According to the European Association of Urology (EAU) guidelines, ADT should be given to patients presenting with metastatic disease, together with chemotherapy if they are fit for it. ADT with an antiandrogen should be offered to all metastatic patients unfit for or unwilling to consider chemotherapy. ADT is recommended in select patients with localized disease, in patients with positive nodes, in locally advanced prostate cancer when local treatment is not possible, or when PSA doubling time is less than 12 months, and the tumor is poorly differentiated, and lastly in metastatic prostate cancer patients.
The LATITUDE study (1) randomized metastatic hormone sensitive prostate cancer patients to either ADT + placebo, or ADT + abiraterone 1000 mg and prednisone 5 mg. The primary endpoint was overall survival. Patients randomized had to have at least two poor-risk features (Gleason >=8, more than 3 bone metastases, or visceral metastases). The results of the study showed a clear advantage to the abiraterone arm with a 38% reduction of the risk of death, as seen in Figure 1. The 3-year survival rate for abiraterone was 66% vs. 49% in the ADT + placebo group. In all secondary endpoints, abiraterone also had a significant advantage: 53% risk reduction in progression free survival, 30% risk reduction in patients without pain progression, 70% risk reduction in patients without PSA progression, and 30% risk reduction in patients without symptomatic skeletal events.
The STAMPEDE trial had a similar comparison, between standard of care (ADT) and ADT + abiraterone. (2) The results demonstrated and overall 37% prolongation of overall survival with abiraterone, and a hazard ratio of 0.63, as shown in figure 2. Abiraterone increased the time until disease progression by 14 months and reduced bone associated problems by 54%.
In the next session, Dr. Cornford discussed some of the controversies of the treatment of MHSPC patients. These included whether earlier treatment is better, how to treat patients with low volume disease, the effect imaging has on diagnosis, and the comparison of the combination treatments. The first study mentioned was the French GETUG 15 study randomizing MHSPC patients to receive either ADT alone or ADT + docetaxel. (3) This study demonstrated improved biochemical progression free survival in the docetaxel group with 22.9 months vs. 12.9 months, p=0.005. However, no difference was seen in overall survival between the two groups. The similar CHAARTED study randomized patients in the same manner and showed an overall survival difference in favor of the docetaxel group. However, when looking specifically at patients with low volume disease, no statistically significant difference was seen between the groups in overall survival. With even further follow-up (4), less evidence of benefit in low volume disease was noticed, with a hazard ratio of 1.04, p=0.86. Very similar results were seen in the STAMPEDE trial, when looking only at patients with M0 disease, demonstrating a hazard ratio of 1.01 (95% CI 0.5-1.56). (5)
The next topic discussed was the role of imaging in these patients. The modality and type of imaging is crucial, as each modality can show different results, due to lack of specificity and sensitivity. PSMA PET/CT imaging is the current most promising modality showing at primary staging sensitivity and specificity of 61%, and 97%, respectively, while at restaging following biochemical recurrence, the sensitivity and specificity are 87-93% and 92-100%, respectively.
The STAMPEDE trial has one arm of patients being treated with ADT and docetaxel, and another arm of patients being treated with ADT and abiraterone. This enables performing a head to head comparison between these two drugs. The results demonstrated a benefit for abiraterone in failure free survival with a hazard ratio of 0.51 (p<0.001), 0.34 (p=0.003), and 0.56 (p<0.001) for all patients, M0 patients, and M1 patients, respectively. However, no differences were seen in the metastatic progression free survival, cancer specific survival, and overall survival between these two groups.
In summary, ADT is still the backbone of all treatments in MHSPC patients. As of 2017, docetaxel or abiraterone should be added to these patients. There is strong data supporting the use of abiraterone due to better failure free survival and progression free survival, but no evidence supporting its superiority in metastatic progression free survival, cancer specific survival and overall survival. Currently, there is no sufficient evidence to support treatment for patients with M0 HSPC.
Speaker: A. Merseburger, Lubeck (DE) P. Cornford, Liverpool (GB)
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter:@GoldbergHanan at the 2nd EAU Update on Prostate Cancer (PCa18)– September 14-15, 2018 – Milan, Italy
1. Fizazi K et al. NEJM 2017
2. James N et al. J Clin Oncol 35, 2017
3. Gravis G et al. Lancet Oncol 2013; 14 (2): 149-58
4. Kyriakopoulos CE et al JCO 2018
5. James N et al. Lancet 2016; 387:1163-1177