Refining Treatments for Prostate Cancer

Moderated by: David Beyer, MD, FASTRO

Tuesday, Oct. 20, 20151:00 p.m. – 2:00 p.m.

Duration of Androgen Deprivation in Locally Advanced Prostate Cancer:

Long-­Term Update of NRG Oncology/RTOG 9202

C. A. F. Lawton1, J. J. Dignam2, G. E. Hanks3, H. Lepor4, D. Grignon5, H. D. Brereton6, M. Bedi1, S. A. Rosenthal7, K. L. Zeitzer8, V. M. Venkatesan9, E. M. Horwitz3, T. M. Pisansky10, H. Kim11, M. B. Parliament12, Y. Kwok13,

M. Roach III14, X. Lin15, and H. M. Sandler16

1Medical College of Wisconsin, Milwaukee, WI, 2NRG Oncology Statistics and Data Management Center, Philadelphia, PA, 3Fox Chase Cancer Center, Philadelphia, PA, 4NYU Langone Medical Center, New York, NY, 5Indiana University, Indianapolis, IN, 6Northeast Radiation Oncology Center, Dunmore, PA, 7Radiation Oncology Center, Sacramento, CA, 8Einstein Medical Center, Philadelphia, PA, 9London Regional Cancer Program, London, ON, Canada, 10Mayo Clinic, Rochester, MN, 11Wayne State University-­Karmanos Cancer Institute, Detroit, MI, 12Cross Cancer Institute -­ Alberta Health Services, Edmonton, AB, Canada, 13University of Maryland School of Medicine, Baltimore, MD, 14University of California, San Francisco, San Francisco,

CA, 15University of Chicago, Chicago, IL, 16Cedars-­Sinai Medical Center, Los Angeles, CA

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

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

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 (long-­term ADT)

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 Endpointo 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 1Phoenix definition

Conclusions• Compared to STAD, LTAD improves:

o Disease Free Survivalo Local Progressiono Distant Metastasis o bNED Survivalo 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

Discussion

• Comparison to other studieso EORTC 22961 – 6 months vs 36 months ADT:

§ 36 months improved Clinical Progression Free Survival

o 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

Long-­term Patient Reported Outcomes From a Phase 3 Randomized Prospective Trial of

Conventional Versus Hypofractionated IMRT Radiation Therapy for Localized Prostate Cancer

T. Shaikh1, T. Li1, M. E. Johnson1, L. Wang1, M. A. Hallman1, R. E. Greenberg1, R. A. Price Jr1, R. Uzzo1, C. M. C. Ma1, D. Chen1,

A. Pollack2, and E. M. Horwitz1

1Fox Chase Cancer Center, Philadelphia, PA, 2University of Miami, Miami, FL

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.

Methods

Clinically Localized Prostate

Adenocarcinoma(Stratified by PSA, GS, and

Risk Group)

Conventional Fractionation 76 Gy in 38 fractions

(2 Gy/fx)

Hypofractionation70.2 Gy in 26 fractions

(2.7 Gy/fx)

RANDOMIZE

**Intermediate risk: ≤4 months androgen deprivation therapyHigh risk: 2 years of androgen deprivation therapy

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)

Baseline Characteristics

Genomic Classifier AUC 0.85

CIMRT HIMRT p-­valueBaseline EPIC, Median (Range)

Urinary Irritative/Obstructive 92.86 (39.29-­100) 91.67 (64.29-­100) 0.90Urinary Incontinence 92.35 (39.5-­100) 100 (52-­100) 0.40

Hormone 93.18 (56.82-­100) 93.18 (54.44-­100) 1.00Sexual 47.77 (0-­93.75) 53.23 (0-­94.23) 0.70

Bowel 95.54 (58.93-­100) 98.21 (60.71-­100) 0.09Baseline IPSS, Median (Range)

Overall 6 (0-­28) 6 (0-­26) 0.8QoL score 2 (0-­6) 2 (0-­6) 0.3

Baseline EQ5D, Median (Range)EQ5D Index 1 (0.4-­1.0) 1 (0.51-­1.0) 0.57EQ5D VSAS 85 (50-­100) 85 (30-­100) 0.17

Results

* Statistically significant difference between groups

• 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 hypofractionatedradiation 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.

* *

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 hypofractionatedradiation versus conventionally fractionated radiation.

• Baseline function is an important predictor of long term quality of life outcomes.

NRG Oncology RTOG 0415: A Randomized Phase III Non-­Inferiority Study Comparing 2 Fractionation Schedules in Patients with Low-­

Risk Prostate Cancer W. R. Lee1, J. J. Dignam2, M. Amin3, D. Bruner4, D. Low5, G. P. Swanson6, B. Shah7, D. P. D'Souza8, J. M. Michalski9, I. S. Dayes10, S. A. Seaward11, W. A. Hall12, P. L. Nguyen13, T. M. Pisansky14, S. Faria15, Y. Chen16,

B. F. Koontz1, R. Paulus17, and H. M. Sandler18

1Duke University, Durham, NC, 2University of Chicago, Department of Public Health Sciences, Chicago, IL, 3Cedars-­Sinai, Los Angeles, CA, 4Emory University, Atlanta, GA, 5University of California, Los Angeles, Los Angeles, CA, 6Baylor Scott & White Healthcare Temple Clinic, Temple, TX, 7York Cancer Center, York, PA, United States, 8London Regional Cancer Program, London, ON, Canada, 9Washington University School of Medicine, St. Louis, MO, 10McMaster University, Hamilton, ON, Canada, 11Kaiser Permanente Northern California, Santa Clara, CA, United States, 12Medical College of Wisconsin, Milwaukee, WI, 13Dana-­Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, 14Mayo Clinic, Rochester, MN, 15McGill University Health Center, Montreal, QC, Canada, 16Wilmot Cancer Institute, University of Rochester, Rochester, NY, 17NRG Oncology, Philadelphia, PA, 18Cedars-­Sinai Medical Center, Los Angeles, CA

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

Method

• Prostate Cancer• Not palpable• PSA <10•GS ≤6

RANDOMIZE

Arm 141 treatmentsover 8.2 weeks

Arm 2 28 treatmentsover 5.6 weeks

ResultsDisease-­Free Survival

82%76%

ResultsLate 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%) 1.55 0.80-­2.99

Any GU ≥ Grade 3 12 (2.3%) 19 (3.5%) 1.56 0.76-­3.18

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

Acknowledgments• Grant/Sponsor Acknowledgements

o This project was supported by grants U10CA21661 (RTOG-­Ops-­Stat), U10CA37422 (CCOP), CA81647 (ATC), U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC) from the National Cancer Institute (NCI). NCT 00331773

• Author affiliationso 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

NRG Oncology/RTOG 96-­01A 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. Shipley1, W. Seiferheld2, H. Lukka3, P. Major3, N. M. Heney1, D. Grignon4, O. Sartor5, M. Patel3, J. P. Bahary6, A. L. Zietman1, T. M. Pisansky7, K. L. Zeitzer8, C. A. F.

Lawton9, F. Y. Feng10, R. D. Lovett11, A. Balogh12, L. Souhami13, S. A. Rosenthal14, K. J. Kerlin15, and H. M. Sandler16

1Massachusetts General Hospital, Harvard Medical School, Boston, MA, 2NRG Oncology Statistics and Data Management Center, Philadelphia, PA, 3Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, ON, Canada, 4Indiana University, Indianapolis, IN, 5Tulane University, New Orleans, LA, 6Hopital Notre-­Dame du CHUM, Montreal, QC, Canada, 7Mayo Clinic, Rochester, MN, 8Einstein Medical Center, Philadelphia, PA, 9Medical College of Wisconsin, Milwaukee, WI, 10University of Michigan, Ann Arbor, MI, 11University of Vermont Medical Center, Burlington, VT, 12Tom Baker Cancer Centre, Calgary, AB, Canada, 13McGill University Health Center, Montreal, QC, Canada, 14Radiation Oncology Center, Sacramento, CA, 15Wayne

Radiation Oncology, Goldsboro, NC, United States, 16Cedars-­Sinai Medical Center, Los Angeles, CA

Method

*AAT: Anti Androgen Therapy (peripheral androgen blockade)** During and after RT for 24 months

• Surgical margins: positive or not• Nadir PSA level: < 0.5: yes or no• Entry PSA level: < 1.6 or 1.6 – 4.0• Pre RP neoadjuvant STAD: yes or no

RANDOMIZE

Arm 1RT (64.8 Gy) plus AAT* (Bicalutamide150 mg) QD**

Arm 2 RT (64.8 Gy) plus placebo QD**

Stratification Variables

Patients• Enrolled March 1998 – March 2003• 761 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

ResultsOverall Survival

OS at 10 yrs:82% vs 78%

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 = 0.036 )o Reduced metastatic PCo 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

Validation of a genomic classifier for prediction of metastasis following

postoperative salvage radiation therapy

R. B. Den1, V. Choeurng2, L. Howard3, A. De Hoedt4, M. du Plessis2, K. Yousefi2, L. Lam5, C. Buerki5, E. Trabulsi1, A. P. Dicker1, E. Davicioni5,

J. R. Karnes6, and S. Freedland3,4

1Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, 2GenomeDx Biosciences Inc, Vancouver, BC, Canada, 3Duke University, Durham, NC, 4Veteran Affairs Medical Center, Durham,

NC,5GenomeDx Biosciences, Vancouver, BC, Canada, 6Mayo Clinic, Rochester, MN

Background

• 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

Challenges in Management of Prostate Cancer

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 multi-­variable analysis, c-­index and decision curve analysis

ResultsGenomic Classifier is the most significant

prognostic factor for development of clinical metastasesGenomic Classifier

AUC 0.85

ResultsPatients with High Risk GC had improved survival

with early salvage RT

Increase in mets-­free survival with early salvage RT in GC high risk

No significant difference in survival in GC low risk

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

Q & A

Questions?Contact ASTRO’s Press Officein San Antonio, Oct. 18-­21

210.258.8104703.772.2510press@astro.org

Slides, photos, and a link to the recording will be available following the briefing in ASTRO’s online press room:www.astro.org/AMPress