X, Y and Z of Prostate Cancer Dr Tony Michele Medical Oncologist
Prostate cancer Epidemiology Current EUA (et al) guidelines on Advanced Prostate Cancer Current clinical management in specific scenarios (cases) Met CRPC Met Non Castrate Disease High tumour burden at diagnosis M0 CRPC search for oligometastatic disease Pivotal Trials
Histopathology >95% adenocarcinoma Gleason score; Sum of the 2 most common cell type in biopsy Max score is 5+5=10 Grade; Low 2-4 Intermediate 5-7 High 8-10
RP Case 1 70yo PCa Dx 11/3/10 based on PSA Biopsy Gleason 4+4=8 WBBS normal Definitive RT PSA 5/12 = 0.6 PSA 2/14 = 28.5 Lucrin commenced PSA 6/14 = 0.18 PSA 8/15 = 1.25 added Anandron/Cosudex PSA 3/17 = 218 WBBS positive Please review
RP Case 1 issues Is he castrate resistant? What is his prognosis without systemic treatment? Management decisions RT Systemic treatment options Chemotherapy AR modulation Bone protection
CRPC is defined as castrate serum testosterone <50 ng/dl or 1.7 nmol/l plus one of the following types of progression: Biochemical progression: Three consecutive rises in PSA 1 wk apart, resulting in two 50% increases over the nadir, and PSA >2 ng/ml Radiologic progression: The appearance of new lesions: either two or more new bone lesions on bone scan or a soft tissue lesion using the Response Evaluation Criteria in Solid Tumours
Chemotherapy With Mitoxantrone Plus Prednisone or Prednisone Alone for Symptomatic Hormone-Resistant Prostate Cancer: Canadian trial 1996 PCPA 2017 Tony Michele 161 symptomatic patients Randomised M (12mg/m2 q3weeks) +P (5mg bd) vs P Primary endpoint palliative response 29% vs 12% (p=0.01) Other results Longer duration of palliation 48 vs 18 weeks (p<0.001) Quality of life improvement Well tolerated Cardiac toxicity 5 No change in OS Tannock, IF J Clin Oncl 14 1756-1764 1996
Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer Ian F Tannock et al TAX 327 2004 PCPA 2017 Tony Michele Phase 3, 1006 patients with mhrpc Docetaxel 75mg/m2 q 3weeks + Pred Docetaxel 30mg/m2 weekly + Pred Mitoxantone 12mg/m2 3 weekly + Pred Primary endpoint OS Secondary endpoints Pain PSA levels Quality of Life NEJM 351;15 1502-12 Oct 7 2004
TAX 327 Median OS T q3w 18.9mo MP 16.5mo
TAX 327 T q 3 weekly T q weekly MP >50% decrease PSA 48% 45% 32% Pain improvement 31% 35% 22% Quality of life 23% 22% 13% Adverse events 26% 29% 20%
Docetaxel and Estramustine Compared with Mitoxantrone and Prednisone for Advanced Refractory Prostate Cancer Daniel P Petrylac et al SWOG 9916 2004 PCPA 2017 Tony Michele Phase 3 trial 674 patients Docetaxel + Estramustine Mitoxantrone + Prednisolone Primary endpoint Overall Survival DE(17.5 mo) Vs MP (15.6 mo) AE 15% grade 3 or higher in DE NEJM 351; 1513-1520 Oct 7 2004
SWOG 9916 PCPA 2017 Tony Michele
A Randomized, Placebo-Controlled Trial of Zoledronic Acid in Patients With Hormone-Refractory Metastatic Prostate Carcinoma Fred Saad et al 2002 PCPA 2017 Tony Michele Bisphosphonate Phase 3 double blind trial 643 patients bone mets Zometa 4mg IV 3 weekly for 15 months Zometa 8mg IV 3 weekly (reduced to 4mg due to renal toxicity) Placebo IV 3 weekly Primary objective Proportion of patients experiencing 1 or more SRE Fracture, spinal cord compression, surgery or RT to bone or change of antineoplastic treatment for bone pain
Zometa - Results Approx 1/3 patients completed trial Proportion of patient experiencing an SRE Significantly reduced in Z 4mg (33.2%) v Placebo (44.2%) Median time to 1 st SRE Placebo Zometa 8/4mg Zometa 4mg 321 days 363 days not reached Better pain control (NS) No changes in disease control, QoL scores, Performance status AE Flu like symptoms, hypocalcaemia, renal impairment in 8mg dose. No ONJ
Zometa PCPA 2017 Tony Michele
Targeting Bone Denosumab (Xgeva) PCPA 2017 Tony Michele Human monoclonal antibody targeting RANK L RANK ligand regulates osteoclasts International randomised double blind phase 3 study 1901 men with bony met mcrpc Primary endpoint Non inferiority to zometa Time to first on study SRE Secondary endpoint Time to first or subsequent on study SRE
Skeletal related event Fracture, Radiation to bone, Surgery to bone Spinal cord compression 1:1 randomisation Denosumab 120mg subcutaneosly Q4 weeks Zometa 4mg IV infusion (15min) Q4weeks
Results 1 st SRE HR 0.82 >1 st SRE HR 0.82 AE ONJ 22 (D) 12(Z) Overall survival and time to disease progression unchanged
ONJ PCPA 2017 Tony Michele
RP Case 1 management check testosterone level continue Lucrin withdraw anti androgen OPG and dental review Urgent RT review to treat sacrum Offered Docetaxel after completion of RT if not tolerant or unsuitable then could offer AA or Enza Xgeva if possible on progression 2nd line cabazitaxel, Enza or AA
JH Case 2 56 yo married man, referred acutely via Emerg with significant back pain. PMHx hypercholesterolaemia, otherwise fit MRI spine; bony lesions, enlarged pelvic and retroperitoneal nodes no urinary symptoms, hard mass on DRE LHD 603 (120-250), ALP 204 (35-110) PSA 3768
JH Case 2 issues Diagnosis Core biopsy of paraaortic nodes - Prostate adenocarcinoma Gleason 4+4 = 8 de novo metastatic disease Pain management Systemic therapy options; ADT (LHRH analogues vs antagonists) +/- Chemotherapy Radiotherapy
JH Case 2 treatment Admitted for analgesia titration Firmagon (degarelix) LHRH antagonist commenced Docetaxel x 6 cycles PSA nadir 0.94 10/15 persistent pain in low spine despite chemotherapy so pall RT
JH Case 2 Developed CRPC April 2016 Rapid PSA DT Commenced Enzalutamide (Xtandi) Denosumab (Xgeva) after dental review PSA DT improved but PSA climbing clinically well Jan 2017 new bone mets from baseline and L hip pain Commenced Cabazitaxel
The Oncologist 2013, 18:558-567. PCPA 2017 Tony Michele
GN Case 3 60 yo 2012 dx PCa abnormal DRE biopsy Gleason 4+3=7 adenocarcinoma PSA 2.9, staging negative Brachytherapy as definitive treatment PSA nadir to 1.9 PSA 4 by 6/14, MRI prostate heterogeneous gland but no focally suspicious areas repeat prostate biopsy Gleason 8 confirmed Referred for salvage surgery, CT/WBBS staging negative PSMA PET - low volume metastatic disease
GN Case 3 issues not offered radical surgery Role of PSMA PET Guidelines suggest limited value in PSA < 1.0 Treatment of oligometastatic disease 3 or fewer non-castrate met lesions outside of the prostate Metastasis directed therapy Treatment of asymptomatic met disease ADT vs ADT/chemotherapy
SB Case 4 68 yo, PHx GORD, Type 2 DM Metastatic PCa 2013, PSA 8, Gleason 4+4=8 Commenced Lucrin July 2016 - PSA 139 Cosudex added, no response Seen Oct 2016 PSA 445, testosterone < 0.09 nmol/l Leucoerythroblastic blood picture; Hb 83, Wcc 6.8 Plt 28 LDH 418, Ca++ 2.7 CT multiple bone and nodal metastases
SB Case 4 management Analgesia for back pain Commenced Xtandi and Xgeva Transfused Over the following 4 weeks Plt 87, still anaemia At 8 weeks Plt 229, Hb 92, PSA 99 March 2017 PSA rise but normal FBE Commenced Docetaxel
Conclusions mcrpc No longer considered a chemotherapy resistant disease Available 2 nd line drugs post docetaxel Cabazitaxel Abiraterone or Enzalutamide Sequencing and PBS access to be sorted Where does Immunotherapy fit into the schema? Increasing understanding of resistance mechanisms Current trials Abi/Enza + ADT in de novo met disease Lutetium labelled PSMA (Peter Mac)