Early Vs. Late Androgen Deprivation: Lessons from the Literature and the Clinical Implications Douglas S. Scherr, M.D. Assistant Professor of Urology Clinical Director, Urologic Oncology Weill Medical College-Cornell University New York, N.Y.

The Modern Treatment Failure: Rising PSA Scope of the Problem Definition Evaluation Treatment Local Systemic

Rising PSA: Scope of the Problem* Approximately 30-40% of patients will experience a rising PSA after local therapy 180,400 patients diagnosed with prostate cancer in 2000 2/3 (119,064) of these patients receive definitive local therapy 30-40% (35,719-47,6259) recur *Based on SEER statistics. 1998

Rising PSA Common problem Definition Evaluation Treatment Local Systemic

Rising PSA: What is a Biochemical Recurrence? Radical Prostatectomy Nadir within 2months after surgery Multiple PSA “cutoffs” used to define failure Radiotherapy Nadir may take 27 months to reach ASTRO criteria used to define failure 3 consecutive rises in PSA, 6 months apart

Rising PSA: What is a Biochemical Recurrence? Mayo Clinic study with 2,782 patients after RP between 1987 and 1993 Percentage of patients with a rise in PSA within 3 years of Cut-Point 0.2 ng/mL 49% 0.3 ng/mL 62% 0.4 ng/mL 72% Conclusion: PSA ≥0.4 ng/mL is best level to consider biochemical failure ASTRO criteria favorably biases biochemical results Amling CL, et al. J Urol 2001;165: 1146

Rising PSA: What is a Biochemical Recurrence? Definition for Brachytherapy 591 men treated from 1992-1996 T1-T2NX prostate cancer, median pretreatment PSA=7.3ng/mL I-125 implant + external beam PSA nadir <0.2 ng/mL – 99% 8-year disease free survival rate, only 16% if nadir 0.3-1.0ng/mL Critz. J Urol. 2002

Rising PSA: What is a Biochemical Recurrence? Definition for Brachytherapy Substantially fewer recurrences 65 recurrences vs. 93 recurrences, if ASTRO criteria rather than 0.2ng/mL cut point used (p<0.0001) Conclusion: PSA nadir should be <0.2 ng/mL Studies should use similar PSA criteria to compare outcomes Critz. J Urol. 2002

Rising PSA: Definition of PSA Recurrence Conclusions Radical Prostatectomy PSA>0.4ng/ml Radiation – three consecutive rises above a nadir (ASTRO criteria) Brachytherapy – rise above a nadir of 0.2ng/mL

Rising PSA Common problem Definition Evaluation Treatment Local Systemic

Rising PSA: Evaluation After Local Therapy Factors to differentiate local vs. metastatic disease Pre-Rx PSA, path. specimen (stage, grade) Slope of PSA rise or PSA doubling time Bone scan/CT Digital Rectal Exam/Fossa biopsy ProstaScint scan Endorectal coil MRI, PET and SPECT scans

Rising PSA: Evaluation After Local Therapy Clinical factors which favor metastatic disease High preoperative PSA> 20, seminal vesicle invasion, Gleason score 8-10 A PSA>0.4ng/mL in the first year PSA velocity->0.75ng/mL per year PSA doubling time <6months

Rising PSA: Value of the Bone Scan “High Threshold” 100 80 Predicted Probability of Positive Bone Scan (%) 60 40 20 1 5 10 15 20 25 30 35 45 80 200 Trigger PSA (ng/mL) Cher, et al. J Urol. 1998;160:1387.

Rising PSA: Detection of Local Recurrence CT scan not very helpful (especially with PSA<40) Digital rectal exam-not very sensitive, scarring may give false positives Prostatic fossa biopsy Overall 50% positive If PSA <1.0 ng/mL only 25% positive Multiple biopsies increase sensitivity but also patient discomfort

Rising PSA: ProstaScint Scan Radiolabeled monoclonal antibody to prostate-specific membrane antigen (PSMA) for patients who are at high risk of lymph node metastases for patients who have a rising PSA after radical prostatectomy What is a ProstaScint Scan? ProstaScint is a whole murine monoclonal antibody, 7E11-C5.3, produced by hybridoma cell line. Reacts with >95% of prostate adenocarcinomas. It also reacts with the glycoprotein PSMA which is found on both benign and malignant prostate epithelial cells.

Rising PSA: ProstaScint Antibody to PSMA radiolabeled with Indium-111 and injected intravenously Gamma camera detects sites of antibody localization if present Gamma-emitting Radionuclide Antibody Linker Chemically Stable Linker 7E11-C5.3 GYK-DTPA Indium 111 ProstaScint: How Does it Work? ProstaScint is a radiolabeled monoclonal antibody radiolabeled with In 111 and injected intravenously over 5 minutes. The antibody targets and binds to prostate cancer sites expressing PSMA (Prostate Specific Membrane Antigen). ProstaScint is detected by a gamma camera and computerized images identify sites of the antibody location.

Rising PSA: ProstaScint – Fossa Recurrence Delayed 54-year-old post-radical prostatectomy PSA up to 2.4 ng/mL ProstaScint – Fossa Recurrence Upper Row: Blood Pool Bottom Row: Delayed ProstaScint images

Rising PSA: Evaluation of ProstaScint 158 patients-s/p RRP (T2 or T3 disease) Rising PSA  positive DRE PSA <1.0 ng/mL and positive DRE, or PSA >1.0 ng/mL any DRE Negative or equivocal bone scan, CT/MRI Scheduled for fossa needle biopsy Recurrent Disease Phase III Patient Selection Results of ProstaScint compared to results of fossa biopsy. Moul et al.

Rising PSA: Evaluation of ProstaScint Number of Patients ProstaScint + ProstaScint - Biopsy + 29 30 Sensitivity 49% Biopsy - 29 70 Specificity 71% Recurrent Disease Patients: ProstaScint vs. Fossa Biopsy Of the 158 phase III patients with recurrent prostate cancer and prostate biopsy, 58 patients (37%) had positive Indium In 111 ProstaScint images in the prostatic fossa: Of these 50% (29 patients) did not have recurrent prostate cancer on biopsy. One hundred patients (63%) had negative Indium In 111 ProstaScint images: Of these 30% (30 patients) had recurrent prostate cancer on biopsy. The overall accuracy of Indium In 111 ProstaScint immunoscintigraphy, as measured against prostatic fossa biopsy, was 63% (99/158). Sensitivity of the fossa was 49% and specificity was 71%. Kahn D, et al: 111 Indium Capromab Pendetide in the Evaluation of Patients with Residual or Recurrent Prostate Cancer After Radical Prostatectomy. J Urol 159:2041-2047, 1998. Positive predictive value 50% Negative predictive value 70% Overall accuracy 63% Moul et al

Rising PSA: PET and SPECT Scans Positron emission tomography Uses 18FDG or 11C-methionine to detect increased metabolism of metastatic sites 18 FDG hard to interpret because it accumulates in the urine Prostate cancer often with slow growth rate and may get false negatives Single photon emission computed tomography Allows more accurate localization of bone metastases Endorectal coil MRI investigational

Rising PSA: Limitations of Localization Studies Conclusions Currently no study reliably localizes tumor to pelvis Positive study doesn’t exclude mets

Rising PSA Scope of the Problem Definition Evaluation Treatment Local Systemic

Rising PSA: Clinical Course Radical prostatectomy (N=1,997 between 1982 and 1997) PSA-only recurrence (N=315; 15%) Clinical metastases Death from prostate cancer 8 years median 5 years median Pound, et al. JAMA. 1999;281:1591.

Rising PSA: Treatment Treatment options Salvage XRT Salvage RRP or cryotherapy(after XRT) Early hormonal therapy

Rising PSA: Salvage XRT Predictive factors for successful salvage XRT Gleason score <7 No seminal vesicle invasion Undetectable post RRP nadir PSA <2ng/mL preXRT treatment Garg, et al. Urology. 1998;51:998-1002 Pisansky et at J. Urol 2000;163:845-850 .

Rising PSA: Salvage XRT Salvage Radiotherapy to the Prostatic Bed for Radical Prostatectomy PSA-Only Recurrence Salvage XRT Given for PSA Above: 2.5 ng/mL 1.1 ng/mL 2.0 ng/mL 1.0 ng/mL Disease-Free Outcome 8% 26% 33% 17% Author Wu, et al Schild, et al Forman, et al Zelefsky, et al

Rising PSA: Salvage RRP 66% of patients with a positive biopsy after XRT developed clinical recurrence 29% with negative biopsies relapsed However 18% with positive biopsies did not develop clinical recurrence at 10 years Scardino et al. J. Urol 1986

Rising PSA: Salvage RRP Patients should have had localized disease prior to XRT Increased rate of post operative complications Anastomotic strictures 10-27% Rectal injuries 0-15% Incontinence (severe >2 pads/day) 10-60% Impotence 90-100%

Rising PSA: Salvage RRP Results Preoperative PSA<10ng/mL 5 yr biochemical free survival-50% Preoperative PSA>10ng/mL 5 yr biochemical free survival-29% Organ confined 5 yr biochemical free survival-100% Non organ confined 5 yr biochemical free survival-28-71% Rogers et al. J Urol 1995

Rising PSA: Salvage RRP Conclusions Salvage RRP after XRT best for: PSA<10ng/mL Organ confined disease Motivated patients with >10 years life expectancy

Rising PSA: Salvage Cryotherapy 5 year follow-up in 150 patients who underwent salvage cryotherapy after XRT All cases biopsy proven recurrence and no clinical evidence of metastatic disease Overall disease free survival at 5 years was 40% Izawa et al. JCO 2002: 2664

Rising PSA: Salvage Cryotherapy Predictors of failure High pre-XRT clinical stage (>T2) Pre cryotherapy PSA>10ng/mL Pre cryotherapy Gleason score >9 Increasing PSA despite hormonal therapy Complications of cryotherapy urinary incontinence rate of 6-8% in contemporary series

Rising PSA Conclusions Many PSA recurrences after definitive local therapy probably represent occult metastatic disease

NCCN Guidelines Post-Definitive Therapy Surveillance PSA level checked q6 mos. X 5 years, then yearly 45% of PSA recurrence occurs < 2years 77% < 5 years 23% >6 years Pound et al. JAMA 281: 1591-97, 1999 Bone scans when symptoms develop or rapid rise in PSA Probability of positive bone scan <5% if PSA<40ng/ml or PSA slope < 5.0ng/ml/month Cher et al. J Urol. 160: 1387-91, 1998

NCCN Guidelines Failure of PSA to Normalize If + surgical margin – XRT +/- hormones Hormonal therapy alone less preferred If negative surgical margin – observation or hormonal intervention (no consensus)

NCCN Guidelines Rising PSA Definitions of PSA failure vary (0.2-0.6) Attempts to identify local recurrence vs. distant disease have been disappointing CT, MRI, Prostascint, Bone scan

Rising PSA: Treatment Questions? Is early hormonal treatment better than later treatment?

VACURG I c.) No effect on survival in III and IV patients How does DES-5mg compare with orchiectomy and does orch+DES>orch alone? Results: a.) 5mg DES high CV toxicity b.)All endocrine tx, when given at diagnosis had slower disease progression in stage III and IV patients c.) No effect on survival in III and IV patients d.) DES better than orchiectomy in preventing cancer deaths e.) 44% of placebo arm went on to receive endocrine therapy…could infer that early therapy better than delayed

VACURG II Randomized 506 men in stage III and IV to either placebo vs. 0.2mg, 1.0mg and 5.0mg DES. DES-1.0mg =DES 5mg in delaying cancer progression DES-1mg given at diagnosis improved survival compared with placebo, 0.2mg and 5mg DES DES 1mg, early intervention recommended in younger patients with high grade tumors, but not in elderly

VACURG III Stage III and IV men randomized to either Premarin 2.5mg, Provera 30mg, Provera + DES-1mg and DES-1mg alone No difference in overall survival between groups DES 1mg alone better than other tx in delaying progression of disease from stage III to IV Delay in progression most pronounced in younger men (<75 years) and high grade (Gleason 7-10) DES-1mg can still have increased CV effects in elderly or ill men

6 Conclusions from VACURG DES-5mg high CV toxicity profile Orch + DES=orch or DES alone (DES>orch in delaying progression) DES 1mg=DES 5mg Reduced CV hazard for DES-1mg Premarin/provera no better than DES-1mg VACURG studies suggest survival benefit of early vs. late therapy

Leuprolide Vs. DES Leuprolide Study Group: compared DES-3mg to Lupron 1mg SQ QD form men with metastatic prostate cancer Lupron=DES-3mg in survival and response rate Less side effects with leuprolide NEJM, 311(20): 1281-1286, 1984

Rising PSA: Treatment MRC study Bolla study (EORTC) Trials Demonstrating a Prostate Cancer Progression/Survival Benefit for Early Hormonal Therapy MRC study Bolla study (EORTC) ECOG/Intergroup D1 study (Messing) Casodex Early Prostate Cancer Trialist Group

Rising PSA: Treatment MRC Study 934 patients studied 55% no metastatic disease by bone scan (M0) 25% with metastatic disease (M1) 20% metastatic status unknown (MX) Randomized to early hormonal therapy (469 patients) vs. delayed therapy (465 patients) Patients followed for progression, complications, and survival

Rising PSA: Treatment MRC Study-complications Spinal cord compression and pathologic fractures 20/469 in immediate treatment vs. 44/465 in deferred treatment Patients requiring TURP 65/469 in immediate vs. 141/465 in deferred treatment Ureteric obstruction 33/469 in immediate vs. 55/465 in deferred treatment

Rising PSA: Treatment MRC study-survival P=0.001

MRC Study-Survival Survival advantage seen in M0 patients, but not in M1/MX men Patients with M1/MX disease had fewer side effects with early therapy

Critique of MRC Trial Initially powered for 2000 men, only 938 enrolled Intention to treat analysis rather than a true comparison of two treatment arms Significant number of MX patients in which presence of mets not know Immediate tx = within 6 weeks 50% of M1 deferred arm received tx within 9 months

Goserelin Plus Radiotherapy in Locally Advanced Prostate Cancer Patients With Stage T1 - T4 Disease Randomize (N=415) external irradiation (N=208) external irradiation + Zoladex (N=207) Slide 70 Radiation: 50 Gy over 5 weeks plus 20 Gy over 2 weeks Zoladex: 3.6 mg SC every 4 weeks starting Day 1 of radiation for 3 yr Cyproterone: 150 mg po qd for 1 month starting 1 week prior to zoladex From 1987 to 1995, 415 patients with locally advanced prostate cancer were randomly assigned to receive radiotherapy alone or radiotherapy plus immediate treatment with goserelin. Patients were eligible if they were less than 80 years old, had no previous treatment for prostate cancer and no history of malignant disease (except for treated basal-cell carcinoma of the skin). Cyproterone acetate (Androcur, Schering), a steroidal antiandrogen, was given to prevent the consequences of the transient rise in testosterone levels caused by goserelin. Radiation therapy was administered once a day, 5 days/week for 7 weeks. Planning target volume for the first 5 weeks was the whole pelvis. During the last 2 weeks, in which an additional 20 Gy was administered, the planning target volume was the prostate and seminal vesicles. Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med. 1997;337:295-300. Bolla M, et al. N Engl J Med. 1997;337:295-300.

Goserelin Plus Radiotherapy in Locally Advanced Prostate Cancer Patients With Stage T1 - T4 Disease Randomize (N=415) external irradiation (N=208) external irradiation + Zoladex (N=207) Slide 70 Radiation: 50 Gy over 5 weeks plus 20 Gy over 2 weeks Zoladex: 3.6 mg SC every 4 weeks starting Day 1 of radiation for 3 yr Cyproterone: 150 mg po qd for 1 month starting 1 week prior to zoladex From 1987 to 1995, 415 patients with locally advanced prostate cancer were randomly assigned to receive radiotherapy alone or radiotherapy plus immediate treatment with goserelin. Patients were eligible if they were less than 80 years old, had no previous treatment for prostate cancer and no history of malignant disease (except for treated basal-cell carcinoma of the skin). Cyproterone acetate (Androcur, Schering), a steroidal antiandrogen, was given to prevent the consequences of the transient rise in testosterone levels caused by goserelin. Radiation therapy was administered once a day, 5 days/week for 7 weeks. Planning target volume for the first 5 weeks was the whole pelvis. During the last 2 weeks, in which an additional 20 Gy was administered, the planning target volume was the prostate and seminal vesicles. Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med. 1997;337:295-300. Bolla M, et al. N Engl J Med. 1997;337:295-300.

Kaplan-Meier Estimate of the Disease-Free Interval 100 80 85% (78%-92%) Combined treatment 60 Percentage of Patients 48% (38%-58%) Radiotherapy 40 20 P=0.001 (overall log-rank test) Slide 78 2 4 6 8 10 Years The Kaplan-Meier estimate of disease-free survival at 5 years was 85% (95% CI, 78% to 92%) for the combined-treatment group and 48% (95% CI, 38% to 58%) in the radiotherapy group (P<0.001). The 5-year failure-free rate after biologic response was 81% for the combined-treatment group and 43% for the radiotherapy only group. Time to first treatment failure was 6.6 years (95% CI, 3.5 to 5.3) compared to 4.4 years (95% CI, 5.8 to 9.0); hazard ratio = 0.17; 95% CI, 0.11 to 0.48; P<0.001. Seventy-eight patients had disease progression in the radiotherapy group vs 20 in the combined treatment group with a median follow-up of 2.5 years. Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med. 1997;337:295-300. No. of Patients at Risk Radiotherapy 208 163 107 59 38 19 11 5 3 1 Combined treatment 207 189 138 108 78 51 36 16 5 0 No. Who Died 78 20 Bolla M, et al. N Engl J Med. 1997;337:295-300.

Kaplan-Meier Estimate of Overall Survival 100 79% (72%-86%) 80 Combined treatment 60 Percentage of Patients 62% (52%-72%) 40 Radiotherapy 20 P=0.001 (overall log-rank test) Slide 77 2 4 6 8 10 The Kaplan-Meier estimate of overall survival at 5 years in the combined treatment group was 79% (95% CI, 72-86%) as compared with 62% (95% CI, 52-72%) for the radiotherapy only group (P<0.001). There were 58 deaths in the radiotherapy group and 35 in the combined treatment group. Of these deaths, 26 in the radiotherapy group and 6 in the combination-treatment group were due to prostate cancer. Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med. 1997;337:295-300. Years No. of Patients at Risk Radiotherapy 208 183 139 96 67 39 23 10 6 1 Combined treatment 207 190 144 111 82 55 39 19 7 0 No. Who Died 58 35 Bolla M, et al. N Engl J Med. 1997;337:295-300.

Zoladex Plus Radiotherapy in Locally Advanced Prostate Cancer Conclusion Adjuvant treatment with zoladex for 3 years, when started simultaneously with external irradiation, improves local control and survival in patients with locally advanced prostate cancer Slide 80 The investigators concluded that adjuvant treatment with goserelin, when started simultaneously with external radiation and continued for 3 years, improves local control and survival in patients with locally advanced prostate cancer. The findings on improved local control with combined-therapy are in agreement with those of Pilepich et al (1995). This is the first published study to show an increase in survival with this combination therapy in patients with locally advanced prostate cancer. Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med. 1997;337:295-300. Pilepich MV, Krall JM, Al-Sarraf M. Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the Radiation Therapy Oncology Group. Urology. 1995;45:616-623. Bolla M, et al. N Engl J Med 1997;337:295-300.

Critique of EORTC Trial 45 months median follow up – projected survival rates are uncertain until longer follow up Improved effect of hormones+XRT may be cytoreductive and not have any real effect on micrometastatic disease

Journal of Medicine Rising PSA: Treatment The New England ©Copyright, 1999, by the Massachusetts Medical Society VOLUME 341 December 9, 1999 NUMBER 24 IMMEDIATE HORMONAL THERAPY COMPARED WITH OBSERVATION AFTER RADICAL PROSTATECTOMY AND PELVIC LYMPHADENECTOMY IN MEN WITH NODE-POSITIVE PROSTATE CANCER Edward M. Messing, MD, Judith Manola, MS, Michael Sarosoy, MD, George Wilding, MD, E. David Crawford, MD, and Donald Trump, MD

Rising PSA: Treatment Immediate Hormone Therapy vs. Observation Population 98 Men with node-positive prostate cancer s/p radical prostatectomy and pelvic lymphadenectomy Study design Randomly assigned to immediate LHRH q 28 days or bilateral orchiectomy or observation until disease progression Endpoint Overall survival, prostate cancer-specific survival and progression-free survival Sample n=47 – immediate antiandrogen therapy n=51 – observation Duration Median 7.1 years (3-10) Messing EM, et al. N Engl J Med. 1999;341:1781-1788.

Rising PSA: Treatment N=98; 1988-1992 Mean follow-up: 7.2 years Results of Immediate Hormone Therapy vs. Observation N=98; 1988-1992 Mean follow-up: 7.2 years IHT Observation 4.3% 30.8% Death-PC (P<.01) 18.8% 75.0% Progression (P<.001) Messing EM, et al. N Engl J Med. 1999;341:1781-1788.

Progression-Free Survival

Overall Survival

Rising PSA: Treatment Conclusions Early hormone therapy provides a progression and survival advantage for patients with metastatic prostate cancer. *Messing EM, et al. N Engl J Med. 1999;341:1781-1788.

Critique of ECOG Study Powered for 204 patients but closed after 98 37/51 men in observation group received hormonal intervention…really a comparison of early vs. late therapy? Median PSA at the start of tx in the observation group was 14 Gleason score not predictive of survival in entire cohort (no central path review) Delayed therapy cohorts of men who underwent RRP with + nodes in series from Johns Hopkins, UCLA and Mayo did significantly better than in ECOG study

Biclutamide Monotherapy 3 randomized, placebo-controlled, double blind studies Efficacy of biclutamide (Casodex) alone as immediate therapy in men with localized or locally advanced CaP or as adjuvant to treatment of curative intent 150mg biclutamide qday vs placebo Data now available for 8,113 men with 3 year median follow-up See et al. J Urol., 168: 429-435, August 2002

Biclutamide Monotherapy 42% reduction in objective disease progression (bone scan) in biclutamide group 33% reduction in incidence of bone mets 59% reduction in PSA progression Trial 23 (North America) failed to show a difference in objective disease progression No survival benefit noted yet with short follow-up

Biclutamide Monotherapy 25.8% of men in biclutamide group withdrew due to side effects Gynecomastia and breast tenderness most common

Rising PSA: Early Hormonal Therapy If we believe that a majority of men with PSA-only recurrence actually have occult D1/D2 disease, then early traditional hormonal therapy should provide a disease-specific survival advantage Implications from ECOG D1 trial* *Messing EM, et al. N Engl J Med. 1999;341:1781-1788

Rising PSA: Conclusions Rising PSA after surgery is a difficult and not uncommon problem The definition of a rising PSA varies PSA>0.4ng/mL after RRP Three consecutive rises after nadir for XRT Three consecutive rises above 0.2ng/mL for brachytherapy

Rising PSA: Conclusions No study consistently differentiates local versus metastatic disease Clinical factors help predict Radiologic studies help predict From studies of adjuvant therapy, most PSA recurrences seem to represent metastatic disease

Rising PSA: Conclusions Early hormonal therapy provides a progression advantage and probably a survival advantage for metastatic prostate cancer Hormone therapy in addition to radiation therapy provides a survival advantage

Failure of First Line Salvage Therapy Consider addition of anti-androgen If on complete androgen blockade—withdraw anti-androgen—1/3 will respond with decline in PSA lasting 4-6 months Second line hormonal agents—ketoconazole, megestrol, glucocorticoids, cytotoxic chemotherapy

Rising PSA: Conclusions No standard of care for treatment Trials may help answer questions and identify agents which provide a definite survival advantage