Thomas de los Reyes PGY 1 Department of Urologic Sciences University of British Columbia. Meet Mr. S

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1 Thomas de los Reyes PGY 1 Department of Urologic Sciences University of British Columbia Meet Mr. S 74 M admitted for back pain X-ray: sclerotic lesions along spine PSA 800 Nuclear Medicine Bone Scan 1

2 Prostate Cancer Canadian Statistics The Spectrum of Bone Complications in Patients with Prostate Cancer Castration Induced: Osteopenia Osteoporosis Bone Metastases Pathologic Fractures 2

3 Objectives 1. Review the physiological aspects of bone homeostasis and discuss the pathophysiology of skeletal metastasis in prostate cancer 2. Discuss the impact that volume of metastasis has on patient outcomes 3. Evaluate the current standard of diagnosing metastasis and a possible alternative 4. Provide an overview of the different management options for bone metastasis in castrate resistant prostate cancer Bone Physiology: Overview 3

4 Outline 1. Review the physiological aspects of bone homeostasis and discuss the pathophysiology of skeletal metastasis in prostate cancer Role of osteoblasts and osteoclasts Physiologic changes in disease 2. Discuss the impact that volume of metastasis has on disease and patient outcomes STAMPEDE Trial SWOG-9346 Trial CHAARTED Trial 4

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7 SWOG-9346 Trial: Study Design INDUCTION REGISTRATION Newly diagnosed metastatic prostate cancer PSA 5 ng/ml INDUCTION ADT: LHRH (Goserelin) + antiandrogen (bicalutamide) x 7 mos If PSA 4 ng/ml at 6 and 7 mos R A N D O M I Z E CADT: LHRH AA IADT: PSA No ADT PSA PSA PSA * PSA LHRH AA * CADT LHRH AA Disease progression Disease progression *Duration of off-treatment interval and switch to CADT based on PSA and clinical progression: ADT resumed if PSA rose to 20 ng/ml or returned to baseline in those with PSA < 20 ng/ml at enrolment HussainM, et al. N EnglJ Med 2013;368:

8 SWOG Trial: Median Survival No. of Deaths Median Survival (yr) Survival (%) Continuous therapy Intermittent therapy HR % CI ( ) Years since randomization HussainM, et al. N EnglJ Med 2013;368: SWOG Trial: Median Survival According to Extent of Disease Minimal disease Extensive disease Survival (%) Continuous therapy Intermittent therapy HR % CI ( ) Years since randomization Median No. of Survival Deaths (yr) Survival (%) Continuous therapy Intermittent therapy Years since randomization Median No. of Survival Deaths (yr) Minimal disease = disease confined to the spine, pelvic bones, or lymph nodes Extensive disease = disease present in the ribs, long bones, or visceral organs HussainM, et al. N EnglJ Med 2013;368:

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11 Outline 1. Review the physiological aspects of bone homeostasis and discuss the pathophysiology of skeletal metastasis in prostate cancer Role of osteoblasts and osteoclasts Physiologic changes in disease 2. Discuss the impact that volume of metastasis has on disease and patient outcomes SWOG-9346 Trial CHAARTED Trial STAMPEDE Trial 3. Evaluate the current standard of diagnosing metastasis and a possible alternative Nuclear Medicine Bone Scintigraphy Na-F PET/CT Bone scan to screen for bone metastasis Imaging of the chest, abdomen/pelvis to monitor for lymph nodes and visceral metastasis 11

12 Nuclear Medicine Bone Scan: Basics Technetium-99 most commonly used False positive findings due to: Degenerative changes Inflammation Trauma Sensitivity ~ 50% and specificity ~ 80% Sodium-Fluoride PET/CT Fluorodeoxyglucose (FDG) not suitable for metastatic prostate cancer Radiolabelled Na-F used instead 12

13 Inclusion Criteria: 1. Biopsy proven prostate cancer 2. Bone scan consistent with one or more metastasis 3. Ability to safely postpone initiation of androgen deprivation until after all scans were completed 4. The ability to undergo an MRI which they used as the standard Na-F PET/CT vs. WBC 13

14 BCCA Imaging Protocol: NaF-PET/CT as a Replacement for Bone Scintigraphy Outline 1. Review the physiological aspects of bone homeostasis and discuss the pathophysiology of skeletal metastasis in prostate cancer Role of osteoblasts and osteoclasts Physiologic changes in disease 2. Discuss the impact that volume of metastasis has on disease and patient outcomes STAMPEDE Trial SWOG-9346 Trial CHAARTED Trial 3. Evaluate the current standard of diagnosing metastasis and a possible alternative Nuclear Medicine Bone Scintigraphy Na-F PET/CT 4. Provide an overview of the different management options for bone metastasis in castrate-resistant prostate cancer Bisphosphonates and Denosumab Abirateroneand Enzalutamide Radium 223 Stereotactic Ablative Radiotherapy (SABR) 14

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17 Median time to SRE 16.7m vs 13.3m Combined Used of Bone Targeted Therapy and Abiraterone (COU-AA-301) Patients on BTT at start of trial: 184/546 (33.7%) Prednisone 169/542 (31.2%) Abiraterone + Prednisone Type of BTT: zoledronic acid (n = 330) bisphosphonates (n = 16) denosumab (n = 22) Saad, ASCO

18 Combined Used of Bone Targeted Therapy and Abiraterone (COU-AA-301) End Points BTT use Median, months (95% CI) No BTT use median, months (95% CI) Hazard Ratio (95% CI) P Value rpfs ( ) ( ) ( ) OS N/E (30.88, N/E) ( ) ( ) 0.02 Time to opiate use N/E (27.63, N/E) ( ) ( ) Time to chemotherapy ( ) ( ) ( ) Time to ECOG PS deterioration ( ) ( ) ( ) < Time to PSA Progression 8.34 ( ( ) (0.750=1.028) Saad, ASCO 2013 Combined Used of Bone Targeted Therapy and Enzalutamide (AFFIRM) 18

19 Summary Presence of metastases is an important factor that affects patient outcomes. Patients with low volume disease at the time of treatment initiation tend to have greater median OS compared to those with a higher burden of disease. However, what DEFINES low volume vs. high volume is still unknown. More sensitive imaging modalities for detecting metastasis (ie. Na-F PET/CT) currently being evaluated à? How much of an effect will this have in the overall picture Summary Bisphosphonates and Denosumab delay median time to first SRE Does combination therapy with bone targeted therapy and novel hormonal agents offer increased clinical benefits? Some hypothesis-generating data from BTT and abiraterone with possible increased protection from SRE 19

20 Dr. Scott Tyldesley Dr. Alan So Thank You Essential properties: Calcium analogue High energy alpha-emission Radium 223 Induce DNA double-strand breaks causing apoptosis at all stages of cell cycle Soft tissue penetrance <0.1 mm (2-10 cell diameters) Minimizes myelotoxicity Intermediate half-life (11.4 days) 20

21 ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design PATIENTS Confirmed symptomatic CRPC 2 bone metastases No known visceral metastases Postdocetaxel or unfit for docetaxel STRATIFICATION Total ALP : < 220 U/L vs 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No R A N D O M I S E D 2:1 TREATMENT 6 injections at 4-week intervals Radium-223 (50 kbq/kg) + Best standard of care Placebo (saline) + Best standard of care N =

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