STAMPEDE-ing for New Approaches to Prostate Cancer

It is difficult (but not impossible) to reflect on the fact that one of the key reasons I went into medical oncology was the seminal study by Bonadonna published in 1976 showing a dramatic reduction in cancer recurrence among women with breast cancer and positive axillary nodes who received CMF chemotherapy. Subsequently, tens of thousands of women participated in clinical trials to further refine which drugs (including many new ones), which clinical presentations (e.g. node positive or node negative, hormone and growth factor receptor status, menopausal status…) benefited most from different treatments in randomized controlled trials. Medical oncologists, surgeons, and radiation oncologists collaborated in advancing our understanding of how best to treat these patients, resulting in multidisciplinary clinics that are now a standard of care in most medically advanced countries.

What went wrong with prostate cancer? Certainly, there were some efforts to replicate the breast cancer experience. Indeed, The National Prostate Cancer Project studied single agents in the late 1970’s with hints of improvement in progression free survival. Yet, it was 17 YEARS (!) before the CMF regimen (“combination chemotherapy”) was found to have minimal activity in advanced prostate cancer in a small clinical trial. Following this, mitoxantrone as a single agent, was found to improve quality of life in metastatic prostate cancer and my colleagues and I started a study to evaluate it in combination with two years of ADT in high risk post-surgery patients. However, it wasn’t until a truly active chemotherapy class, the taxanes became available that real progress could be forecast. Never-the-less, the numbers of patients being placed on trials remained abysmal compared to breast cancer. Cooperation between medical, surgical (urologic), and radiation oncologists has lagged in the U.S. as physicians debated “who really knows this disease best?” rather than relying on collaborative improvement in care.

Potentially, we are finally at the end of this dark tunnel. The ASCO/ASTRO/SUO annual GU cancer symposium started off with a few hundred participants and now attracts thousands of physicians and scientists from around the world. Moreover, we are seeing the fruits of improved collaboration in the form of the CHAARTED trial, as well as the new data emerging from the STAMPEDE trial. This European trial has multiple arms and in a pre-ASCO meeting press conference, chemotherapy with docetaxel  has again been shown to improve survival for men with metastatic disease compared to ADT alone. Moreover, the study will soon have mature data on the use of such treatment in the adjuvant setting following surgery/radiation and we look forward to the results. My colleague, Dr. Garnick has urged caution in rushing to establish early use of docetaxel as a new standard of care, pointing out the potential benefit of adding the newer second line hormones (abiraterone, enzalutamide, TAK 007, etc.) which have fewer side effects. This seems like sound advice, particularly since one of the mechanisms of action of docetaxel may indeed be inhibition of translocation of the androgen receptor to the nucleus of cancer cells – in other words, docetaxel might be just a more toxic way of inhibiting the AR signaling pathway.

The good news is that after watching Koman and women “race for the cure” we are no longer “crawling for the cure” in prostate cancer. Men of good will (including all of you who support Movember) and their physicians are newly energized to make progress. It is an altogether satisfying situation to observe as I near the end of my oncology career!

Published Abstract from the ASCO meeting:

Background: STAMPEDE is a randomised controlled trial using a novel multi-arm multi-stage design. It recruits men (pts) with high-risk locally advanced or metastatic prostate cancer (PCa) starting long-term hormone therapy (HT) for the first time. The trial initially assessed adding 1 or 2 of 3 treatment approaches to standard of care (SOC). We report primary survival results for 3 research comparisons that recruited through all their intermediate analyses: docetaxel (D), zoledronic acid (ZA) & the combination (D+ZA). Methods: SOC was hormone therapy for > = 3yrs; RT was encouraged for N0M0 pts up to Nov-2011, then mandated; RT was optional for N+M0 pts. Stratified randomisation allocated pts 2:1:1:1 to SOC (control), SOC+D, SOC+ZA or SOC+D+ZA. 4mg ZA was given for six 3-weekly cycles then 4-weekly until 2yrs. D was given as 75mg/m² for six 3-weekly cycles with prednisolone 10mg daily. The primary outcome measure was survival (time from randomisation to death from any cause). Pairwise comparisons to control on survival for each research arm had 90% power at 2.5% 1-sided alpha for a hazard ratio of 0.75 requiring ~400 control arm deaths, accounting for 3 intermediate lack-of-benefit analyses on failure-free survival. Analyses used the Cox model of the logrank test, adjusted for stratification factors. Results: From Oct-2005 to Mar-2013, 2,962 pts were randomised to the 4 arms. The groups were balanced with median age 65yrs; 61% metastatic, 14% N+/XM0, 22% N0M0; 93% diagnosed within 6m of randomisation; median PSA 65ng/ml. Median follow-up was 42m. Grade 3-5 toxicity was reported for 31% SOC, 50% SOC+D, 32% SOC+ZA and 52% SOC+D+ZA.There were 405 deaths on the control arm (84% from PCa). The hazard ratio was 0.76 (95% CI 0.63, 0.91; p = 0.003) for SOC+D vs SOC; 0.93 (95% CI 0.79, 1.11; p = 0.437) for SOC+ZA vs SOC; and 0.81 (95% CI 0.68, 0.97; p = 0.020) for SOC+D+ZA vs SOC. Median survival was increased by 10m from 67m on SOC to 77m on SOC+D. Results in M0 and M1 disease will be shown. Conclusions: Survival data from STAMPEDE show a clinically and statistically significant improvement in survival from adding docetaxel but not from adding zoledronic acid in men starting long-term hormone therapy for the first time. Clinical trial information: NCT00268476