Theoretical tips It has been reasoned that discontinuation of ADT in non orchiectomized patients may have detrimental effect on patients with CRPC as discontinuation of ADT can result in renewed release of testosterone and possible stimulation of remaining androgen sensitive elements. When exogenous testosterone therapy is administeredto to patients with symptomatic CRPC, adverse responses can be induced.
Taylor (JCO 1993) retrospective (341 pts) continued testicular androgen suppression was an important tpredictor of survival lduration (modest advantage) Hussain (JCO 1994) retrospective (205 pts) no obvious bi advantages in response to chemotherapy or survival for pts with continued gonadal suppression Lee (Am J Clin Oncol 2011) prospective (78 pts) brr (48.7% vs 66.7% p=0.27) PFS (4.9 mosvs5.0 mos p=0.57)
ADT is advocated to be used continuously, when chemotherapy is proposed p for CRPC
No robust evidences support the ADT maintenance during chemo Theoretical advantages could be postulated If well tolerated, ADT may be continued
1990 s scenario HT XRT PIB HT HT CHT RP HT CHT hormone res metastases
Mitoxantrone Tannock JCO 1996; 14:1756 MIT+PDN PDN Kantoff JCO 1999; 17: 2506 MIT+HC HC Better palliation with MIT Increased DFS with MIT No differences in survival
SWOG and TAX studies in HRPC
TAX327 original results Pr robability of Surviving 1.0 0.9 D 3 wkly 0.8 D wkly 0.7 Mitoxantrone 0.6 0.5 0.4 0.3 0.2 0.1 Median Hazard Survival Ratio P value Combined: 18.2 083 0.83 0.003003 D 3 wkly: 18.9 0.76 0.009 D wkly: 17.4 0.91 0.3 Mitoxantrone: 16.5 0 6 12 18 24 30 00 0.0 Months Tannock et al, N Engl J Med 2004; 351: 1502 1512 30 months
TAX327 confirmatory data of survivi ing Pro obability 1.0 0.8 0.6 0.4 0.2 Docetaxel q3w Docetaxel qw Mitoxantrone Median survival Hazard (months) ratio p value Docetaxel q3w: 19.2 0.79 0.004 Docetaxel qw: 17.8 0.87 0.086 Mitoxantrone 16.3 0.0 0 1 2 3 Years 4 5 6 7 30 months 48 months Berthold DR, et al. J Clin Oncol 2008;26:242 245
1990 s scenario HT XRT PIB HT HT CHT RP HT CHT hormone res metastases
2004 scenario HT XRT PIB HT HT CHT RP HT CHT hormone res metastases
M0 Maintain castration levels of testosterone Clinical trial Observation Further hormonal manipulation ASYMPTOMATIC M1 Maintain castration levels of testosterone SYMPTOMATIC only bone mets DOC Zoledronic acid SYMPTOMATIC visceral mets DOC
TAX327:Multivariate Cox proportional p hazards Variable Multivariate 95% CI p value HR Liver metastases 1.66 1.09 2.54 0.019 Number of metastatic sites (>2 vs 2) 1.63 1.23 2.15 0.001 Pain at baseline 1.48 1.23 1.79 <0.0001 Performance status ( 70 vs 80) 1.39 1.06 1.82 0.016 Progression type Measurable disease 1.37 1.10 1.70 0.005 Bone scan 1.29 1.06 1.57 0.010 Baseline PSA doubling time (<55 days vs 55 days) 1.19 0.99 1.42 0.066 Baseline log PSA (for every unit rise in log(psa) in ng/dl) 1.17 1.10 1.25 <0.001 Tumour grade (Gleason 8 or WHO 3 4 vs Gleason 7 or WHO 2 3) 1.18 0.99 1.42 0.069 Alkaline phosphatase (log scale) (per log unit rise, IU/L Haemoglobin) 127 1.27 115 1 1.15 1.39 0.001001 Haemoglobin (per unit rise, g/dl) 1.11 1.03 1.19 0.004 Armstrong et al Clin Canc Res 2007;13:6396 403
Prognostic Nomogram in CRPC Chemotherapy type Liver metastases Number of sites Pain at baseline Points 0 10 20 30 40 50 60 70 80 90 100 Weekly Doce (6) Q3 Doce Mitox (18) No Yes (23) <=2 >2 (22) No Yes (18) Karnofsky performance status >=80 <70 (15) Progression type: Measurable disease No Yes (15) Progression type: Bone scan progression No Yes (12) Tumour grade Baseline PSA (ng/ml) Alkaline phosphatase (IU/L) Haemoglobin (g/dl) Baseline PSA doubling time Total points Median survival time (mo) Low Grade 0 18 High Grade (8) 17 5 10 20 50 100 200 500 1000 2000 5000 10000 20000 50000 1 2 5 10 20 50 100 200 500 1000 2000 5000 16 15 3 6 (5) 1 2 (13) 14 >6 2 3 (12) <1 (19) 13 12 11 10 9 0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 1 yr survival probability 0.95 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 2 yr survival probability 5 yr survival probability 0.6 0.5 0.4 0.3 0.2 0.1 0.8 0.7 36 0.6 28 24 0.5 0.4 20 18 0.3 16 0.2 14 0.1 12 10 8 6 Armstrong et al Clin Canc Res 2007;13:6396 403
Simplified Model Risk factors Anemia (hemoglobin <13.0) laboratory data Progression by bone scan criteria clin. data Visceral metastases clin. data Presence of clinically significant pain (TAX 327 definition) clin. data Armstrong et al Clin Canc Res 2007;13:6396 403
Simplified Model
Simplified Model Low Risk: 0-1 risk factors Intermediate Risk: 2 risk factors High Risk: 3-4 risk factors
TAX 327 Survival: pain vs no pain/minimal Docetaxel q3w Docetaxel qw Mitoxantrone (n = 335) (n = 334) (n = 337) N O P A I N P A I N n 183 183 184 Median survival 23.0 21.1 19.8 Hazard ratio 0.73 0.95 p value 0.009 0.65 n 152 151 153 Median survival 14.9 15.1 12.8 Hazard ratio 0.85 0.8 p value 0.17 0.068 Berthold DR, et al. J Clin Oncol 2008;26:242 45
TAX 327 Survival: pain vs no pain/minimal Docetaxel q3w Docetaxel qw Mitoxantrone (n = 335) (n = 334) (n = 337) N O P A I N P A I N n 183 183 184 Median survival 23.0 21.1 19.8 Hazard ratio 0.73 0.95 p value 0.009 0.65 n 152 151 153 Median survival 14.9 15.1 12.8 Hazard ratio 0.85 0.8 p value 0.17 0.068 Berthold DR, et al. J Clin Oncol 2008;26:242 45
Pre Treatment PSA DT 1.00 0.75 PSADT >6 months PSADT 4 6 months PSADT 2 3 months PSADT 1 2 months PSADT <1 month Surviva al (%) 050 0.50 6 and 3-6 Med OS NYR mean OS 25 and 22.5 months 025 0.25 < 1 mo. 13.3 months 0 Log-rank p<0.001 0 5 10 15 20 25 30 35 40 45 50 Survival (months) Armstrong et al Clin Canc Res 2007;13:6396 403
Overall Survival according to bone pain intensity i and PSA doubling time (DT) No or minimal pain Mild pain Moderate or severe (n=79) (n=41) pain (n=25) Median OS 21.4 mos (16-26.8) 15 mos (8.2-21.8) 13.1 mos (9.8-16.1) PSA DT > 45 days 32.4 mos 18.4 mos 16.1 mos PSA DT < 45 days 16.5 mos 11.2 mos 8.3 mos OS at 1 year (%) 75% 56% 52% OS at 2 years (%) 43% 20% 20% OS at 3 years (%) 29% 11% 4% S. Oudard et al, 2009, 103, 12:1641-1646
M0 Maintain castration levels of testosterone Clinical trial Observation Further hormonal manipulation ASYMPTOMATIC M1 Maintain castration levels of testosterone SYMPTOMATIC only bone mets DOC Zoledronic acid SYMPTOMATIC visceral mets DOC
M0 Maintain castration levels of testosterone Clinical trial Observation Further hormonal manipulation ASYMPTOMATIC T slow growth Clinical trial Further hormonal manipulation Immunotherapy M1 Maintain castration levels of testosterone ASYMPTOMATIC fast growth SYMPTOMATIC only bone mets DOC Clinical trial DOC Zoledronic acid SYMPTOMATIC visceral mets DOC
Symptomatic CRPC patients should start CT as soon as possible Asymptomatic CRPC patients with aggressive features should start CT before PS worsening Asymptomatic CRPC patients with no aggressive features should be enrolled in clinical trials or should undergo watchful waiting (no advantages from further HTs)
New HTs CT Abiraterone Enzalutamide Cabazitaxel Cabazitaxel Doc cetaxel CT New HTs Cabazitaxel Cabazitaxel Abiraterone Enzalutamide New HTs New HTs Abiraterone Enzalutamide Enzalutamide Abiraterone 3 strategies t 6 combinations
Abiraterone Enzalutamide Enzalutamide Abiraterone Cabazitaxel Enzalutamide Cabazitaxel Abiraterone Cabazitaxel Cabazitaxel Abiraterone Enzalutamide Abiraterone Cabazitaxel Enzalutamide Cabazitaxel Enzalutamide Abiraterone
CT HT vs HT CT
CT HT vs HT CT Author sequence # pts brr mos Mezynski ABI DOC 35 26% 12.5 m Aggarwal* KETO DOC 277 61% 21.1 m Pond** KETO DOC 40 42.5% 17.0 m *no differences compared to 728 pts not treated with KETO ** better trend without significance compared to 180 pts not treated with KETO after adjustment
Outcomes with different sequences of cabazitaxel and abiraterone acetate following docetaxel inmetastatic castration resistant resistant prostate cancer (mcrpc). 113 pts assessed 77 pts 36 pts Caba Abi Abi Caba Median OS, TTF1, and TTF2 were analyzed by Kaplan Meier method from start of second line therapy post D to death for OS, to end of second line (TTF1), and to end of combined second and third line therapies (TTF2). Sonpavde et al. ESMO 2013, abs 2905
Outcomes with different sequences of cabazitaxel and abiraterone acetate following docetaxel inmetastatic castration resistant resistant prostate cancer (mcrpc). Sonpavde et al. ESMO 2013, abs 2905
Outcomes with different sequences of cabazitaxel and abiraterone acetate following docetaxel inmetastatic castration resistant resistant prostate cancer (mcrpc). Median TTF1 Median TTF2 DCA: 5.2 mos (95% CI 4.3 7) DCA: 10.4 mos (95% CI 9.2 12.1) DAC: 4.3 mos (95% CI 2.4 5.1) DAC: 7.1 mos (95% CI 5.6 8.1) Sonpavde et al. ESMO 2013, abs 2905
Sella a et al. ASCO GU 2013 Abs 186
Prognostic factors of survival in patients with metastatic castration resistant prostate cancer (mcrpc) treated with cabazitaxel: Sequencing mightmatter. matter. Angelergues et al. J Clin Oncol 31, 2013 (suppl; abstr 5063)
ENZ ABI vs ABI ENZ
ENZ ABI vs ABI ENZ
ENZ ABI vs ABI ENZ Author sequence # pts brr mpfs Loriot ENZ ABI 38 8% 2.7 m Noonan ENZ ABI 30 3% 3.8 m Schrader ABI ENZ 35 28.6% NR Bianchini ABI ENZ 39 12.8% 28m 2.8
A decision making flow chart proposal Gallardo et al. Crit Rev Oncol/Hemat 2013, in press
l id i No clear evidence supports one sequencing strategy vs another Preliminary and observational experiences suggest CABA before HTs seems to provide better survival outcomes HT HT activity seems to be limited To date the sequencing strategy should be tailored to the single patient profile (when it is possible, more lines seem better)
Sipuleucel T: Autologous APCs Cultured with Antigen Fusion Protein Recombinant Prostatic Acid Phosphatase (PAP) fusion antigen combines with resting antigen presenting cell (APC) APC takes up the antigen Antigen is processed and presented on surface of the APC Active T-cell Fully activated, the APC is now sipuleucel-t Inactive INFUSE PATIENT T-cell T-cells proliferate and attack cancer cells sipuleucel-t activates T-cells in the body The precise mechanism of sipuleucel-t in prostate cancer has not been established.
PSA TRICOM (PROSTVAC) is a vector based vaccine consisting of recombinant fowlpox boosts which contains transgenes for PSA and three co stimulatory molecules (TRICOM)
Randomized Phase 3 IMPACT Trial (IMmunotherapy Prostate AdenoCarcinoma Treatment) Asymptomatic or Minimally Symptomatic Metastatic Castration Resistant Prostate t Cancer (N=512) 2:1 Sipuleucel-T Q 2 weeks x 3 Placebo Q 2 weeks x 3 P R O G R E S S I O N Treated at Physician Discretion Treated at Physician Discretion and/or Salvage Protocol S U R V I V A L Primary Endpoint: Overall Survival Secondary Endpoint: Objective Disease Progression
P = 0.032 (Cox model) HR = 0.775 [95% CI: 0.614, 0.979] Median Survival Benefit = 4.1 Mos. (25.8 vs 21.7)
Metastatic Castration Resistant Prostate Cancer (N=125) 2:1 PROSTVAC Q 4 weeks x 6 Placebo Q 4 weeks x 6 Primary Endpoint: Progression Free Survival
Tumor Growth Rate Tumor Bu urden Time
Sipuleucel T: Logistics of Therapy Day 1 Day 2-3 Day 3-4 Leukapheresis sipuleucel-t is manufactured Patient is infused Apheresis Center Central Processing Doctor s Office COMPLETE COURSE OF THERAPY: COMPLETE COURSE OF THERAPY: Weeks 0, 2, 4
No clear evidences supports the advantages of an immunotherapy strategy for the largest majority of CRPC pts Economic and factory matters will limit its use in Italian context
parameters clinical issues performance status pain laboratory issues PSA bone biomarkers imaging issues CT scan bone scan PET scan (??)
objectives true PD to avoid late therapy stop (for on treatment pts) to avoid later therapy start (for off treatment pts) false PD to avoid early therapy stop (for on treatment pts) to avoid early therapy start (for off treatment pts)
on treatment regular PSA assessment biochemical PD requires radiological confirmation of progression to lead to therapy end regular clinical status assessment baseline and final instrumental assessment CT : on demand during the treatment HT : every 4 6 months
off treatment regular PSA assessment biochemical PD should be confirmed by radiological assessment clinical status should be regularly monitored to avoid a deterioration which prevents further treatments to detect symptoms appearance no regular instrumental follow up should be planned