Prostate Cancer Teaching Session Dr Anthony Joshua Kinghorn Cancer - - PowerPoint PPT Presentation

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Prostate Cancer Teaching Session Dr Anthony Joshua Kinghorn Cancer - - PowerPoint PPT Presentation

Jan 25, 2023 1.35k likes •2.15k views

Prostate Cancer Teaching Session Dr Anthony Joshua Kinghorn Cancer Centre St Vincents Hospital, Sydney Natural History of Prostate Cancer Hormone-Sensitive Castrate-Resistant Tumor Volume & Activity Androgen

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SLIDE 1

Prostate Cancer

Teaching Session

Dr Anthony Joshua Kinghorn Cancer Centre St Vincents Hospital, Sydney

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Natural History of Prostate Cancer

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NOTE: This diagram represents typical disease progression. Note that some patients are metastatic at diagnoses, and are thus still hormone-sensitive. 1. Chen Y, et al. Lancet Oncol. 2009;10:981-991. 2. Hofland J, et al. Cancer Res. 2010;70:1256-1264.

Symptomatic

Androgen Deprivation Postchemotherapy Death

Tumor Volume & Activity

Therapies After LHRH Agonists and Antiandrogens

Hormone-Sensitive Castrate-Resistant

Surgery and Radiation

Asymptomatic Premetastatic Radiographically Metastatic

Chemotherapy Immunotherapy

7-15 years 3-5 years

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Question 1

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Gleason Score

Small Uniform Glands More Space Between Glands Infiltration of cells from glands at margins Irregular masses of cells few glands Lack of glands, sheets

  • f cells

More Aggressive

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Question 2

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Presentation to Medical Residents

The patient-based meta-analysis showed no significant benefit

  • f MAB after 8000+

pts and 27 trials MAB is expensive, has increased toxicity, and should not be used

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SLIDE 7

Presentation to Medical Residents

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SLIDE 8
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Median survival was 5.8 years in the continuous-therapy group and 5.1 years in the intermittent-therapy group (HR for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P<0.001 and P=0.003, respectively) at month 3 but not thereafter.

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Minimal disease was disease confined to the spine, pelvic bones, or lymph nodes, and extensive disease was disease present in the ribs, long bones, or visceral organs.

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The median survival after randomization among patients with extensive disease was 4.9 years in the intermittent-therapy group, as compared with 4.4 years in the continuous-therapy group (hazard ratio for death with intermittent therapy, 1.02; 95% CI, 0.85 to 1.22). The median survival after randomization among patients with minimal disease was 5.4 years in the intermittent- therapy group, as compared with 6.9 years in the continuous-therapy group (hazard ratio for death with intermittent therapy, 1.19; 95% CI, 0.98 to 1.43).

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Question 3

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The CHAARTED Hypothesis

Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

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E3805 – CHAARTED Treatment

Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

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Primary endpoint: Overall survival

Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

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Causes of Death

Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

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OS by extent of metastatic disease at start of ADT

Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

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ADT + Docetaxel benefited all subgroups

Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

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Secondary Endpoints

Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

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Question 4

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Presentation to Medical Residents

Secondary hormonal therapy

  • Mr Rodrigues is prescribed the anti-

androgen bicalutamide in addition to his goserelin injections.

  • His PSA decreases and his pain improves,

but about 6 months later he again has a rising PSA and pain.

  • The bicalutamide is stopped and he again

has a transient response for about 3 months

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SLIDE 23

Presentation to Medical Residents

Secondary hormonal therapy

  • About 80% of men respond to orchiectomy or LHRH

agonist for a median of 1-2 years.

  • About 30% respond to the subsequent addition of an

anti-androgen for a few months

  • About 20-30% of those who responded to addition of

an anti-androgen will respond to its withdrawal (Antiandrogens start to stimulate prostate cancer cells instead of killing them!)

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Prednisone

 Low dose steroid  5 mg in morning and 5mg in afternoon  Improves energy, appetite, weight  Minimal side effects  ~30% PSA response rate

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Ketoconazole

  • Antifungal agent suppresses adrenal androgens
  • Given concurrently with Hydrocortisone
  • Some patients show PSA response
  • Side effects: Decreased energy, Nausea, Liver

toxicity

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New Hormonal agents

 Abiraterone  Enzalutamide  TAK700  Galeterone

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Question 5

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Abiraterone Acetate

  • 250mg tablet formulation
  • Irreversible and specific

steroidal inhibitor of CYP17 (P450c17)1

  • Abiraterone acetate is a

novel inhibitor of androgen synthesis uniquely blocking testosterone production in the testes, adrenal glands, and intra-tumoral prostatic tissue.

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3β-Acetoxy-17- (3-pyridyl) androsta-5,16-diene

MW = 391.55

  • 1. Shah et al Expert Opin. Investig Drugs 2010
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SLIDE 29

Pregnenolone 17OH-Pregnenolone DHEA Deoxycorticosterone 11-deoxycorticol Androstenedione Corticosterone Cortisol Testosterone Renin-angiotensin- aldosterone loop Aldosterone Estradiol ACTH 17α-hydroxylase C17,20-lyase

x5 x2 < 0.34 nmol/L < 1 nmol/dl < 3 pmol/l x2 x3 x2 x10 x40 x1.5

The Suppression of Testosterone By Abiraterone Acetate’s Inhibition Of CYP17 In Men With Castration-Resistant Prostate Cancer

  • 1. Cougar Biotechnology Investigator’s Brochure Sept 2010

Hypertension Fluid overload

Positive drive Negative feedback

Hypokalemia

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Pregnenolone 17OH-Pregnenolone DHEA Deoxycorticosterone 11-deoxycorticol Androstenedione Corticosterone Cortisol Testosterone Aldosterone Estradiol ACTH 17α-hydroxylase C17,20-lyase

Selective androgen biosynthesis inhibitor

Attard G et al. J Clin Oncol 2008; 26(28): 4563-4571

Low-dose steroid replacement minimizes Mineralocorticoid-related toxicty

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COU302 pre-chemo

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COU302

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COU302

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Question 6

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MDV-3100 Enzalutamide

Scher et al, NEJM epub Aug 15, 2012

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CONFIDENTIAL – FOR INTERNAL, NON-PROMOTIONAL USE ONLY. PROPRIETARY INFORMATION OF ASTELLAS. DO NOT COPY OR DISTRIBUTE.

PREVAIL: A Multinational Phase 3, Randomized, Double-Blind, Placebo- Controlled Efficacy and Safety Study of Oral MDV3100 in Chemotherapy- Naïve Patients with Progressive Metastatic Prostate Cancer Who Have Failed Androgen Deprivation Therapy

Co-primary endpoints OS and PFS

Planned evaluations – OS/radiographic PFS – Time to first SRE – Initiation of cytotoxic chemotherapy – QoL

  • FACT-P, EQ-5D

– PSA progression – Pain palliation

  • BPI-SF

– Safety

  • AEs, vital signs, physical

exam, lab evaluations, ECG – Pharmacokinetics – Subgroups Enzalutamide 160 mg qd* Placebo qd* R 1:1 n=1717 mCRPC Asymptomatic or mildly symptomatic Progresion after ADT

*Patients required to be on continuous ADT (castration or

GnRH analogue) with study drug or placebo

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Enzalutamide Reduced Risk of Death by 29%

3 7

Estimated median OS, months (95% CI): Enzalutamide: 32.4 (30.1, NYR); Placebo: 30.2 (28.0, NYR)

NYR = Not Yet Reached Enzalutamide 872 Placebo 845 863 835 850 781 824 744 797 701 745 644 566 484 395 328 244 213 128 102 33 27 2 2

Duration of Overall Survival (Months) Survival (%)

60 50 40 30 20 10 90 80 70 100 3 6 9 12 15 18 21 24 27 30 33 36

Enzalutamide Placebo Hazard Ratio: 0.706 (95% CI: 0.60,0.84) P<0.0001

Patients at Risk

Patients still alive at data cut off Enzalutamide: 72%; Placebo: 63%

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Enzalutamide Prolonged Radiographic Progression-Free Survival

Enzalutamide 832 Placebo 801 514 305 256 79 128 20 34 5 5 1

Time from Randomization (Months)

3 6 9 12 15 18 21 Radiographic Progression-Free Survival (%) 60 50 40 30 20 10 90 80 70 100

Enzalutamide Placebo Hazard Ratio: 0.186 (95% CI: 0.15, 0.23) P<0.0001

Patients at Risk

Estimated median rPFS, months (95% CI): Enzalutamide: NYR (13.8, NYR); Placebo: 3.9 (3.7, 5.4)

NYR = Not Yet Reached

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Subsequent Therapies Were Used More Commonly in the Placebo Group

Enzalutamide (n=872) Placebo (n=845) Patients with at least one subsequent life-extending therapy

40.3% 70.3%

Percentage of Patients Receiving Subsequent Therapies Docetaxel 32.8% 56.7% Abiraterone 20.5% 45.6% Cabazitaxel 5.8% 13.0% Enzalutamide 1.0% 4.4% Sipuleucel-T 1.4% 1.2%

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Enzalutamide Delayed Median Time to Chemotherapy by 17 Months

Enzalutamide 872 Placebo 845 854 734 799 518 751 415 665 324 575 257 388 165 252 103 158 64 78 25 21 9 2

Time to Initiation of Cytotoxic Chemotherapy (Months) Cytotoxic Chemotherapy Free (%)

60 50 40 30 20 10 90 80 70 100 3 6 9 12 15 18 21 24 27 30 33 36

Hazard Ratio: 0.35 (95% CI: 0.30, 0.40) P<0.0001

Median Enzalutamide 28.0 months Placebo 10.8 months Enzalutamide Placebo

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Patients at Risk

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Presentation to Medical Residents

Mr Rodrigues tries ketoconazole and hydrocortisone for 3 months, but his pain gets worse and his PSA continues to rise He now has castrate resistant prostate cancer Mr Rodrigues has severe pain in his right hip. He is fatigued and has several other painful areas What treatment should be given?

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Hormone Refractory Prostate Cancer (HRPC/CRPC)

  • Progression despite hormonal therapy
  • Disease progression
  • PSA progression
  • Clinical Progression
  • Radiologic Progression
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Presentation to Medical Residents

Principles of Management for CRPC

  • Optimize Mr Rodrigues’ pain control with regular dosing
  • f narcotic medication, such as morphine
  • Give regular laxatives to control the constipation that will

be caused by morphine

  • Give local radiotherapy to the right hip, his dominant site
  • f pain
  • Consider chemotherapy for men with diffuse symptoms or

rapid PSA progression

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Presentation to Medical Residents

“I feel a bit better, he says 4 weeks later, but I still have aching bones, I’m very tired, and my PSA has gone up again (to 150)”

Mr Rodrigues is treated with radiotherapy to his painful hip

Mr Rodrigues is offered treatment with chemotherapy

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Presentation to Medical Residents

TAX 327 Study

(Tannock et al, NEJM, 2004;351:1502-12)

Docetaxel 30 mg/m2 weekly for 5 of 6 weeks x 5 cycles Mitoxantrone 12 mg/m2 q3 wks x 10 cycles Docetaxel 75 mg/m2 q3wks x 10 cycles All patients received prednisone 10mg/day

1006 patients with HRPC

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Presentation to Medical Residents

TAX 327: Secondary Endpoints

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Presentation to Medical Residents

Two large chemotherapy studies: TAX- 327 and SWOG 9916

  • These studies confirm the palliative benefit of

chemotherapy with Mitoxantrone + Prednisone, and this wel-tolerated treatment remains appropriate for many patients

  • On the basis of its survival advantage,

Docetaxel + Prednisone is preferred treatment for most patients with HRPC

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Presentation to Medical Residents

He has relief of his pain and by the third course of treatment he is able to stop taking morphine His PSA declines steadily from 150 to 25 with the first 6 courses of treatment, but then begins to rise again to 70 after 8 courses. He develops numbness in his hands and feet His docetaxel is stopped because of this progression and to avoid further side effects

Mr Rodrigues is treated with docetaxel every three weeks and prednisone

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Presentation to Medical Residents

Three months after stopping docetaxel, Mr Rodrigues is beginning to experience new pain in several areas and is back on morphine. His PSA is fairly stable in the range of 60-80.

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Presentation to Medical Residents

What are second line options for Mr Rodrigues in 2014

  • Hormonal options: Abiraterone or MDV 3100
  • Chemotherapy option: Cabazitaxel or Mitoxantrone
  • Radiopharmaceuticals
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Question 8

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Cabazitaxel

 New semi-synthetic taxane

 Selected to overcome the emergence of taxane resistance  Not a substrate for drug efflux pumps

 Preclinical data

 As potent as docetaxel against sensitive cell lines and tumor

models

 Active against tumor cells/models resistant to currently available

taxanes

 Clinical data

 In Phase I & 2 trials dose-limiting toxicity was neutropenia

Attard G, et al. Pathol Biol (Paris) 2006;54(2):72-84; Pivot X, et al. Ann Oncol 2008;19(9):1547-1552; Mita AC, et al. Clin Can Res 2009;15(2):723-730. de Bono JS, et al. Lancet 2010; 376: 1147–54.

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Cabazitaxel TROPIC Study

Primary endpoint: Overall Survival Secondary endpoints: PFS, response rate, and safety cabazitaxel 25 mg/m² q 3 wk + prednisone for 10 cycles (n=378) mitoxantrone 12 mg/m² q 3 wk + prednisone for 10 cycles (n=377)

Stratification factors

ECOG PS (0, 1 vs. 2) • Measurable vs. non-measurable disease

CRPC progressing on or after docetaxel (N=755)

de Bono JS, et al. Lancet 2010; 376: 1147–54

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Cabazitaxel Overall Survival

MP CBZP Median OS (mo) 12.7 15.1 Hazard Ratio 0.70 95% CI 0.59-0.83 P value  .0001 Probability of OS (%)

80 60 40 20 100

0 Months 6 Months 12 Months 18 Months 24 Months 30 Months

Combined median follow-up: 12.8 mo 30% Reduction in risk of death

MP CBZ P

de Bono JS, et al. Lancet 2010; 376: 1147–54.

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Abiraterone Overall Survival

AA 797 736 657 520 282 68 2 Placebo 398 355 306 210 105 30 3 21 Hazard ratio = 0.646 (0.54-0.77) P < 0.0001 Placebo: 10.9 months (95% CI,10.2-12.0)

Abiraterone acetate: 14.8 months (95% CI, 14.1-15.4)

100 80 60 40 20 Survival (%) 0 0 3 6 9 12 15 18

Placebo AA

Time to Death (Months) 3.9 months

de Bono et al. NEJM. 2011; 364(21): 1995-2005.

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Overall Survival

Scher et al, NEJM epub Aug 15, 2012

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Adverse Events

Scher et al, NEJM epub Aug 15, 2012

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Presentation to Medical Residents

Mr Rodrigues has treatment with mitoxantrone

He improves for about 4 months but then starts to have pain again and is tired. His treatment is stopped, and he accepts that treatment will now be designed to minimize his symptoms.

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Question 9

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Supportive Treatments

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Key Risk Factors for Osteoporosis

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Normal Bone Physiology

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Bisphosphonates

Modulate signaling from OB to OC

Inhibit OC formation, migration, osteolytic activity; promote apoptosis Bisphosphonates released during bone resorption Bisphosphonate concentrated in new bone

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Zolendronic acid

A nitrogen containing bisphosphonate Improves Bone Density Reduce SRE by ~22% Side effect: ONJ 0.83% No improvement in OS Dosing remains a question

  • Emerging evidence suggests once yearly dosing

improves bone health

  • Markers of bone turnover remain suppressed
  • Reduced ONJ?
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Presentation to Medical Residents

Zoledronate Study

(Saad et al, JNCI 2002;94:1458-68 and 2004;96:879-82)

643 pts with CRPC Zoledronte 8mg q3wks Zoledronte 4mg q3wks Placebo q3wks

  • 1. 8mg dose caused renal insufficiency and

dropped

  • 2. Less bone events with 4mg dose (44%)

comapred to placebo (33%, p=0.02) but no difference in QL

  • 3. More low-grade toxicity with zoledronate
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Rank Ligand is also a Mediator of Osteoclast Formation, Function and Survival

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Denosumab-Rank Ligand Inhibitor

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Denosumab-Mechanism of Action

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Time to First On-Study SRE

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Question 10

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Natural History of Prostate Cancer

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NOTE: This diagram represents typical disease progression. Note that some patients are metastatic at diagnoses, and are thus still hormone-sensitive. 1. Chen Y, et al. Lancet Oncol. 2009;10:981-991. 2. Hofland J, et al. Cancer Res. 2010;70:1256-1264.

Symptomatic

Androgen Deprivation Postchemotherapy Death

Tumor Volume & Activity

Therapies After LHRH Agonists and Antiandrogens

Hormone-Sensitive Castrate-Resistant

Surgery and Radiation

Asymptomatic Premetastatic Radiographically Metastatic

Chemotherapy Immunotherapy

7-15 years 3-5 years