New Combinations Improve Survival in Prostate Cancer

The treatment landscape of metastatic and non-metastatic prostate cancer is evolving rapidly. Practice-changing results from PEACE-1 and STAMPEDE clinical trials, which evaluated new combinations of standard drugs for treating metastatic hormone/castration-sensitive prostate cancer (mCSPC) and high-risk, non-metastatic disease, respectively, were presented during the recent ESMO 2021 virtual conference Presidential Symposium.  

  • PEACE-1: Metastatic castration-sensitive prostate cancer (mCSPC)

Prostate cancer is a hormonally driven disease, and for decades androgen-deprivation therapy (ADT), which is intended to lower testosterone levels, has been the prevailing therapeutic strategy for mCSPC. In recent years, clinical trials have showed that the addition of docetaxel or androgen receptor pathway inhibitors – such as abiraterone acetate, enzalutamide, and apalutamide – to ADT improves survival compared with ADT alone, and these combinations are now standard of care (SOC). The phase III PEACE-1 trial investigated the effect of the triple combination of ADT, docetaxel, and abiraterone acetate (used with prednisolone; AAP) on patient outcomes, and results from the study were presented by Karim Fizazi, MD, PhD (University of Paris-Saclay, Paris, France). The study had a 2×2 factorial design and included 1173 patients with untreated mCSPC. At the time of analysis, the median follow-up was 4.4 years. The results showed that the addition of AAP to docetaxel plus ADT extended median radiographic progression-free survival (rPFS) by 2.5 years (4.5 vs 2.0 years; hazard ratio [HR], 0.5; P<0.0001). Overall survival (OS) was also improved, with a 25% reduction in the risk of death compared with ADT plus docetaxel treatment (OS not estimable [NE] vs 4.4 years; HR, 0.75, P=0.017). In men with high-volume metastases, OS was 5.1 vs 3.5 years, respectively (HR, 0.72; P=0.019), translating to a lifetime gain of 1.5 years for patients with aggressive disease. The data for men with low-volume metastases are not yet mature, and the trial is ongoing to evaluate the survival benefit in this patient population. There were no apparent synergistic side effects associated with the addition of abiraterone to docetaxel plus ADT combination, with very few severe side effects reported. Dr Fizazi concluded that these data are practice changing and that patients with high-volume mCSPC should now be offered the triple combination.

  • STAMPEDE: High-risk M0 prostate cancer

For patients with non-metastatic high-risk prostate cancer (M0 PCa), the combination of ADT for 3 years and local radiotherapy has been shown to improve patient outcomes vs either treatment alone and is the established SOC; however, post-treatment failure rates remain high. The addition of docetaxel failed to prolong survival. It is known that adding second-generation anti-androgens to ADT improves outcomes for patients with metastatic prostate cancer (M1 PCa), but there is a question whether this combinatorial approach provides benefits for high-risk M0 PCa. This question was evaluated in the STAMPEDE trial, which uses a multi-arm, multi-stage platform design. In the trial, 1974 men with high-risk M0 PCa were randomized to receive ADT (SOC) or ADT plus AAP with/without enzalutamide (ENZ). The median follow-up was 6 years. The results, which were presented by Gerhardt Attard, MD, PhD (University College London, London, UK), showed that addition of 2 years of AAP to ADT significantly improved metastasis-free survival (MFS; HR, 0.53; P=2.9 x10-11) and OS (HR, 0.60; P=9.3×10-7) compared with ADT alone, with an improvement in the 6-year rate of MFS from 69% to 82% and survival from 77% to 86%, respectively. The 6-year prostate cancer-specific survival was also improved (from 85% to 93%). Of note, the addition of ENZ to AAP had no discernible effect on efficacy but increased toxicity. Dr Attard concluded that the addition of 2 years of AAP to ADT significantly improved MFS and OS in high-risk M0 PCa patients and should be considered a new standard of care for these patients. He noted that a shorter treatment duration may be as effective, but that it was not evaluated in the trial.

Dr. Eleni Efstathiou (University of Texas MD Anderson Cancer Center, Houston, Texas, US), the discussant for both the PEACE-1 and STAMPEDE abstracts, commented that the data are clinically meaningful and should lead to a change in practice for high-risk M0 PCa, and to a significant degree for metastatic hormone-sensitive PCa. She concluded that “earlier combinatorial treatment with ‘enhanced’ androgen signaling inhibition is now a requirement for men with (advanced) hormone-sensitive prostate cancer” and emphasized that physicians should be adapting their practice based on the data, given that these agents are available.

Fizazi K, et al. ESMO 2021; Asbtract LBA5_PR
Attard G, et al. ESMO 2021; Abstract LBA4_PR