ASCO 2017. LBA 3. LATITUDE: A phase III, double-blind, randomized trial of androgen deprivation therapy with abiraterone acetate plus prednisone or placebos in newly diagnosed high-risk metastatic hormone-naive prostate cancer.
Karim Fizazi et al.
Conclusions: Early use of AA+P added to ADT in pts with high-risk mHNPC yielded significantly improved OS, rPFS, and all secondary end points vs ADT+PBOs alone. ADT+AA+P had a favorable risk/benefit ratio and supports early intervention with AA+P in newly diagnosed, high-risk mHNPC.
ASCO 2017. LBA 5003. Adding abiraterone for men with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): Survival results from STAMPEDE
Nicholas D. James et al.
Results: 1,917 pts were contemporaneously randomized to these arms (Nov 2011- Jan 2014). Groups were balanced: median age 67yrs; 52% metastatic, 20% N+/X M0, 28% N0M0; 95% newly-diagnosed; median PSA 53ng/ml. Median follow-up was 40m. There were 262 control arm deaths (82% PCa). The adjusted HR = 0.63 (95% CI 0.52-0.76; p=0.115×10-7; 184 deaths) for SOC+Abi vs SOC, with 3yr OS improved from 76% to 83%. There were 535 control arm FFS events; the adjusted HR = 0.29 (95% CI 0.25-0.34; p = 0.377×10-63, 248 FFS events) for SOC+Abi vs SOC. Grade 3 & 4 adverse events were seen in 29% & 3% SOC, 41% & 5% SOC+Abi; Grade 5: 3 & 9 (1 & 2 related).
Conclusions: The results show a clinically & statistically significant effect on overall survival & failure-free survival from adding abiraterone at start of ADT with a manageable increase in toxicity. ADT (+/- RT) + abiraterone is a new standard of care for this group. Clinical trial information: NCT00268476
CARE™ Faculty Perspective:
Abiraterone has established a survival benefit for patients with advanced prostate cancer. The combination of abiraterone, prednisone, and androgen deprivation therapy (ADT) is able to stop the production of hormones directly at the testicular level and through inhibition of CYP17, an enzyme that convers cholesterol in androgens.
The STAMPEDE and LATITUDE trials support the use of upfront treatment of abiraterone with prednisone and ADT for advanced prostate cancer. The STAMPEDE trial investigated almost 2000 patients. Patients were eligible if they had metastatic disease, or if they had local/locoregional disease with high risk features. For all comers, the 3-year survival rate when adding abiraterone and prednisone to ADT was 83% compared to 76% when using ADT alone. The LATITUDE trial concluded that when abiraterone (with prednisone) is added to ADT therapy, a 38% improvement in OS was noted and PFS was 33 months compared with 14.8 months with ADT alone. These results could change the treatment paradigm of patients with advanced but castrate sensitive disease moving forward.
There is still much to be learned about the optimal treatment combination or sequence. We still do not know how abiraterone compares to docetaxel, and whether combination of the two is better than either agent alone. It will be interesting to see the results of trials looking at these types of combinations that are currently underway, such as the PEACE 1 & 2 trials and the ENZAMET study (although patients were randomized to enzalutamide or bicalutamide, roughly 50% of patients in either arms also received docetaxel as part of standard of care). This will give us an idea of the impact of abiraterone and docetaxel with ADT, and how the standard-of-care may be impacted.
Whether abiraterone is better than docetaxel, at least in patients with metastatic disease, remains untested in head to head randomized trials. However, as eloquently shown by Eric Small during his discussion of the two studies, the results observed in LATITUDE seem to quite closely mirror the results of CHAARTED – given the cost and toxicity differences in these two treatment approaches, deciding on an optimal regimen in these patients may require a personalized approach and payers may potentially end up taking some the decisions away from the prescriber and patient.
Treatment efforts do not end with this combination. It is also important to consider treatment sequencing after a patient [inevitably] progresses. Recent retrospective trials focused on sequencing have suggested that post- ADT, chemotherapeutic options (docetaxel followed by cabazitaxel) may extend OS. It is therefore important to monitor patients closely with PSA and regular imaging and not wait until symptomatic progression to consider further treatment. Otherwise, the opportunity to maximize subsequent lines of therapy may be less effective and/or not valid.
With the number of specialists involved in the management of prostate cancer (i.e. medical oncologists, urologists, radiation oncologists), collaboration and education on the entire course of therapy is of value, along with considerations for referral to another specialist if the patient’s current management approach is no longer working.