1. SYSTEMIC THERAPY OF PROSTATE CANCER
Amiran Matitashvili M.D.
Medical Oncologist

2. INCIDENCE AND EPIDEMIOLOGY
Most common cancer detected in men
Second leading cancer cause of death in men
Incidence increases rapidly with age
Probability of developing prostate CA:
Age of 40 is 1 in
Age it is 1 in 103
Age it is 1 in 8

3. INCIDENCE AND EPIDEMIOLOGY
Approximately 11.6 percent of men will be diagnosed with prostate cancer at some point during their lifetime, based on data

4. Management of metastatic prostate cancer
Offer Surgical of Medical castration(LHRH agonist or antagonist)
Androgen suppression should be continued indefinitely in these patients
Offer Medical castration + Chemotherapy (CHARTEED Study ) to pts with High volume disease fit enough for Chemotherapy
Offer Medical castration alone with or without Chemotherapy to pts unfit for combination treatment

5. Management of metastatic prostate cancer
Hormone naïve disease
Continues ADT
ADT+
CHemotherapy
Castrate resistant disease
Abirateron, enzlutamid,Radium223,Docetaxel rechalange , Cabazitaxel

6. Hormone Sensitive Disease in prostate cancer
De Novo Metastatic
Biochemical Recurrence
Recurrent Metastatic Hormone Sensitive

7. Practice changing Date 2014 - 2017
Phase 3, multicenter, open label study
(N = 790)
CHAARTED
Patient Characteristics
R A N D O M I Z E D
Evaluate every 3 weeks while receiving docetaxel and at week 24 then
every 12 weeks
ARM A
ADT + Docetaxel 75 mg/m2 21 days for maximum 6 cycles
Diagnosis of prostate cancer with metastatic disease
ECOG PS 0-2
Prior adjuvant ADT was allowed if the duration o ≤24 months and progression >12 months after completion
Patients receiving ADT for metastatic disease were eligible if no evidence of progression and treatment commenced
≤120 days before randomization
Follow up for time to progression and overall survival
Chemotherapy at investigator’s discretion at progression
ARM B
ADT (androgen deprivation therapy alone)
Evaluate every 12 weeks 1
: 1
Stratification
Extent of metastasis: high volume vs low volume*
Age: ≥70 vs <70 years
ECOG: 0-1 vs 2
CAB > 30 days: yes vs no
SRE prevention: yes vs no
Prior adjuvant ADT: ≤12 vs >12 months
ADT allowed up to 120 days prior to randomization
Intermittent ADT dosing was not allowed
Standard dexamethasone premedication but no daily prednisone
*At study start only pts with high volume disease were to be enrolled. Study was amended to also include patients with low-volume disease.

8. CHAARTED Overal Survival
High Volume:
>=4 bone mets at least 1 Outside axial skeleton Or /and visceral mets
p=0.0006
HR=0.60 ( )
Median OS:
ADT + D: 49.2 months ADT alone: 32.2 months

9. CHAARTED UPDATED SURVIVAL POINTS TO HETEROGENEITY
First data (NEJM 2015)
High Volume:
>=4 bone mets at least 1 Outside axial skeleton Or /and visceral mets
HR=0.60 (95%CI )
Updated data (ESMO 2016)
HR=0.63 (95%CI ) Updated Survival Analysis :
Low Volume mHSPC
Does not derive benefit from Addition of Docetaxel
High volume disease
HR=1.04 (95%CI )
HR=0.60 (95%CI )
Low volume disease

10. STAMPADE
Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial
Evaluate every 3 weeks while receiving docetaxel and at week 24 then
every 12 weeks
Follow up for time to progression and overall survival
Chemotherapy at investigator’s discretion at progression
ARM BAT (androgen deprivation therapy alone)
Evaluate every 12 weeks
Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive nonmetastatic (N+M0) disease. Stratifi ed randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m²) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard logrank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models.

11. STAMPADE Docetaxel: Survival
SOC SOC+Doc
405 deaths
165 deaths
HR (95%CI) 0.76 (0.63, 0.91)
P-value 0.003
Non-PH p-value 0.51
Median OS (95% CI)
SOC SOC+Doc
67m (60, 91m)
77m (70, NR)
Restricted mean OS time
SOC SOC+Doc Diff (95%CI)
58.8m
63.4m
4.6m (1.8, 7.3m)

12. Meta-analysis OS: ADT + docetaxel in M1 HSPC
Results based on 2993 men/2198 events
10% absolute improvement in survival (40% to 50%) at 4 years

13. Docetaxel in mHSPC Conclusions
Docetaxel added to ADT in hormone naïve metastatic disease
with “high volume” prolongs survival (CHAARTED)
Docetaxel exhibits an overall survival benefit in hormone sensitive metastatic disease in two studies and does not in one
De novo metastatic disease derives consistent benefit in both
positive studies
Marrow Toxicity remains a concern

14. LATITUDE Trial

15. LATITUDE Trial

16. CRPC - Definition Castarte serum Testosteron <50ng/ml or 1,7nml/L
3 consecutive rise of PSA , resulting in 2 increases over nadir
Radiological progression : >2 new bone lesion on scan; symptomatic progression is not sufficient alone to diagnose CRPC

17. denosumab/bisphosphonates)
CRPC
Death
Local therapy
mCRPC
asymptomatic
(failed ADT)
mCRPC
mildly
symptomatic
mCRPC
post-
docetaxel
Hormone
sensitive
mCRPC
symptomatic
ADT
Abiraterone
Enzalutamide
Abiraterone
Enzalutamide
Cabazitaxel
mHSPC ADT +
Docetaxel
Docetaxel
Radium 223
mHSPC ADT +
Abiraterone 2017
Sipuleucel-T
supportive care (eg
denosumab/bisphosphonates)

18. mCRPC Prognosis and type of Metastases

19. Number of drugs are available for mCRPC
Agents
Survival prolongation on average 3.5 months in mCRPC
Most trials to date focused on drug development irrespective of risk category
Giving Perspective :
Docetaxel
Cabazitaxel
Sipeuleucel-T
Abiraterone
Enzalutamide
Rad 223
Pembrolizumab for MSI (5-10% of PCa)

20. Rechallange Docetaxel in mCRPC

21. Treatment Options In CRPC after Docetaxel

22. Survival in mCRPC post chemotherapy treatment

23. Short Response to 1 st hormonal therapy predicts weak response to Enzalutamide

24. Primary resistance to AR –targeted agents
 Enzalutamide demonstrated a significant improvement in the primary endpoint of overall survival (OS) with a hazard ratio (HR) of 0.63 (95% confidence interval [CI] 0.53, 0.75; p < 0.001); the median OS was 18.4 months in the enzalutamide group versus 13.6 months in the placebo group
The median overall survival was 14.8 months in the Abiraterone acetate group and 10.9 months in the placebo group

25. Tools for early identification of primary resistance

26. Which treatment should we offer after progression

27. Which treatment should we offer after progression

28. Conclusion

29. Case PSA - 2492 ng/ml Patient 69 y old
Complained : increasing fatigue, mild back pain, palpable lesion in his right neck , contender, fixed
Biopsy of neck was done: Histology and IHC confirmed metastases of prostate adenocarcinoma
CT scan : extensive bone metastases and lymph node involment
PSA ng/ml

30. CT scan Images
6,5 cm
5 cm

31. Treatment
Patient started treatment with ADT ( LHRH agonist – Gozerelin 3,6 mg s.c. injection every 28 plus Bicalutamid 3 weeks
Docetaxel 75mg/m2 every 3 weeks
6 cycles of chemotherapy was done with ADT
No seriosu advers event

32. After 6 cycles of chemotherapy plus ADT

33. Follow up Patient is asymptotic at this moment Fully active
PSA = 13 ng/ml
Continues ADT Gozerelin 3,6 mg s.c. injection every 28 d and started zometa 4 mg every month infusions