351:1502-1512. 7. de Bono JS, et al. Lancet. 2010;376:1147-1154. 8. Kantoff PW, et al. N Engl J Med. 2010;363:411-422. 9. Fizazi K, et al. Lancet. 2011;377:813-822. 10. de Bono JS, et al. N Engl J Med. 2011;364:1995-2005. 11. Scher HI, et al. ASCO GU 2012. Abstract LBA1. 12. Parker C, et al. ASCO GU 2012. Abstract 8. 1996 2002 2004 .... 2010 2011 Mitoxantrone[3] Docetaxel*[5,6] Sipuleucel-T*[8] LHRH agonists*[1,2] Abiraterone*[10] Reversible AR blockers[1,2] Cabazitaxel*[7] Denosumab[9] Zoledronic Acid[4] ENZALUTAMIDE [11] Radium-223[12] * Approved agent for PCa Still not available in market
- 5. Until 2004, the therapeutic arena for these patients had remained stagnant, with no agent Having shown a survival gain in the CRPC setting. Two landmark publications changed the prostate cancer treatment landscape by providing ‘level-1 evidence’ that docetaxel-based chemotherapy led to prolongation in overall survival (OS). This was followed by the approval of cabazitaxel in 2010 on the basis of phase III data demonstrating its efficacy in patients pretreated with docetaxel. More recently, a number of next-generation androgen-directed agents (e.g. Abiraterone and
- 7. THE ENDOCRINE AXIS IN PROSTATE CANCER
- 8. COU-AA-302: STUDY DESIGN Ryan CJ. N Engl J Med 2013;368:138-48. Abiraterone 1000 mg daily Prednisone 5 mg BID (Actual n = 546) 8
- 9. RESULT Median OS = 34.7 months in abiraterone arm compared with 30.3 months in the placebo arm (HR = 0.81, P = .0033). 19% reduction in risk of death and reduced the risk of disease progression by 47% Significantly delayed the time to chemotherapy use = 27.1 months Median time to opiate use = 33.4 vs. 23.4 months, respectively; HR = 0.72., P = .0001) After a median follow-up of more than 4 years (49.2 months) * Ryan C, Smith M, Fizazi K, et al: Final overall survival analysis of COU-AA-302, a randomized phase 3 study of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy. ESMO 2014 Congress. Abstract 753O. Presented September 28,
- 10. DISEASE PROGRESSION ON HORMONAL THERAPY CHEMOTHERAPY
- 11. Berthold DR et al. J Clin Oncol 2008;26(2):242-245; Tannock IF et al. N Engl J Med 2004;351:1502-12. Median overall survival: 19.2 versus 17.8 versus 16.3 months 50% decrease in serum PSA: 45% versus 48% vs 32% Pain reduction: 35% versus 31% versus 22% Improved QoL: 22% versus 23% versus 13% Docetaxel q 3 wk + Prednisone R 1:1 Mitoxantrone + Prednisone PHASE III TAX-327 STUDY OF DOCETAXEL Docetaxel q wk + Prednisone N = 1,006 • Patients with mCRPC • Increasing PSA
- 12. Median survival Hazard (mos) ratio P-value Combined: 18.2 0.83 0.03 D 3 wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months ProbabilityofSurviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Eisenberger M, et al. ASCO Annual Meeting Proceedings. June 2004. Abstract 4. DOCETAXEL – CRPC OVERALL SURVIVAL—TAX 327
- 13. PHASE III TRIALS OF DOCETAXEL COMBINATIONS To date, no combination improves on docetaxel and prednisone Docetaxel+Prednisone vs Docetaxel Combined With: Status Results Bevacizumab Completed Negative VEGF-Trap (aflibercept) Completed Negative Atrasentan Completed Negative ZD4054 Completed Negative Dasatinib Completed Negative Lenalidomide Completed Negative Custirsen (OGX-011) Ongoing Pending, completion December 2013
- 14. www.clinicaltrials.gov; April 2013 (NCT00417079) De Bono JS et al. Lancet 2010;376(9747):1147-1154. Median overall survival: 15.1 versus 12.7 months Median progression-free survival: 2.8 vs 1.4 months Most common AE > Grade 3 with cabazitaxel: neutropenia, diarrhea Cabazitaxel + Prednisone (n = 378) R 1:1 Mitoxantrone + Prednisone (n = 377) PHASE III TROPIC STUDY OF CABAZITAXEL Eligibility (n = 755) • Patients with progressive mCRPC during or after treatment with a docetaxel- based regimen
- 15. ONGOING CABAZITAXEL-BASED COMBINATION TRIALS Schweizer MT et al. Asian Journal of Andrology (2014) 16,334–340
- 16. ADVERSE EVENTS As per NCCN, Docetaxel is a low-risk regimen (< 10% of FN) CRPC patients likely to receive chemotherapy agents at an elderly age when their performance status is poor and several comorbid conditions exist. As per several studies, if an elderly pt becomes febrile, a poorer outcome can be expected than in a younger pt because of excessive toxicities. NCCN guidelines categorize Docetaxel as a low-risk CT regimen with respect to development of FN, but Prostate Ca pts have a higher risk.Shigeta K et al. Int J Clin Oncol.2014 Sep 9. [Epub ahead
- 17. COMPARISON OF HORMONAL THERAPY VS CHEMOTHERAPY IN TERMS OF EFFICACY & SAFETY PROFILE Chemotherap y Hormonal Therapy
- 18. NEW ASCO/CCO MCRPC TREATMENT GUIDELINE INCORPORATES LATEST APPROVED DRUGS Offer abiraterone/prednisone (for men whose cancer has spread predominantly to the bones) in addition to ADT, as all three treatments are associated with improved survival, quality of life, and favorable balance of benefits and harms. (Recommendation level: strong) If considering chemotherapy, offer docetaxel/prednisone, but discuss side-effect risks. (Recommendation level: moderate) If a patient’s disease worsens despite treatment with docetaxel, consider offering cabazitaxel plus prednisone, but discuss side-effect risks. (Recommendation level: moderate) Consider offering mitoxantrone plus prednisone, accompanied by a discussion of limited clinical benefit and side-effect risk. (Recommendation level: weak) http://www.asco.org/guidelines/genitourinary
- 19. ASCO 2014 Plenary Session: Results From the CHAARTED Trial • Starting chemotherapy along with hormone therapy in men with newly diagnosed hormone- sensitive prostate cancer improved overall survival (OS) by more than 13 months in comparison with hormone therapy alone, a phase III study found. • The survival benefit was even greater in men with high-volume disease. mCRPC (N =790) • Arm A = six cycles of docetaxel + ADT • Arm B= ADT alone. 20 J Clin Oncol 32:5s, 2014 (suppl; abstr LBA2)
- 20. QUESTIONS UNANWSERED In this era of next-generation androgen-directed therapies (e.g. Abiraterone and Enzalutamide) the role of cytotoxic CT is becoming less clear although still has a distinct role. With so many new treatment options available, a number of questions remain. These include: o How to best sequence chemotherapy with these newer hormonal agents, o The clinical implication of cross-resistance between taxanes and androgen-directed agents o Which subsets of patients may benefit most from early use of chemotherapy.
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