The gentleman of interest is 58-years-old with a PSA of 5 ng/mL who eventually underwent a radical prostatectomy for Gleason 8 prostate cancer, pN-, negative margins. His post-op PSA was 0.06 ng/mL and bone and CT scan were normal. Two years post-operatively his PSA was 0.21 and he eventually received salvage radiotherapy to the prostate bed with a PSA decrease to 0.06. However, two years thereafter his PSA started to rise again. Dr. Fizazi points out that based on the Freedland et al. paper from 2005 , PSA doubling time after biochemical recurrence is highly predictive of prostate cancer specific mortality (PCSM). For instance, a PSA doubling time <3 months is associated with median prostate cancer survival of ~5 years, whereas a PSA doubling time >9 months is essentially without risk of PCSM.
Based on this clinical situation, the main question is whether ADT should be used ‘early’ (ie. before the onset of metastases) in men with rising PSA post-local treatments? In fact, there are three clinical trials in this disease space: (i) TROG 03.06 and VCOG PR 01-03 was a phase III RCT that randomized 293 men to immediate ADT vs deferred ADT (delay of at least 2 years) . Over a median follow-up of 5 years, the HR for OS was significantly improved among men receiving immediate ADT (0.55, 95%CI 0.30-1.00, p=0.05); (ii) GETUG-AFU 16 was a phase III RCT that randomized 734 men with pT2-T4 post-radical prostatectomy and PSA 0.2-2 ng/mL to radiotherapy with 66 Gy vs radiotherapy 66 Gy + goserelin 10.8 mg x 2 doses . Relapse-free survival was significantly improved for patients receiving radiotherapy + goserelin (HR 0.50, 95%CI 0.38-0.66); (iii) RTOG 9601 randomized men with post-prostatectomy rising PSA to radiotherapy +/- bicalutamide and found a significantly improved OS among patients receiving radiotherapy + androgen receptor blockade (HR 0.77, 95%CI 0.59-0.99; 12-year OS 76% vs 71%, p=0.04) . Despite three trials supporting earlier use of ADT in biochemical failures after local therapy, Dr. Fizazi poses the pertinent question of whether PSA doubling time is still significant (and possible all that is necessary) to guide decision making, considering the convincing results in the Freedland et al.  study.
The second issue for this patient is the question regarding intermittent vs continuous ADT for his PSA relapse. Dr. Fizazi points out that the NCIC Canadian trial randomized 1,386 patients with PSA regression after radiotherapy (primary or salvage) and PSA >3 to continuous vs intermittent ADT, finding that there was no difference in OS between these groups . In this study, definition of intermittent ADT was 8 months of ADT, which was then stopped after PSA < 4 and recycled when the PSA reached >10. In the current case, the patient was started on intermittent ADT, however several years later his PSA was rising in the setting of a castrate testosterone (CRPC M0). In this disease space, Dr. Fizazi notes there are several trials that support doubling time as a reliable metric for time to bone metastases or death. Furthermore, he highlights, three phase III trials in the M0 CRPC that failed to improve OS, including the use of atrasentan, zibotentan, and denosumab. At this point, the patient agreed to enter the Prosper phase III trial assessing enzalutamide vs placebo. This trial is an ongoing RCT randomizing M0 CRPC men with PSA doubling time ≤10 months (n=1,560) 2:1 to enzalutamide vs placebo with a primary endpoint of metastasis-free survival. This study is awaiting maturation of data. As Dr. Fizazi notes, he was likely randomized to the control arm as his PSA is now rising; a bone scan, CT scan and PET-choline were ordered at this point and all were normal.
This case and discussion set the stage for the final two presentations in this symposium discussing imaging techniques in the M0 disease space.
Speaker: Karim Fizazi, Institut Gustave Roussy, University of Paris Sud, Villejuif, France
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the European Society for Medical Oncology Annual Congress - September 8 - 12, 2017 - Madrid, Spain
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2. Duchesne GM, Woo HH, Bassett JK, et al. Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): A randomized, multicentre, non-blinded, phase 3 trial. Lancet Oncol 2016;17(6):727-737.
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