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

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 10 000 Age 40-59 it is 1 in 103 Age 60-79 it is 1 in 8

INCIDENCE AND EPIDEMIOLOGY Approximately 11.6 percent of men will be diagnosed with prostate cancer at some point during their lifetime, based on 2012-2014 data

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

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

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

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.

CHAARTED Overal Survival High Volume: >=4 bone mets at least 1 Outside axial skeleton Or /and visceral mets p=0.0006 HR=0.60 (0.45-0.81) Median OS: ADT + D: 49.2 months ADT alone: 32.2 months

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 0.45-0.81) Updated data (ESMO 2016) HR=0.63 (95%CI 0.50-0.79) Updated Survival Analysis : Low Volume mHSPC Does not derive benefit from Addition of Docetaxel High volume disease HR=1.04 (95%CI 0.70-1.55) HR=0.60 (95%CI 0.32-1.13) Low volume disease

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.

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)

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

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

LATITUDE Trial

LATITUDE Trial

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

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)

mCRPC Prognosis and type of Metastases

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)

Rechallange Docetaxel in mCRPC

Treatment Options In CRPC after Docetaxel

Survival in mCRPC post chemotherapy treatment

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

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

Tools for early identification of primary resistance

Which treatment should we offer after progression

Which treatment should we offer after progression

Conclusion

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 - 2492 ng/ml

CT scan Images 6,5 cm 5 cm

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

After 6 cycles of chemotherapy plus ADT

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