From the Desk of Evan Yu: Another advance in metastatic hormone-sensitive prostate cancer may change standard of care options but not attitude toward clinical trials.

For the longest time metastatic hormone-sensitive prostate cancer has been treated with androgen deprivation therapy (ADT).  Recently, the CHAARTED1 trial and STAMPEDE,2 both showed a dramatic survival benefit when 6 cycles of docetaxel was added to ADT.  For the CHAARTED trial, subgroup analyses confirmed survival benefit for those patients with high volume disease, defined as ≥4 bone metastases with at least one in the appendicular skeleton and/or a visceral metastasis. 

At the American Society of Clinical Oncology (ASCO) meeting in June 2017, we learned from the LATITUDE3 and STAMPEDE4 again that abiraterone acetate also offers a dramatic survival benefit when added to standard of care (SOC), generally ADT, vs. SOC alone.  From LATITUDE, ADT + abiraterone 1000 mg po qd + prednisone 5 mg po qd had an improvement in overall survival over ADT + placebos with HR 0.62 (95% CI, 0.51-0.76); p<0.0001.  The SOC + abiraterone + prednisolone arm of the STAMPEDE trial also showed a survival benefit over SOC alone with HR 0.63 (95% CI, 0.52-0.76); p = 0.00000115.  Notably, the STAMPEDE trial had a heterogeneous group of patients including a mix of M1 (52%) and M0 (48%) patients.

The real clinical question is now, “who should we give ADT + docetaxel to and who should we give ADT + abiraterone to?”.  There is no good answer to that question right now.  As in most things, we must all use our own good clinical judgment, building on the foundation of literature that exists. 

Therefore, for low volume metastatic disease, I am planning on offering abiraterone, as even the M0 subgroup from the STAMPEDE trial has a confidence interval that just slightly crosses 1 (HR 0.75, 95% CI, 0.48-1.18).  However, for high volume disease, there is no way to compare between the benefits of adding abiraterone compared to those of adding docetaxel.  A practical discussion with patients would compare side effects (likely greater with docetaxel over abiraterone), duration of therapy (shorter with docetaxel compared with abiraterone) and financial toxicity (more affordable with docetaxel compared with abiraterone).  Some patients will have a strong preference after consideration of these factors, and most patients will at least lean one way or another.

There are two frequent questions I have heard from patients since ASCO 2017.  The first is if a patient receives ADT alone or ADT + docetaxel, resulting in an outstanding prostate-specific antigen (PSA) decline, should he now receive abiraterone?  In this situation, my answer is “no,” since the patient already falls outside the duration of eligibility to have enrolled on either LATITUDE or STAMPEDE.  We have no data to guide us for patients in this setting, so my default is just to continue on ADT alone.  Another question is whether we should combine abiraterone and docetaxel with ADT?  Outside of strong pharmacokinetic data to show that abiraterone and docetaxel do not antagonize one another and efficacy data to show benefit of such a combination, my answer is also currently “no.”

Questions like this emphasize the fact that although we have another new potential standard of care with abiraterone for patients with metastatic hormone-sensitive prostate cancer, we still have many unanswered questions for patients with this disease state.  Fortunately, trials like Enzamet (ADT +/- enzalutamide with docetaxel allowed as dealers’ choice)  and SWOG 1216 (ADT + bicalutamide vs. ADT + orteronel) have recently completed accrual, and we avidly await results. 

However, there are many other trials ongoing in this setting testing novel 2nd generation androgen pathway inhibitors, and we should not shy from presenting these options to our patients.  Please see below for details of select ongoing phase 3 trials for patients with metastatic hormone-sensitive prostate cancer and links to their clinicaltrials.gov websites.

Highlighted Trials
ADT with either Enzalutamide vs. placebo  (NCT02677896) – 6 cycles of prior docetaxel allowed as long as completed within 2 months of day 1.
ADT with either Apalutamide vs. placebo (TITAN)  – 6 cycles of prior docetaxel allowed as long as completed within 2 months of day 1.
• ADT + docetaxel with either Darolutamide vs. placebo (ARASENS) 

Written by: Evan Yu, MD 

References
1. Sweeney C, et al.  N Engl J Med 2015; 373:737-46.
2. James ND, et al.  2016; 387:1163-77.
3. Fizazi K, et al.  N Engl J Med 2017; Epub June 4, 2017.
4. James ND, et al.  N Engl J Med 2017; Epub June 3, 2017.

Related Content:

WATCH: A Clinical Conversation with Alicia Morgans and Charles Ryan: Considerations of ASCO 2017 LATITUDE and STAMPEDE

WATCH: ASCO 2017: Discussion of LATITUDE and STAMPEDE Trials

ASCO 2017 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

Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer

ASCO 2017: Adding abiraterone for men with high-risk prostate cancer starting long-term androgen deprivation therapy: Survival results from STAMPEDE

Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy