A. Shamseddine - Prostate and renal cancer - State of the art and update on systemic therapy of prostate cancer
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A. Shamseddine - Prostate and renal cancer - State of the art and update on systemic therapy of prostate cancer
- 1. Prostate Cancer State of the art in Management Ali Shamseddine, MD Professor of Medicine Head, Hematology and Oncology Division American University of Beirut Medical Center Amman Oct.2011
- 3. Clinical States of Prostate Cancer Clinically localized Biochemically relapsed Non-metastatic, hormone- responsive Metastatic, hormone- responsive Non- metastatic CRPC Metastatic CRPC 10 -15 years + Death from co-morbidities Prostate cancer- specific death From George D. ASCO Prostate 2007
- 4. Risk Groups for Clinically Localized Prostate Cancer DāAmico A, et al. Oncology 2001; 15: 1049-1059; DāAmico A, et al. JAMA 1998; 280: 969-974. Risk group Characteristics Expected 10-yr PSA failure-free survival Low PSA < 10 and Gleason score < 7 and AJCC stage T1c, T2a 80 - 85% Intermediate PSA = 10 - 20 or Gleason score = 7 or AJCC stage T2b 50 - 60% High PSA > 20 or Gleason score > 7 or AJCC stage T2c, T3 30 - 40%
- 6. Secondary Hormonal Therapies? 1 Small EJ, et al. J Urol 1997; 157: 1204ā1207. 2 Orlando M, et al. Ann Oncol 2000; 11: 177ā181. 3 Weitzman AT, et al. J Urol 2000; 163: 834-837 4. Lucas A, Petrylak DP, et al. J Urol 2006; 176: S72 Secondary hormonal therapies have not been shown to improve survival 4 ā PSA >50% Ketoconazole (+HC) 62% 1 Estrogens 80% 2 Dexamethasone 61 - 0% 1,3
- 9. Beer T, modified Disease Burden Median Survival Chemotherapy Indicated Rising PSA only ~4 years ? ? Asymptomatic metastases (limited) ~18 to 24 months Individualize Asymptomatic metastases (extensive) ~18 months Yes Symptomatic metastases ~9 to 16 months Yes
- 13. Chemotherapy
- 18. SWOG 9916 Overall Survival HR=0.80 (95% CI: 0.67ā0.97); p=0.02 TaxotereĀ® + estramustine Mitoxantrone + prednisone No. at risk 338 336 No. of deaths 217 235 Median OS (months) 17.5 15.6 Months 0 0.2 0.4 0.6 0.8 1.0 0 12 24 36 48 TaxotereĀ® + estramustine Mitoxantrone + prednisone Probability of surviving 0 0.2 0.4 0.6 0.8 1.0 0 12 24 36 48 Petrylak et al, N Engl J Med 2004; 351: 1513-1520 HR: 0.80 (95% CI 0.67, 0.97), p = 0.01
- 19. Overall Survival Every 3 week Docetaxel 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 ā ā Months Probability of Surviving 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 Tannock I, N Engl J Med, 2004 Oct 7;351(15):1502-12 18.9 mos 16.4 mos
- 20. TAX 327 3-yr Updated Survival Analysis Berthold D et al. J. Clin. Oncol. 2008; 26:242-45 Median survival Hazard (mos) ratio P-value D 3 wkly: 19.3 0.79 0.005 D wkly: 17.8 0.87 0.10 Mitoxantrone 16.3 ā ā
- 21. Overall survival by 30% PSA decline Armstrong A J, et al. J Clin Oncol 2007, 26: 3965-3970
- 22. Overall survival by PSA normalization 0 0.25 0.50 0.75 1.00 0 5 10 15 20 25 30 35 40 45 50 PSA not normalized (n=743 ) PSA normalized (n=115) HR 0.30 (95% CI: 0.23ā0.39) p<0.0001 Proportion surviving (%) Survival Time (months) Armstrong A J, et al. J Clin Oncol 2007, 26: 3965-3970
- 23. TAX 327 Survival by PSADT 0.25 0.50 0.75 1.00 Survival (%) 0 5 10 15 20 25 30 35 40 45 50 Survival (months) Log-rank p<0.001 0 Armstrong A J, et al. Clin Cancer Res 2007; 13 (21):6396-6403 PSADT <1 month PSADT 1ā2 months PSADT 4ā6 months PSADT >6 months PSADT 2ā3 months
- 24. ITT Age < 65 Age ā„ 65 Age ā„ 75 Pain no Pain yes KPS ā„ 80 KPS ā¤ 70 Docetaxel Mitoxantrone TAX 327: Survival Benefit Across All Subgroups Hazard ratio in favor of Improved survival in asymptomatic,symptomatic and elderly Berthold DR, et al. ASCO Prostate 2007 ; abstract # 147
- 25. Chemotherapy for mCRPC SWOG 99-16 TAX 327 update Docetaxel PSA Response Rate 50% 45.4% Mitoxantrone PSA Response Rate 27% 32% Docetaxel Overall Survival 18 mos 19.3 mos Improvement in Survival 2 mos 3 mos Hazard Ratio vs M+P 0.80 0.79 p value 0.01 0.005
- 27. Facing the Challenge of CRPC
- 29. TROPIC: Randomized, Prospective, Open-Label, Multinational Phase III Trial Cabazitaxel* 25 mg/m 2 IV q3w + Prednisone 10 mg/day PO for 10 courses (n = 378) Mitoxantrone 12 mg/m 2 IV q3w + Prednisone 10 mg/day PO for 10 courses (n = 377) Patients with metastatic CRPC progressing on docetaxel (N = 755) * Cabazitaxel group premedicated with antihistamine, steroid, and H 2 antagonist IV at least 30 min prior to each cabazitaxel dose. Antiemetic prophylaxis administered as necessary in either arm. Stratified by ECOG performance score (0,1 vs 2), and measurable vs nonmeasurable disease De Bono JS, et al. ASCO 2010. Abstract 4508.Lancet 2010;1147-54
- 30. TROPIC: Primary EndpointāOS Updated ITT Analysis De Bono JS, et al. ASCO 2010. Abstract 4508. 100 OS (%) 80 60 40 20 0 0 6 12 18 24 30 Mos MP CBZP 377 299 195 94 31 9 378 321 241 137 60 19 Patients at Risk, n MP CBZP Censored Combined median follow-up: 13.7 mos 28% reduction in risk of death MP CBZP Median OS, Mos 12.7 15.1 HR 0.72 95% CI 0.61-0.84 P value < .0001
- 31. TROPIC: Progression-Free Survival De Bono JS, et al. ASCO 2010. Abstract 4508. PFS (%) 0 6 9 12 15 21 Mos MP CBZP 377 55 30 12 9 4 378 92 55 18 6 1 MP CBZP Censored Combined median follow-up: 13.7 mos 25% reduction in risk of progression 3 117 168 18 6 1 100 80 60 40 20 0 Patients at Risk, n MP CBZP Median PFS, Mos 1.4 2.8 HR 0.75 95% CI 0.65-0.87 P value .0002
- 35. Facing the Challenge of CRPC
- 36. Ā
- 37. Preparation
- 38. Mechansim of Action Courtesy of Provenge website: http://www.provenge.com/hcp/mechanism-of-action.aspx Accessed on August 15, 2011
- 41. Facing the Challenge of CRPC
- 42. Facing the Challenge of CRPC
- 43. Ā
- 45. Results de Bono et al. N Engl J Med.Ā 2011 May 26;364(21):1995-2005 . Overall Survival Time to PSA Progression Progression-free Survival
- 46. de Bono et al. N Engl J Med.Ā 2011 May 26;364(21):1995-2005 de Bono et al. N Engl J Med.Ā 2011 May 26;364(21):1995-2005
- 47. Ā
- 50. Denosumab vs Zoledronic Acid: Time to First On-Study SRE Fizazi K, et al. ASCO 2010. Abstract LBA4507. 1.00 0.75 0.50 0.25 0 0 3 6 9 12 15 18 21 24 27 Proportion of Subjects Without SRE Study Mo Denosumab Zoledronic acid HR: 0.82 (95% CI: 0.71-0.95; P = .0002 noninferiority; P = .008 superiority) KM Estimate of Median, Mos 20.7 17.1 Patients at Risk, n Zoledronic acid Denosumab 951 950 733 758 544 582 407 472 299 361 207 259 140 168 93 115 64 70 47 39
- 53. CALGB 90401: Overall and Progression-Free Survival Kelly WK, et al. ASCO 2010. Abstract LBA4511. Outcome, Mos (Range) Bevacizumab (n = 524) Placebo (n = 526) HR (95% CI) P Value Median OS 22.6 (21.1-24.5) 21.5 (20.0-23.0) 0.91 (0.78-1.05) .181 Median PFS 9.9 (9.1-10.6) 7.5 (6.7-8.0) 0.77 (0.68-0.88) < .0001
- 54. Addition of Bevacizumab Significantly Improved Other Clinical Endpoints Kelly WK, et al. ASCO 2010. Abstract LBA4511. Outcome, % (95% CI) Bevacizumab (n = 524) Placebo (n = 526) P Value ā„ 50% decline in PSA 69.5 (65.2-73.5) 57.9 (53.3-62.3) .0002 Objective response 53.2 (46.8-59.6) 42.1 (36.2-48.2) .0113
- 55. ASCENT2: Docetaxel + DN-101 (Calcitriol Formulation) in Patients With mCRPC ASCENT Arm DN-101 45 Ī¼ g PO on Days 1, 7, 14 + Docetaxel 36 mg/m 2 IV on Days 2, 8, 15 + Dexamethasone PO 12, 3, 1 hrs before docetaxel 28-day cycles (n = 477) Patients with progressive, metastatic CRPC (N = 953) Control Arm Prednisone 5 mg PO BID Docetaxel 75 mg/m 2 IV on Days 1, 22 Dexamethasone PO 12, 3, 1 hrs before docetaxel 21-day cycles (n = 476) 30 wks Scher HI, et al. ASCO 2010. Abstract 4509.
- 56. OS Shorter With ASCENT vs Control Treatment Scher HI, et al. ASCO 2010. Abstract 4509. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 5 10 15 20 25 30 35 Mos From Enrollment Proportion Surviving Log rank P = .002 Control (n = 476; 137 died) ASCENT (n = 477; 174 died) Median follow-up for patients alive: 11.7 mos
- 57. Facing the Challenge of a Metastatic Disease in 2011 Metastatic Disease Docetaxel Resistant CRPC ADT resistant
- 58. Ā
Editor's Notes
- ADT, androgen deprivation therapy; LHRH, luteinizing hormone-releasing hormone. Ā The suppression of the patientās testosterone through either orchiectomy or a luteinizing hormone-releasing hormone (LHRH) agonist is the sine qua non by which we determine whether a patient is castrate refractory. Patients must be castrate. Therefore, if we are dealing with a patient, the first thing we think about is what is the testosterone level. Is the patient castrate (testosterone < 50 ng/mL), and did he undergo orchiectomy or is he on an LHRH agonist? It is important to remember that sometimes LHRH agonists do not fully lower the testosterone < 50 ng/mL. If the answer to both of these questions is yes, we generally define the patient as being castrate resistant.
- ADT, androgen-deprivation therapy; CRPC, castrate-resistant prostate cancer; PSA, prostate-specific antigen. Ā Nearly all patients will develop resistance to androgen deprivation therapy. A rising PSA level is usually the harbinger of this event, but nodal visceral metastases or growth of measurable diseaseāfor example, in the lung or liverācan also be associated with resistance. Therefore, prostate cancer is defined as castrate resistant when there is growth despite castrate levels of testosterone. The Prostate Cancer Trials Working Group has defined criteria for when to treat these patients. Patients typically have at least 2 bone lesions, recurrence of primary tumor after surgery, or new lesions at other sites of metastases.
- Individualize (Experimental therapy)
- BMP, bone morphogenetic proteins; FGFs, fibroblast growth factors; IGF, insulin-like growth factor; IL, interleukin; M-CSF, macrophage colony-stimulating factor; PDGF, platelet-derived growth factor; PGE2 , prostaglandin E2 ; PTHrP, parathyroid hormoneārelated peptide; TGF, transforming growth factor. Prostate cancer cells favor growth in the bone; metastases appear first in the axial skeleton, then in the appendicular skeleton. Bone metastases are the primary cause of prostate cancerāassociated morbidity. Prostate cancer cells involved in the āvicious cycleā produce growth factors for osteoblasts, which in turn produce RANK ligand that in turn stimulates osteoclasts. Stimulated osteoclasts release factors that further stimulate proliferation of prostate cancer cells. This process can be partially interrupted by bisphosphonates, with other agents in development.
- SRE, skeletal-related event. Ā In general, the time to the first skeletal-related event is at least 160Ā days. Zoledronic acid significantly decreases this time vs placebo and may even be useful in the hormoneāsensitive phase. Zoledronic acid is, therefore, recommended by experts and physicians for all prostate cancer patients.
- Chemotherapy is the mainstay in prostate cancer treatment for patients who fail hormonal therapy. Ā
- CRPC, castrate-refractory prostate cancer; PSA, prostate-specific antigen. Ā Patients receive chemotherapy when there is nodal spread with no evidence of bone or visceral metastases. Symptomatic patients with retroperitoneal lymph nodes involvement should receive chemotherapy, although the need is not urgent. Prostate cancer patients who have bone disease with pain should receive chemotherapy as soon as possible. Visceral metastases, liver or otherwise, are also typical indications for chemotherapy. Patients who have a locally progressing tumor without metastases or who have a rising PSA level with no evidence of metastases should not receive chemotherapy (although they may benefit from local radiotherapy). A rule of thumb is that the patientās PSA level should be > 30 ng/mLĀ and rising. Patients with PSA levels < 30 ng/mL usually do not need chemotherapy. Ā
- Recently, however, two landmark Phase III trials with docetaxel-based therapy (TAX 327 and SWOG 9916) have shown a survival benefit with chemotherapy for patients with metastatic androgen-independent prostate cancer (AIPC), prompting a change in patterns of care.
- The present analysis confirms previous findings that survival of men with mHRPC is significantly longer following treatment D3/P than with M/P. The updated survival analysis confirms significantly better survival for D3P but not D1P as compared to MP Median difference in survival for D3P compared to MP is 3 months Similar hazard ratios among subgroups is evidence for robust data About 15% of pts respond to M after D, and about 30% respond to D after M
- Survival benefit of docetaxel was consistent across subgroups
- Chemotherapy for HRPC Remarkable consistency SWOG didnāt meet its expectations powered to detect a have a 33% improvement in survival but found a 20% improvement. even less would be clinically significant (none in past) but a trial powered to detect a 10% improvement would require > 2000 pts. The larger TAX study
- As previously mentioned, cabazitaxel is a tubulin-targeted agent and similar to docetaxel, the mechanism of action of cabazitaxel also promotes tubulin assembly and stabilizes microtubules against depolymerization. Specifically, it works by promoting tubulin polymerization, stabilizing the formed microtubules, and preventing their depolymerization, thereby inhibiting mitotic progression leading to tumor cell death: Inhibition of microtubule depolymerization and cell division; 2) Cell cycle arrest in the G2/M phase; 3) Inhibition of tumor cell proliferation Unlike other taxane compounds however, cabazitaxel has been shown to have poor affinity for the membrane-associated P-gp efflux pump and may be useful for treating multidrug-resistant tumors. To better understand this unique feature, I will next outline mechanisms of resistance to taxanes and describe the role cabazitaxel may have within this context.
- AE, adverse event; TROPIC, Treatment of Hormone-Refractory Metastatic Prostate Cancer Previously Treated With a Taxotere- Containing Regimen; TTP, time to progression.