ESMO 2018: The Best of Munich 2018 Congress Genitourinary Tumors, Prostate

Munich, Germany (UroToday.com) Silke Gillessen, MD summarized the highlights of prostate cancer studies presented this year in ESMO.  A total of four important prostate cancer studies in three different prostate cancer settings were presented in this session, deemed to be very important by Dr. Gillessen. These four studies included:
  1. In localized prostate cancer: study 7910 GETUG 121
  2. In advanced prostate cancer: hormone-sensitive disease two studies were presented:
  1. In advanced prostate cancer: metastatic castrate resistant prostate cancer (mCRPC) – LBA30 – ERA – 223 The combination of abiraterone, prednisone and Radium 223 vs. abiraterone and prednisone alone.4
According to present guidelines, the therapeutic options for patients with high risk or locally advanced prostate cancer include external beam radiotherapy plus hormonal treatment or radical prostatectomy plus pelvic lymph node dissection.

In the 7910 GETUG 12 trial – patients with high risk localized prostate cancer were randomized to either androgen deprivation therapy (ADT) for three years with local treatment, or ADT for three years with local therapy and with the addition of 4 cycles of docetaxel. The study design is demonstrated in Figure 1. Data presented at ESMO included 12 years of follow-up.  The primary endpoint was relapse-free survival (RFS). The docetaxel arm conferred significantly improved RFS, with no statistically significant difference in the metastasis-free survival (MFS), as can be seen in figure 2. Only 2% of patients had developed a neutropenic fever with no increase in secondary cancers after 12 years of follow-up. Lastly, the quality of life was not different at the 1-year mark.

In summary, approximately 40% of patients were “cured” with no PSA relapse at 12 years with standard treatment alone. Four cycles of docetaxel reduced RFS, but not MFS, cancer-specific survival or overall survival. Therefore, this trial does not confer any change in the current recommended treatment guidelines for the high risk locally advanced disease.

Figure 1 - GETUG 12 trial design:
Figure 1- GETUG 12 trial design.png

Figure 2 – Relapse-free and metastasis-free survival in GETUG 12:
Figure2–RelapseFreeMetastasis-Free_Survival_GETUG12.png
The next two studies discussed were the STAMPEDE trials that were presented in ESMO. STAMPEDE is a multi-arm, multi-stage design trial, assessing various drugs and outcomes in patients starting on long-term ADT with M1 or high-risk M0 disease. The primary endpoint is overall survival.

Abiraterone + prednisone has been shown both in the LATITUDE study5, and the STAMPEDE study6 to confer a significant overall survival advantage in mHSPC patients. This has results in the guidelines of ESMO, NCCN, and EAU to recommend ADT + Abiraterone as a first-line treatment option for mHSPC. In the LBA4 study, the impact of abiraterone on low volume metastatic disease was assessed.  This study was a retrospective subgroups analysis. Radiographic scans were centralized and stratified for risk according to the definition used in LATITUDE and CHAARTED studies (Figure 3). The results demonstrated a clear advantage favoring abiraterone in low volume disease.

Figure 3 – Risk stratification according to Latitude and CHAARTED:
Figure3–Risk_Stratification_Latitude_CHAARTED.png
The next study discussed was LBA5 – radiotherapy to the prostate in mHSPC patients. In this study, men with newly diagnosed metastatic prostate cancer were randomized to either ADT +/- docetaxel alone, or to ADT +/- docetaxel and radiotherapy to the prostate. The trial design is shown in Figure 4. The primary endpoint was overall survival, with the secondary endpoints being failure-free survival, symptomatic local events, and toxicity. The results were also stratified by disease volume.

Figure 4 - LBA5 – STAMPEDE – Radiotherapy to the prostate in mHSPC patients:
Figure4-LBA5– STAMPEDE-Radiotherapy-mHSPC.png
The results demonstrated no overall survival difference between the arms when patients were analyzed together, and when only high burden disease patients were analyzed. However, a clear benefit for the radiotherapy arm was seen in the low volume patients (Figure 5). There was also a difference in failure-free survival, in favor of the radiotherapy arm (HR 0.76, 95% CI 0.68-0.84, p=0.000000336). 

Figure 5 – Overall survival in LBA5 stratified by disease volume:
Figure 5 – OS_LBA5_Stratified_by_Disease_Volume.png
Summarizing the results of these two trials – there is a clear benefit in adding abiraterone to ADT + prednisone in low-risk patients. Prostate radiotherapy improved survival in men with a low burden of disease, and according to the authors, it should be considered the new standard of care for men with the low metastatic burden.

The last study discussed was LBA30 – ERA 223 – assessing the combination of abiraterone + prednisone + Radium 223. This study randomized mCRPC patients with bone-predominant disease who were asymptomatic or mildly symptomatic with good performance status to either abiraterone + prednisone + matching placebo, or to abiraterone + prednisone + Radium 223, as can be seen in the trial design shown in figure 6. The primary endpoint was symptomatic skeletal events free survival (SSE-FS).

Figure 6 – LBA30 – ERA 223 trial design:
Figure6–LBA30–ERA 223trialdesign.png

The trial was unblinded prematurely since more fractures and deaths had occurred in the combination arm. The results showed no statistical difference in the overall survival and SSE-FS, as seen in Figure 7. Interestingly, more fractures (traumatic, osteoporotic and pathological) were witnessed in the combination arm (26% vs. 10%). Use of bone health agents did not alter this difference, although the number of fracture in patients who took them, was lower.

In summary, the combination treatment of abiraterone and Radium did not improve SSE-FS and overall survival. There was an increased risk of clinical fractures in the combination arm, with the majority not being at the metastases sites. The evidence is quite clear that Radium 223 should not be given in combination with abiraterone.

Figure 7 – Overall survival and symptomatic skeletal event-free survival:
Figure 7_OS_symptomatic_skeletal_event-free_survival.png

Presented by: Silke Gillessen, MD, St. Gallen, CH

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter: @GoldbergHanan at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23,  2018, Munich Germany 

References:
  1. Fizazi K et al. ESMO 2018
  2. Hoyle A et al. ESMO 2018
  3. Parker C et al. ESMO 2018
  4. Smith M et al. ESMO 2018
  5. Fizazi K et al. NEJM 2017
  6. James ND et al. NEJM 2017
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