2nd Annual Prostate Cancer ForumSeptember 10, 2011 • Robert H. Lurie Medical Research Center • Chicago, IL

Keynote AddressOverview of Prostate

Cancer Treatment OptionsWilliam Catalona, MDProfessorNorthwestern University Feinberg School of MedicineDepartment of Urology

Overview of Prostate Cancer Treatment Options

William J Catalona MDDirector, Clinical Prostate Cancer Program

Robert H Lurie Comprehensive Cancer CenterNorthwestern

Purpose

1. Provide brief overview of treatments, discussing advantages and disadvantages

2. In reporting differences, attempt to be objective

3. Acknowledge my personal editorial perspective

4. For balance, refer to contrary opinions

Disclose Partners from Industry

• Beckman Coulter, Inc – manufacturer of PSA tests

• OHMX, Inc - developer of urine PSA test• deCODE genetics, Inc - developer of genetic

tests for prostate cancer

U.S. Prostate Cancer Statistics 2010

Ca: Cancer Journal for Clinicians 2010;60:277-300

• 217,730 new cases• Most common malignancy•Accounts for 28% of all male cancer

• 32,050 deaths from prostate cancer•11% of all male cancer deaths•Second only to lung cancer

2010 Prostate Cancer StatisticsDD

Incidence

DD

Deaths

PSA ERA

DD

Relative 5-Year Survival

DD

Early Detection

PSA Screening Saves Lives

In the European Randomized Study of Screening for Prostate Cancer (ERSPC)• Screened men had 40% fewer

advanced PC at diagnosis

• 20% lower prostate cancer death rate in screening arm –(27% lower in men actually screened)

• Mortality benefit observed largely in men aged 55-69

Schroder FH et al, NEJM 360:1320, 2009

Prostate Cancer-Specific Mortality with Minimal or No Co-Morbidity in PLCO Trial

Crawford ED et al. J Clin Oncol 29:355, 2010

44% ↓ in PCa-Specific Mortality

Controls

Screened

Göteborg Results

• 41% decrease in advanced disease in screening arm– 66% lower in men actually screened

• 44% decrease in PCa mortality in screening arm–56% lower in men actually screened

Hugosson, J, et al. Lancet Oncol 2010; 11: 725–732

Active Surveillance

Rationale for Active Surveillance

Low-risk tumors generally grow slowly, so there may be time to “watch” them while retaining option for treatment if they show signs of progression on repeat PSA testing or repeat biopsy

Caveats

1. There may be biopsy sampling errors, i.e., the tumor may be worse than the biopsy shows

2. Some low-grade tumors may become more aggressive over time

3. In watchful-waiting studies, prostate cancer death rates are generally low for men with a low-grade tumors in the short term, but a marked increase in prostate cancer progression and death with long-term follow-up has been reported

With time, all active surveillance studies have shown a) Significant under-grading or

under-staging of some tumorsb) Some patients develop

metastasesc) Some die of prostate cancer

The criteria for low-risk prostate cancer are wrong 1/3 of the time

• Biopsy is correct 95% of the time when it shows “high-risk” tumor features

• But is correct only 66% of the time when the biopsy suggests low-risk features

Epstein et al J Urol 160: 2407, 1998;Epstein et al, JAMA 271:368, 1994

Diffusion Weighted Imaging with MRI

• Lower Apparent diffusion coefficient (ADC) correlated with grade and % tumor involvement on biopsy

Woodfield et al. AJR 194:316-22, 2011

T2W MRI and ADC map

• Tumors more likely to be visible on DWI if higher grade• True sometimes, but not highly accurate

An example of misleading MRI imaging studies• In 96 potential candidates for active surveillance who

had MRI imaging but chose to have surgery instead – 24% had a high Gleason grade or cancer that had

spread beyond the prostate – MRI did not significantly which patients had these

adverse tumor features

Ploussard G, et al. BJU Int 2010. Epub

NCCN Guidelines: “The timing and value of periodic imaging studies in AS has not been determined.”

Active surveillance has risks a) Risks of repeat prostate biopsies

a) Discomfort of having repeated prostate biopsiesb) Infections, bleeding, urinary difficultiesc) Possible erectile dysfunction with multiple biopsies

b) Anxiety of living with untreated prostate cancerc) Non-compliance with regular follow-up protocold) Possible increased complexity of delayed treatment

with more side effects (postoperative radiation or hormone therapy)

e) Progression to metastases or prostate cancer death while on surveillance

1Finelli A, et al. Eur Urol 2011;59:509-14

Treatment is compromised for some

a) For some patients, active surveillance amounts to delayed treatment of cancer

b) Repeated biopsies are: 1) Still subject to sampling errors 2) may induce inflammation that cause

increased PSA levels3) may cause scarring that makes nerve-sparing

surgery difficult or impossible and may compromise surgical margins

An example of low cure rate with delayed treatment a) The University of Torontob) 50% of patients who received

delayed treatment had PSA failurec) They are beginning to see some

prostate cancer deaths

Klotz L et al ,J Clin Oncol 28:126,2009 Johansson JE et al JAMA 291:2713,2004

Early treatment has advantages

a) Patients are more likely to be cured with fewer side effects from treatment

b) Patients are less likely to require multiple types of treatment to control the cancer

An example of early RP decreasing progression to metastases and reducing cancer-specific and all-cause mortality

Radical Prostatectomy versus Watchful Waiting for Early Prostate Cancer

Surgery vs. Watchful Waiting

Metastasis Prostate Cancer Death

All Cause Death

All 41% 38% 25%

< age 65 53% 51% 48%

Low Risk 57% 47% 47%

Conclusion

Active surveillance is a reasonable option in men with a limited life expectancy, but should be considered investigational in men with >10 year life expectancy (younger than 73 years old)

OPEN VS DA VINCI ROBOTIC

Surgical Approaches to Radical Prostatectomy

Long-Term Results

• The long-term results of open radical prostatectomy are well documented

• Long-term robotic prostatectomy results are not yet available

Continence (No Pads)

Age T1A/B T1C

<50 -- 95.4%

50-59 100% 96.6%

60-69 90.2% 95.6%

≥70 86.7% 90.2%

Potency (with or without Viagra-like drugs)

AgeAge T1A/BT1A/B T1CT1C

<50 -- 95%

50-59 89% 89%

60-69 65% 81%

≥70 67% 73%

Recurrence-Free Survival (PSA <0.1)

• PSA recurrence- Overall Population

   T1aT1a T1bT1b T1cT1c

10 year 10 year RFS (%)RFS (%) 7979 7474 7878

Prostate Cancer-Specific Survival

• Prostate-cancer specific survival

T1aT1a T1bT1b T1cT1c

% 10 yr % 10 yr CSSCSS 100100 9595 100100

Robotic Laparoscopic Prostatectomy

• Console

Marketing the Robot

• Quicker recovery– Less pain– Shorter hospital stay– Quicker return to normal

activity – Shorter catheterization

• Better visualization• Less bleeding• Better potency• Better continence • Fewer positive margins• Better cosmesis

It is claimed that 70% of radical prostateactomies are performed robotically

In 2008, in Florida 4,542 radical prostatectomies were performed 1,188 (26%) were robotic and 3,354 (74%) were open

12 surgeons co-authored 72% of the published studies on robotic prostatectomy. “The published RALP literature is limited to observational studies of mostly low methodologic quality.” “Our findings draw into question to what extent valid conclusions about the relative superiority or equivalence of robotic prostatectomy to other surgical approaches can be drawn and whether published outcomes can be generalized to the broader community. “

Eur Urol. 2010 Jun;57(6):930-7. Epub 2010 Jan 26.

Low quality of evidence for robot-assisted laparoscopic prostatectomy: results of a systematic review of the published literature.Kang DC, Hardee MJ, Fesperman SF, Stoffs TL, Dahm P.Department of Urology, University of Florida, Gainesville, FL 32610-0247, USA.

4.45-fold more RALP patients regretted their decision to have that type of surgery

“Patients who underwent RALP were more likely to be regretful and dissatisfied, possibly because of higher expectation of an ‘innovative’ procedure.”

Care Path

Essentially equivalent

“The results of this prospective study have shown that both robotic and conventional radical prostatectomy provide comparable short-term postdischarge recovery, including time to normal and full activity, driving, and post-discharge narcotic use.”

Bleeding

With good open surgical technique, there is no significant difference in

blood transfusion rate

Williams SB et al, Urology 2010

Positive Surgical Margin Rates with Open and Robotic Nerve-Sparing Prostatectomy

• 950 cases performed by 2 high-volume surgeons at Brigham and Women’s Hospital (Harvard)

• Analysis of results was adjusted for known preoperative predictors of positive surgical margins

Open Robotic

Nerve-Sparing Surgery (N=908)

7.6%(N=330)

13.5%(N=578)

Invasiveness and Cosmesis

• Robotic: five 1 inch-incisions + one 2 inch incision

• Open: one 4-5 inch incision

Human Touch and Access

• Robotic surgery - cannot feel tissues or appreciate how easily tissues separate from one another

• More complete access with open surgery

“Visual and tactile assessment during open surgery by an experienced surgeon provides valuable information on when and where it is safe to preserve the neurovascular bundles…”

Potency

Continence

Burning the Prostate Out Compromises Nerve Sparing

• The greater use of electricity or heat with robotic surgery to control bleeding can cause irreversible damage to the neurovascular bundles

Comparative Effectiveness of Robotic vs Open Radical Prostatectomy

Percent Robotic Open

Urologic Complications 4.0 2.2Incontinence 18.2 11.9Incontinence Procedures 9.5 8.5Erectile Dysfunction (ED) 33.8 18.2ED Procedures 2.8 2.1

Hu JC et al, JAMA 302; 1557, 2009

Need for Further

Treatment(Adjusted for

Disease Severity)

Robotic Open

Overall 8.2 6.9Radiation 5.1 4.9Hormonal 5.3 3.7

SEER (National Cancer Registry ) Database

“… (minimally-invasive surgery more likely to require salvage therapy within 6 months (27.8% v 9.1%, P < .001 )”

The Most Important Question

What will the cancer control results be in 10

years?

The Most Important Factor

• The skill and experience of the surgeon

HIFU AND CRYOABLATION (FIRE AND ICE)

HIFU

• Heats prostate tissue up to 100 degrees C

• Produces cavity over days to months

• Can be repeated

• Prostate volume is limiting (40 cc)

• Frequently requires preliminary trans-urethral resection (“Roto-Rooter”) operation

Multi-Center French HIFU Study

European Urology 2010: 58: 559-566

DD

•803 patients, minimum 2 year follow-up

•Prostate cancer-specific survival 99%, DFS at 5 years 83%, 72%, and 52% for low-, intermed-, high-risk disease

HIFU

• 43 patients treated in London with 2-year follow-up

• 48% had treatment failure • 3 developed severe scar tissue blocking

urination• 2 developed fistulas between the urinary and

intestinal tracts• They have abandoned the HIFU program

Challacombe BJ et al, BJU Int 2009; (also see Walsh JU 182:537)

Cryoablation

• Argon gas circulating through hollow needles to freeze and kill prostate tissue

• Used primarily as salvage after radiotherapy

• Poor initial results with high complication rates

Results of Cryoablation

• No long-term data

• High risk for erectile dysfunction

Levy et al, Urol 182: 931, 2009

FOCAL THERAPY (“LUMPECTOMY”)

New approach to treatment between active surveillance and surgery or radiation therapy:

minimally-invasive ablation and chemosuppression of residual disease

Middle Ground: Focal Therapy

• Middle-ground treatments for low-risk patients that can ablate some prostate cancer cells but not the whole gland

• Focal therapy (cryoablation, HIFU, or photodynamic therapy + Proscar or Avodart)

Focal Therapy

• Lack of validated data demonstrating that it works well

• Has side effects• Risks compromising subsequent definitive

treatment if it fails to work• Leaves prostate cancer cells and “normal”

prostate cells behind that can become cancerous

• Requires repeated biopsies for monitoring

Focal Therapy

• 80% of prostate cancers involve multiple regions of the prostate gland

• Imaging with MRI is not reliable to localize microscopic cancer cells

• Cannot be certain that the largest tumor is the most dangerous one

• >30% of “low-risk” tumors are really “high risk” tumors

Black P et al, CUAJ 3:331, 2009

Difficulty of Salvage Prostatectomy after HIFU or Cryo

• More difficult surgery• Difficult to perform nerve sparing• More complications• Cancer is frequently found to have

extended beyond the prostate gland

5--Recuctase Inhibitors (Proscar, Avodart)

Claims for “Chemosuppression”

FDA Rejects 5ARI Chemoprevention

Summary

• Focal therapy is unproven and of questionable efficacy

• Proscar and Avodart may not be safe for prostate cancer prevention or suppression

Radiation Therapy• Not all cancer cells are sensitive to radiation

doses that can be safely delivered to the patient

• The radiation may “miss” some cancer cells• Mutations in remaining “normal” prostate

cells can result in second prostate cancers• There may be bladder, rectal, sexual side

effects

Contemporary Prostate Brachytherapy:Trans-perineal Approach

Closed procedure – Day case

Perineal template –Good geometry

TRUS guidance

Pre- or intra-operativeplanning

Smaller tumors

Contemporary Prostate Brachytherapy:Trans-perineal Approach

The radiation oncologist’s tool: The linear accelerator

Proton Beam

Degarelix: More rapid medical castration, nothing more

• 40% of Degarelix patients had injection site pain or redness compared to 1% of leuprolide (Lupron) patients

Prescrire Int. 2010 Jun: 19 (107); 106-108.

Phase II Multicenter Study of Abiraterone Acetate Plus Prednisone Therapy in Patients With Docetaxel-Treated

Castration-Resistant Prostate Cancer

• Evaluated the effectiveness of abiraterone in patients who have castration resistant PCa who failed treatment with docetaxel

• Clearly this drug has efficacy and most likely will replace ketoconazole for use in a similar setting

• Issue about payment if patient has not already had chemotherapy

Danila, DC, et al. J Clin Oncol 2010; 28: 1496

Antitumor Activity of MDV3100 in Castration-Resistant Prostate Cancer

• MDV3100 is an androgen-receptor antagonist• There were substantial and sustained

decreases in PSA, and many patients had regression of soft tissue metastases

• Overall, two-thirds of patients had partial remission or stable disease in radiographically-evident soft tissue and bone lesions

MDV3100 has a different mechanism of targeting the androgen receptor and looks promising in early studies. Scher, HI, et al., Lancet 2010; 375: 1437

New (and Perhaps Better) Drugs in the Pipeline

• There are also other new drugs that similarly affect the androgen-receptor axisTAK700

• VN124-1 (now TOK-001)• BMS-641988• Each has theoretical advantages that may

make them better than abiraterone

Mohler JL and Pantuck AJ. J Urol 185:783,2011

Cabazitaxel vs. Mitoxantrone after Docetaxel• Phase III study in men with castrate-resistant disease

progressing through docetaxel (n=755)

de Bono et al. Lancet 376:1147-54, 2010/SL

• Higher treatment-related death rate with cabazitaxel

Phase II Study of Docetaxel Re-Treatment in Docetaxel-Pretreated Castration-Resistant Prostate Cancer

• 45 patients initially responding to docetaxel and then having disease progression after a period of biochemical remission of at least 5 months were enrolled in a prospective multicenter study and re-treated with docetaxel

• Partial PSA responses in 11 patients (24.5%), 4 (25%) objective responses

• Docetaxel re-treatment preserves anti-tumor activity and is well tolerated in a selected population of pretreated patients with castration-resistant prostate cancer

Di Lorenzo G, et al. BJU Int. 2011;107:234. doi

Sipuleucel-T (Provenge) Immunotherapy for Castration-Resistant Prostate Cancer

• Well tolerated, with none of the typical chemotherapy side effects

• Relatively short course (6 weeks) then allowing men to try chemotherapy

• Improved overall survival for men by 4 months • Has no effect on tumor progression • The drug costs $93,000 and Medicare will cover it

Kantoff, PW, et al. N Engl J Med. 2010;363:411

Other Topics

• Adjuvant versus salvage radiation for patients with adverse pathology findings after radical prostatectomy

• Management of patients who have PSA recurrence

• Treatment of locally-advanced disease• Website: www.drcatalona.com

Overview of Prostate Cancer Treatment Options

William J Catalona MDDirector, Clinical Prostate Cancer Program

Robert H Lurie Comprehensive Cancer CenterNorthwestern