Refining Treatments for Prostate Cancer

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2 Refining Treatments for Prostate Cancer Moderated by: David Beyer, MD, FASTRO Tuesday, Oct. 20, :00 p.m. 2:00 p.m.

3 Duration of Androgen Deprivation in Locally Advanced Prostate Cancer: Long-Term Update of NRG Oncology/RTOG 9202 C. A. F. Lawton 1, J. J. Dignam 2, G. E. Hanks 3, H. Lepor 4, D. Grignon 5, H. D. Brereton 6, M. Bedi 1, S. A. Rosenthal 7, K. L. Zeitzer 8, V. M. Venkatesan 9, E. M. Horwitz 3, T. M. Pisansky 10, H. Kim 11, M. B. Parliament 12, Y. Kwok 13, M. Roach III 14, X. Lin 15, and H. M. Sandler 16 1 Medical College of Wisconsin, Milwaukee, WI, 2 NRG Oncology Statistics and Data Management Center, Philadelphia, PA, 3 Fox Chase Cancer Center, Philadelphia, PA, 4 NYU Langone Medical Center, New York, NY, 5 Indiana University, Indianapolis, IN, 6 Northeast Radiation Oncology Center, Dunmore, PA, 7 Radiation Oncology Center, Sacramento, CA, 8 Einstein Medical Center, Philadelphia, PA, 9 London Regional Cancer Program, London, ON, Canada, 10 Mayo Clinic, Rochester, MN, 11 Wayne State University-Karmanos Cancer Institute, Detroit, MI, 12 Cross Cancer Institute - Alberta Health Services, Edmonton, AB, Canada, 13 University of Maryland School of Medicine, Baltimore, MD, 14 University of California, San Francisco, San Francisco, CA, 15 University of Chicago, Chicago, IL, 16 Cedars-Sinai Medical Center, Los Angeles, CA

4 Purpose To determine whether adding 2 years of adjuvant androgen-deprivation therapy (ADT) improves outcome for patients treated with ADT before and during radiation therapy (RT) This analysis will serve as a final update on outcomes and toxicities

5 Methods Patients with biopsy-proven prostate cancer with ct2c-t4 disease and no extra pelvic lymph node involvement and prostate-specific antigen (PSA) < 150 No distant metastasis KPS > 70 Institute Review Board (IRB) approval and informed consent signed No prior androgen deprivation therapy (ADT), chemo or radiation therapy (RT) allowed

6 Treatment ADT started 2 months prior to RT and continued until RT completed ADT= flutamide (250 mg) orally 3x daily and goserelin (3.6 mg) injected subcutaneously monthly RT= conventional RT to the pelvis 4 field tech to 44-46Gy (> 4MV) followed by a cone down to the prostate to 65-70Gy (isocenter dose) Patients then randomized to no further ADT (short-term ADT) vs 24 additional months of monthly goserelin (longterm ADT)

7 Results Study accrual dates: 6/92-4/95 N=1554 patients registered, 1520 eligible w/ follow-up Median follow-up: 20 years Endpoints: o DFS (Disease Free Survival) = Primary Endpoint o OS (Overall Survival) o LP (Local Progression) o DM (Distant Mets) o BF (Biochemical Free Survival) 1 o DSS (Disease Specific Survival) Death due to dz, treatment or unknown cause after DM Toxicity: No difference in urinary toxicity and minimal difference in bowel toxicity 1 Phoenix definition

8 Conclusions Compared to STAD, LTAD improves: o Disease Free Survival o Local Progression o Distant Metastasis o bned Survival o Disease Specific Survival For LTAD, 10% risk reduction, ~3% absolute OS difference was not statistically significant Patients who have locally advanced prostate cancer should receive radiation therapy and long term ADT

9 Discussion Comparison to other studies o o EORTC months vs 36 months ADT: 36 months improved Clinical Progression Free Survival PCS IV (Canadian Trial) 18 months vs 36 months: No difference in OS, DSS or Distant Mets o DART01/05 GICOR Trial 4 months vs 28 months + high dose RT: OS, DM Free Survival & bned improved with 28 months

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11 Long-term Patient Reported Outcomes From a Phase 3 Randomized Prospective Trial of Conventional Versus Hypofractionated IMRT Radiation Therapy for Localized Prostate Cancer T. Shaikh 1, T. Li 1, M. E. Johnson 1, L. Wang 1, M. A. Hallman 1, R. E. Greenberg 1, R. A. Price Jr 1, R. Uzzo 1, C. M. C. Ma 1, D. Chen 1, A. Pollack 2, and E. M. Horwitz 1 1 Fox Chase Cancer Center, Philadelphia, PA, 2 University of Miami, Miami, FL

12 Background The current standard definitive radiotherapy regimen for localized prostate cancer consists of conventionally fractionated radiation (1.8-2 Gy per fraction) for approximately 8 weeks (76-80 Gy). Hypofractionated radiation therapy delivers doses greater than 2 Gy per day with the potential advantages of reduced treatment cost and patient inconvenience, and a theoretical improvement in the therapeutic ratio for prostate cancer. The Fox Chase Cancer Center hypofractionation trial was a randomized phase III trial comparing hypofractionated radiation therapy with conventionally fractionated radiation therapy. o The final results were published in 2013 which demonstrated no significant difference in biochemical outcomes between subgroups (Pollack et al. JCO. 2013). Purpose: To assess the long term quality of life outcomes for patients undergoing conventionally fractioned radiation therapy versus hypofractionated radiation therapy for clinically localized prostate cancer.

13 Methods **Intermediate risk: 4 months androgen deprivation therapy High risk: 2 years of androgen deprivation therapy Clinically Localized Prostate Adenocarcinoma (Stratified by PSA, GS, and Risk Group) R A N D O M I Z E Conventional Fractionation 76 Gy in 38 fractions (2 Gy/fx) Hypofractionation 70.2 Gy in 26 fractions (2.7 Gy/fx) Patients completed quality of life self-assessment forms pre-radiation: 6 months, 12 months, 24 months, 36 months, 48 months, 60 months (EPIC, IPSS, EQ5D)

14 Baseline Characteristics CIMRT HIMRT p-value Baseline EPIC, Median (Range) Urinary Irritative/Obstructive ( ) ( ) 0.90 Genomic Classifier AUC 0.85 Urinary Incontinence ( ) 100 (52-100) 0.40 Hormone ( ) ( ) 1.00 Sexual ( ) ( ) 0.70 Bowel ( ) ( ) 0.09 Baseline IPSS, Median (Range) Overall 6 (0-28) 6 (0-26) 0.8 QoL score 2 (0-6) 2 (0-6) 0.3 Baseline EQ5D, Median (Range) EQ5D Index 1 ( ) 1 ( ) 0.57 EQ5D VSAS 85 (50-100) 85 (30-100) 0.17

15 Results There was no significant difference in mean score change for the EPIC bowel, sexual, hormonal, or urinary irritative/obstructive domains between the two treatment groups. Patients receiving hypofractionated radiation had worse EPIC urinary incontinence summary scores at 3 years. There was a trend towards a worse IPSS score at 2 and 3 years in the HIMRT group although this improved with further follow-up On multivariate analysis, there was no association between radiation fractionation scheme and any parameter at 48-months. Baseline parameters were strong predictors of all outcomes at 48 months. * * * Statistically significant difference between groups

16 Conclusions In general, hypofractionated and conventionally fractionated radiation result in similar long term quality of life outcomes. Patients receiving hypofractionated radiation appeared to have inferior genitourinary incontinence outcomes versus patients receiving conventionally fractionated radiation. Patients with poor baseline genitourinary function may have worse quality of life outcomes with hypofractionated radiation versus conventionally fractionated radiation. Baseline function is an important predictor of long term quality of life outcomes.

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18 NRG Oncology RTOG 0415: A Randomized Phase III Non-Inferiority Study Comparing 2 Fractionation Schedules in Patients with Low- Risk Prostate Cancer W. R. Lee 1, J. J. Dignam 2, M. Amin 3, D. Bruner 4, D. Low 5, G. P. Swanson 6, B. Shah 7, D. P. D'Souza 8, J. M. Michalski 9, I. S. Dayes 10, S. A. Seaward 11, W. A. Hall 12, P. L. Nguyen 13, T. M. Pisansky 14, S. Faria 15, Y. Chen 16, B. F. Koontz 1, R. Paulus 17, and H. M. Sandler 18 1 Duke University, Durham, NC, 2 University of Chicago, Department of Public Health Sciences, Chicago, IL, 3 Cedars-Sinai, Los Angeles, CA, 4 Emory University, Atlanta, GA, 5 University of California, Los Angeles, Los Angeles, CA, 6 Baylor Scott & White Healthcare Temple Clinic, Temple, TX, 7 York Cancer Center, York, PA, United States, 8 London Regional Cancer Program, London, ON, Canada, 9 Washington University School of Medicine, St. Louis, MO, 10 McMaster University, Hamilton, ON, Canada, 11 Kaiser Permanente Northern California, Santa Clara, CA, United States, 12 Medical College of Wisconsin, Milwaukee, WI, 13 Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, 14 Mayo Clinic, Rochester, MN, 15 McGill University Health Center, Montreal, QC, Canada, 16 Wilmot Cancer Institute, University of Rochester, Rochester, NY, 17 NRG Oncology, Philadelphia, PA, 18 Cedars-Sinai Medical Center, Los Angeles, CA

19 Background Radiation therapy for prostate cancer usually takes 8-9 weeks to deliver Shorter radiation schedules have been tried and appear to work as well This study is a direct comparison of a shorter course and a longer course of radiation therapy in men with early stage prostate cancer

20 Method R Prostate Cancer Not palpable PSA <10 GS 6 A N D O M I Z Arm 1 Arm 2 41 treatments over 8.2 weeks 28 treatments over 5.6 weeks E

21 Results Disease-Free Survival 82% 76%

22 Results Late Adverse Effects 73.8 Gy (n=533) 70.0 Gy (n=542) Rel. Risk 95% CI Any GI Grade 3 14 (2.6%) 22 (4.1%) Any GU Grade 3 12 (2.3%) 19 (3.5%)

23 Conclusion In men with low-risk prostate cancer, treatment delivered in 5.6 weeks works as well as treatment delivered over 8.2 weeks with a possible increase in late side effects

24 Acknowledgments Grant/Sponsor Acknowledgements o This project was supported by grants U10CA21661 (RTOG-Ops-Stat), U10CA37422 (CCOP), CA81647 (ATC), U10CA (NRG Oncology Operations), U10CA (NRG Oncology SDMC) from the National Cancer Institute (NCI). NCT Author affiliations o Duke University, Durham, NC;; University of Chicago, Dept. of Public Health Sciences, Chicago, IL;; Cedars-Sinai, Los Angeles, CA;; Emory University, Atlanta, GA;; University of California, Los Angeles, CA;; Baylor Scott & White Healthcare, Temple, TX;; York Cancer Center, York, PA;; London Regional Cancer Program, London, ON, Canada;; Washington University School of Medicine, St. Louis, MO;; McMaster University, Hamilton, ON, Canada;; Kaiser Permanente Northern California, Santa Clara, CA;; Dana-Farber Cancer Institute, Boston, MA;; Mayo Clinic, Rochester, MN;; McGill University Health Center, Montreal, QC, Canada;; Wilmot Cancer Institute, University of Rochester, Rochester, NY;; NRG Oncology, Philadelphia, PA

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26 NRG Oncology/RTOG A Phase III trial in patients following Radical Prostatectomy (RP) with pt2-3, pn0 prostate cancer and elevated PSA levels: Anti-Androgen Therapy (AAT) with Bicalutamide during and after salvage Radiation Therapy (RT) compared to Placebo + salvage RT W. U. Shipley 1, W. Seiferheld 2, H. Lukka 3, P. Major 3, N. M. Heney 1, D. Grignon 4, O. Sartor 5, M. Patel 3, J. P. Bahary 6, A. L. Zietman 1, T. M. Pisansky 7, K. L. Zeitzer 8, C. A. F. Lawton 9, F. Y. Feng 10, R. D. Lovett 11, A. Balogh 12, L. Souhami 13, S. A. Rosenthal 14, K. J. Kerlin 15, and H. M. Sandler 16 1 Massachusetts General Hospital, Harvard Medical School, Boston, MA, 2 NRG Oncology Statistics and Data Management Center, Philadelphia, PA, 3 Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, ON, Canada, 4 Indiana University, Indianapolis, IN, 5 Tulane University, New Orleans, LA, 6 Hopital Notre-Dame du CHUM, Montreal, QC, Canada, 7 Mayo Clinic, Rochester, MN, 8 Einstein Medical Center, Philadelphia, PA, 9 Medical College of Wisconsin, Milwaukee, WI, 10 University of Michigan, Ann Arbor, MI, 11 University of Vermont Medical Center, Burlington, VT, 12 Tom Baker Cancer Centre, Calgary, AB, Canada, 13 McGill University Health Center, Montreal, QC, Canada, 14 Radiation Oncology Center, Sacramento, CA, 15 Wayne Radiation Oncology, Goldsboro, NC, United States, 16 Cedars-Sinai Medical Center, Los Angeles, CA

27 Method Stratification Variables Surgical margins: positive or not Nadir PSA level: < 0.5: yes or no Entry PSA level: < 1.6 or Pre RP neoadjuvant STAD: yes or no R A N D O M I Z Arm 1 Arm 2 RT (64.8 Gy) plus AAT* (Bicalutamide 150 mg) QD** RT (64.8 Gy) plus placebo QD** E *AAT: Anti Androgen Therapy (peripheral androgen blockade) ** During and after RT for 24 months

28 Patients Enrolled March 1998 March eligible patients were randomized to Bicalutamide & RT or to Placebo & RT Median age at entry: 65 yrs Median follow-up of surviving patients: 12.6 yrs Median interval between RP and study entry: 2.1 yrs Median interval between RP and first detectable PSA: 1.4 yrs Median entry PSA was 0.6 ng/ml;; with 25th to 75th percentiles of 0.4 and 1.1 ng/ml

29 Results Overall Survival OS at 10 yrs: 82% vs 78%

30 Conclusions With a median F/U of greater than 12 years, the addition of 24 mos. of peripheral androgen blockage (AAT) during and after salvage RT significantly: o Improved Overall Survival ( p = ) o Reduced metastatic PC o Reduced death from PC [ from 7.5% to 2.3%;; NNT = 17 ] o Reduced tumor progression and the incidence of local regrowth GI or GU toxicity observed during AAT or placebo treatments were low and similar Gynecomastia was extremely common in the bicalutamide arm

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32 Validation of a genomic classifier for prediction of metastasis following postoperative salvage radiation therapy R. B. Den 1, V. Choeurng 2, L. Howard 3, A. De Hoedt 4, M. du Plessis 2, K. Yousefi 2, L. Lam 5, C. Buerki 5, E. Trabulsi 1, A. P. Dicker 1, E. Davicioni 5, J. R. Karnes 6, and S. Freedland 3,4 1 Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, 2 GenomeDx Biosciences Inc, Vancouver, BC, Canada, 3 Duke University, Durham, NC, 4 Veteran Affairs Medical Center, Durham, NC, 5 GenomeDx Biosciences, Vancouver, BC, Canada, 6 Mayo Clinic, Rochester, MN

33 Background Challenges in Management of Prostate Cancer Current standard practice results in both under- and overtreatment of patients We hypothesized that integration of a genomic classifier (Decipher) can improve identification of men at highest risk of developing metastasis after salvage radiation following prostatectomy, and distinguish those patients where additional therapy is beneficial

34 Method Evaluated 170 men treated at Thomas Jefferson, Durham, VA and Mayo Clinic The generalizability of this study was maximized by using a multi-institutional, multi-ethnic cohort o Greater than 30% of patients were African American men Salvage radiotherapy was defined as delivering radiotherapy when PSA levels were greater than 0.2 ng/ml or by radiation following salvage androgen deprivation therapy Primary endpoint: development of metastasis (regional or distant) as evidenced by positive CT and/or bone scans Prognostic accuracy of the models was tested using multivariable analysis, c-index and decision curve analysis

35 Results Genomic Classifier is the most significant prognostic factor for development of clinical metastases Genomic Classifier AUC 0.85

36 Results Patients with High Risk GC had improved survival with early salvage RT No significant difference in survival in GC low risk Increase in mets-free survival with early salvage RT in GC high risk

37 Conclusions Genomic Classifier adds to clinical information with regard to a patient s prognosis Patients with low GC have excellent prognosis Patients with high GC are at significant risk of metastatic disease and may benefit from intensified systemic therapy Integration of GC into clinical practice can impact on decision-making in the post prostatectomy setting

38 Q & A

39 Questions? Contact ASTRO s Press Office in San Antonio, Oct press@astro.org Slides, photos, and a link to the recording will be available following the briefing in ASTRO s online press room: