5 Background: The place of short term androgen deprivation therapy (STADT) in combination with radiation therapy (RT) for patients with intermediate risk prostate cancer (IRPC) remains controversial. The purpose of this prospective, randomized trial was to compare outcomes between patients with IRPC treated with different doses of RT with or without STADT, (PCS III trial, Clinical Trials.gov, NCT00223145). Methods: From December 2000 to September 2010, 600 patients with IRPC were randomized to 6 months of STADT and two levels of prostate RT doses of 70 (arm 1) or 76 Gy (arm 2) versus prostate dose-escalated RT alone at 76 Gy (arm 3). STADT consisted of bicalutamide and gosereline for six months. RT (2 Gy per fraction) started four months after the beginning of STADT. Biochemical failure and disease-free survival (DFS) were primary end-points, with overall survival (OS) as secondary endpoint. DFS and OS rates were estimated with Kaplan-Meier and compared with log rank test and Cox regression. Results: Patient’s characteristics were well balanced among the 3 arms (median age 71 years, median PSA 10 ng/ml, median Gleason score 7). At a median follow-up of 75.4 months, biochemical failure occurred in 84 (14%) patients (arms 1 to 3: 12.5%, 8.0%, 21.5%) with statistical difference between arm 1 and 3 (p = 0.023) and arm 2 and 3 (p < 0.001). There was no significant difference between arm 1 and 2. A total of 113 (19%) patients had died with only 6 deaths (1%) attributed to prostate cancer. The 5-/10-year DFS rates were 93%, 97.5% and 86%, and 77%, 90% and 64.5%, respectively. Significant differences in DFS between the treatment arms were observed at 5 years but at 10 years it was observed only between arm 1 and 3 (p=0.01) and arm 2 and 3 (p<0.001). The 5-/10-year OS rates were 91%, 95% and 93%, and 64%, 70% and 78%, respectively. There was no statistical difference in OS between arms at 5 and 10 years. Conclusions: In patients with IRPC, the use of STADT in association with RT, even at lower doses, leads to a superior biochemical control and DFS as compared to dose-escalated RT alone. These outcomes did not translate into an improved OS. Source of Funding: AstraZeneca Pharmaceuticals Grant. Clinical trial information: NCT00223145.

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Results: Of the 329 patients, 164 were randomized to hypofractionated RT and 165 to conventional RT. The median follow-up was 36 months (19-55 months). At 24 months, 8 patients in the conventional RT arm and 9 patients in the hypofractionated RT arm had grade 2 or worse gastrointestinal (GI) related adverse events (HR Z 0.76; 95% CI Z 0.26-2.19; P Z ns). Similarly, 7 patients in the conventional RT arm and 5 patients in hypofractionated RT arm had grade 2 or worse genitourinary (GU) toxicities (HR Z 0.57; 95% CI Z 0.17-1.95; P Z ns). Three patients in the hypofractionated RT arm and no patient in the conventional RT arm had grade 3 GI related toxicities, while one patient in hypofractionated RT group and 3 patients in conventional RT group had grade 3 GU related toxicities. There were no grade 4 toxicities in any of the groups. Conclusion: This is the first hypofractionated dose escalated radiotherapy study in high-risk prostate cancer patients treated with contemporary radiation techniques and androgen suppression. The results confirm our original hypothesis and indicate that moderate hypofractionated RT is equally well tolerated as conventionally fractionated radiotherapy at 2 years in high-risk prostate cancer patients.

300 Background: To determine the rate and time of testosterone (T) recovery to normal level in patients (pts) with prostate cancer treated with radiotherapy plus 6, 18 or 36 months of androgen deprivation therapy (ADT) and considered cured from their disease. Methods: We randomized 1230 pts with prostate cancer, into two phase III trials: 600 with intermediate risk and 630 with high-risk. We selected those considered cured to avoid subsequent T variations due to reintroduction of ADT for recurrence. We excluded the following pts: no ADT at all (126) or not receiving exactly 6, 18 or 36 months of ADT (69), survival less than one year (21), no T measured at baseline or during follow-up (75), biochemical failure (195) or evidence of metastatic/recurrent disease (137).T recovery rate was compared between baseline normal/abnormal T (values below biochemical normal range) and by ADT duration with Chi-square test or Fisher's exact test. A multivariable logistic regression model to predict the probability of recovering normal T was performed by including normal/abnormal T at baseline, age, Zubrod, comorbidities and ADT duration. A second model was performed by replacing ADT duration with baseline PSA, Gleason score and stage. The median time to T recovery was calculated only on pts who recovered normal T. Results: Results are reported with a median follow-up of 14 years. 607 pts fit the criteria and are available for analysis: 309 pts in the 6 months ADT schedule, 185 in the 18 and 113 in the 36. Overall, 76.7%, 54.6% and 45.1% pts recovered normal T on the 6, 18 or 36 months schedule, respectively (p<0.001). The median time to T recovery was 1.5, 3.1, and 5.1 years for the 6, 18 or 36 months schedule, respectively (p<0.001). 79.7% presented with a normal T at baseline while 20.3% had an abnormal T level. By splitting pts between a normal vs. abnormal presenting T level, the T recovery rate was as follows: 82.1%, 63.3%, and 50% for the normal T cohort, compared to 53.4%, 28.3% and 21.1% for the abnormal T cohort at 6, 18 or 36 months, respectively. There was a significant difference in the overall recovery rate (p<0.001) between normal vs. abnormal T level and at all ADT duration lengths between the two cohorts. In multivariable model, baseline normal T was a strong predictor of T recovery. Older age, diabetes, longer ADT, higher clinical stage, higher PSA and higher Gleason score reduced significantly the chance for T recovery. In pts recovering T post-ADT, except for the 6 months duration (p=0.01), the median time for T recovery was not significantly different between normal or abnormal T at baseline in 18 and 36 months cohorts. Conclusions: Older age, longer ADT and poor disease features are associated with a lower T recovery. Even after adjusting for several variables and ADT duration, a higher T recovery post-ADT is significantly associated with a normal T at baseline.

34 Background: The purpose of this analysis was to establish causes of death in a population of intermediate-risk (IR) and high-risk (HR) prostate cancer treated on two phase III trials. Methods: From October 2000 to September 2010, 1,230 patients were randomized: 630 with HR (ClinicalTrials.gov, #NCT00223171) and 600 with IR (#NCT00223145). HR was defined as T3-4, PSA >20 g/ml, Gleason >7 (with at least one of these 3 factors). IR was defined as T1-T2, Gleason < 6 and PSA 10-20 ng/ml or T1-T2, Gleason 7 and PSA < 20 ng/ml. Causes of death were compiled until July 2015 and were established from data sent by the different investigators and centrally reviewed. Causes of death were mainly based on data from clinical records, then by family members, obituaries, death certificates and family physicians. Results: The median follow-up for the 1,230 patients was 7.5 years (HR 8 vs. IR 6.8 years, p<0.001). 30.2% (372/1,230) patients had died: (HR 37% vs. IR 23.2%, p<0.001). A total of 8% (99/1,230) patients developed local, regional, and metastatic prostate cancer recurrences: (HR 11.6% vs. IR 4.3%, p<0.001) and 4.4% (54/1,230) died from prostate cancer: (HR 7.3% vs. IR 1.3%, p<0.001). The most frequent cause of death was a second cancer (120/1,230, 9.8%): (HR 10.6% vs. IR 8.8%, p=NS). Cardiovascular deaths occurred in 6.3% (78/1,230) (HR 7.1% vs. IR 5.5%, p=NS) with no statistical difference between the different durations of androgen deprivation therapy (ADT) 0, 6, 18, or 36 months. Other causes of death were pulmonary (3.7%), digestive (1.1%), others (3.3%), and unknown (1.7%). Majority of deaths occurred between 3 and 9 years after randomization (HR 70% and IR 73%). Prostate cancer deaths were distributed over all the follow-up period. The 5/10 year overall survival between HR and IR were 88.6%, 91.8%, and 61.6%, 69.8%, respectively with significant differences (p=0.045 and p=0.016). Conclusions: In patients with localized HR and IR prostate cancer, the first cause of death was a second cancer and prostate cancer came as the third one after cardiovascular disease. There was no statistical difference in the incidence of cardiovascular deaths in patients treated with different durations of ADT. Clinical trial information: Clinical Trials, gov. #NCT00223145 - Clinical Trials, gov. #NCT00223171.