ADT, androgen deprivation therapy; LHRH, luteinizing hormone-releasing hormone. The suppression of the patient’s 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. 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 disease—for example, in the lung or liver—can 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 hormone–related 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 cancer–associated morbidity. Prostate cancer cells involved in the “vicious cycle” 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. In general, the time to the first skeletal-related event is at least 160 days. Zoledronic acid significantly decreases this time vs placebo and may even be useful in the hormone‑sensitive 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.
CRPC, castrate-refractory prostate cancer; PSA, prostate-specific antigen. 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 patient’s PSA level should be > 30 ng/mL and rising. Patients with PSA levels < 30 ng/mL usually do not need chemotherapy.
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 didn’t 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.
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
Crude annual incidence of prostate cancer in the European Union is 78.9/100 000 men
Mortality in the EU is 30.6/100 000 men/year
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
Risk Groups for Clinically Localized Prostate Cancer D’Amico A, et al. Oncology 2001; 15: 1049-1059; D’Amico 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%
Bone: most frequent site of prostate cancer metastasis
Favorable microenvironment for prostate tumor cells
Lesions first appear in axial skeleton, then appendicular skeleton
Main source of prostate cancer –associated morbidity
1. Roodman GD, et al. N Engl J Med. 2004;15:1655-1664. The “vicious cycle” of bone metastases and tumor cell growth in the bone marrow microenvironment  RANKL Tumor Cells PTHrP IL-6 PGE 2 TNF M-CSF Osteoclast Bone BMP PDGF FGFs IGFs TGF- β Osteoblast
Time to 1st SRE in Prostate Cancer Patients: Zoledronic Acid vs Placebo
Median, Days P Value
Zoledronic acid , 4 mg 488 .009
. Saad F, et al. J Natl Cancer Inst . 2004;96:879-882 No. at Risk Zoledronic Acid 4 mg 214 149 97 70 47 35 3 Placebo 208 128 78 44 32 20 3 Patients Without Event (%) 167 days 0 20 40 60 80 100 0 120 240 360 480 600 720 Days From Start of Treatment
ITT Age < 65 Age ≥ 65 Age ≥ 75 Pain no Pain yes KPS ≥ 80 KPS ≤ 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
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
Cabazitaxel: Tubulin-Targeting Drug Microtubule Inhibitor 1,2
Inhibits cell transport
Taxoid site ( b -tubulin) Docetaxel Cabazitaxel 1) Engels FK et al. Br J Cancer 2005;93:173-177; 2) Greenberger LM, Sampath D. Resistance to taxanes. In: Teicher BA, ed. Cancer Drug Discovery and Development: Cancer Drug Resistance . Totowa, New Jersey: Humana Press; 2006:329-358. Cabazitaxel Courtesy of sanofi-aventis Web site: http://www.oncology.sanofi-aventis.com/tcl/cp/en/layout.jsp?scat=4BF14C98-DE0C-4464-A2F1-6AA9C9D806A4 . Accessed March 22, 2010.
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
TROPIC: Primary Endpoint—OS 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
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
1195 patients who had previously received docetaxel were randomly assigned, in a 2:1 ratio, to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients).
de Bono JS, N Engl J Med. 2011 May 26;364(21):1995-2005.
Results de Bono et al. N Engl J Med. 2011 May 26;364(21):1995-2005 . Overall Survival Time to PSA Progression Progression-free Survival
de Bono et al. N Engl J Med. 2011 May 26;364(21):1995-2005 de Bono et al. N Engl J Med. 2011 May 26;364(21):1995-2005
Denosumab superior to zoledronic acid in delaying or preventing SREs in patients with CRPC and bone metastases
No significant difference between treatments in survival or disease progression
High incidence of adverse events in both arms
More patients who received zoledronic acid experienced acute phase reaction
More patients who received denosumab experienced hypocalcemia
ONJ rare but occurred in approximately twice as many patients with denosumab vs zoledronic acid
Denosumab potential treatment option for patients with CRPC and bone metastases
Fizazi K, et al. ASCO 2010. Abstract LBA4507.
CALGB 90401: Phase III Trial of Chemotherapy ± Bevacizumab in CRPC Dexamethasone 8 mg PO x 3 doses + Docetaxel 75 mg/m 2 on Day 1 of 21-day cycle + Prednisone 10 mg/day PO + Bevacizumab 15 mg/kg IV on Day 1 of 21-day cycle (n = 524) Patients with CRPC previously untreated with chemotherapy or biologic agents (N = 1050)
Stratified by 24-mo survival probability (< 10%, 10% to 29.9%, ≥ 30%), age (< 65 yrs ≥ 65 yrs), previous history of arterial events
Dexamethasone 8 mg PO x 3 doses + Docetaxel 75 mg/m 2 on Day 1 of 21-day cycle + Prednisone 10 mg/day PO + Placebo IV on Day 1 of 21-day cycle (n = 526) Kelly WK, et al. ASCO 2010. Abstract LBA4511 .
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
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 ≥ 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
ASCENT2: Docetaxel + DN-101 (Calcitriol Formulation) in Patients With mCRPC ASCENT Arm DN-101 45 μ 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.
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
Facing the Challenge of a Metastatic Disease in 2011 Metastatic Disease Docetaxel Resistant CRPC ADT resistant