Derek Raghavan, MD, PhD, FACP, FRACP, FASCO
FOR DECADES, the status of metastatic prostate cancer trials was not particularly exciting. With an absence of high-impact novel agents, the focus of cancer trial groups was on the improvement of standard care. Well-crafted, large trials of hormonal therapy demonstrated the utility of combined androgen blockade with luteinizing hormone–releasing hormone agonists plus peripheral blockade, a lesser impact of the combination of surgical orchiectomy plus peripheral blockade, the lack of urgency to start androgen-deprivation treatment (ADT) for asymptomatic metastatic prostate cancer, and the respective merits of continuous vs intermittent androgen blockade. Smaller phase II trials identified novel cytotoxic agents with some utility in the management of metastatic prostate cancer, and phase III studies identified improved quality of life with mitoxantrone, modest prolongation of life from docetaxel compared with mitoxantrone, and modest utility of some of the newer-generation agents, such as cabazitaxel (Jevtana), for salvage treatment. Despite rumors to the contrary, mitoxantrone was not adequately assessed for overall survival benefit, as a crossover design was used in the randomized trials that evaluated it.
In the past decade, the pace of progress has improved substantially, building upon improved understanding of androgen receptor and ligand function and its regulation, with the identification of two important parent compounds: abiraterone (Zytiga) and enzalutamide (Xtandi). Abiraterone interferes with the androgen axis by inhibiting the cytochrome P450 enzyme, CYP17, also causing inhibition of androgen biosynthesis. Around the same time, enzalutamide was developed, with the intention of binding to the androgen receptor with higher affinity than other second-line hormone blockers; it also appears to block other steps in the androgen receptor–signaling cascade.
Initial studies of both agents were very encouraging. Two randomized placebo-controlled trials, involving more than 2,000 patients who had previously been castrated and treated with docetaxel at relapse, demonstrated that abiraterone produced clinically important and statistically significant improvements in response, overall survival, and/or progression-free survival.1,2 Similar results were published for a placebo-controlled trial of enzalutamide in a similar clinical setting,3 and a confirmatory subset analysis extended these results to patients with visceral metastases, which are often the most resistant to hormonal manipulation.4 Another large randomized trial demonstrated the superiority of enzalutamide to prednisone as salvage treatment for castrate-resistant prostate cancer.5
Two Pivotal Studies: STAMPEDE and LATITUDE
IN THE PAST YEAR, two pivotal studies have been published, showing clearly there is dramatic utility of abiraterone plus androgen deprivation treatment plus prednisone compared with ADT in the front-line treatment of metastatic prostate cancer.6,7 In a component of the randomized, multiarm, multistage, platform-design STAMPEDE trial, 1,917 cases were treated with these regimens, revealing a major difference in progression-free survival, overall survival, and deaths at the time of reporting.6 At the same time, 1,199 patients were treated on the LATITUDE trial, comparing similar arms, with overall survival at 3 years being 55% and 49% respectively.7 All secondary endpoints, including the median time to pain progression, the median time to progression-free survival, the time to chemotherapy, and the time to the next cancer treatment favored the novel combination.
As usual, the Medical Research Council meta-analysis crew8 provided a meta-analysis of the two trials (noting also there is a third similar trial, PEACE-1, in progress but for which they did not yet have data). It confirmed that, when added together, two statistically significant trials still produced a statistically significant result!
It is noteworthy that the novel combination regimen clearly has greater levels of grade 3/4 toxicity, particularly hypertension, cardiovascular and respiratory events, hypokalemia, and hepatic dysfunction. This toxicity needs to be factored into the decision of where to place this treatment in the metastatic algorithm.
“The novel combination regimen clearly has greater levels of grade 3/4 toxicity, which needs to be factored into the decision of where to place this treatment in the metastatic algorithm.”— Derek Raghavan, MD, PhD, FACP, FRACP, FASCO
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SO NOW WHAT? Clearly, the routine addition of either agent will substantially increase cost and toxicity. However, one must acknowledge that the STAMPEDE and LATITUDE trials seem sufficiently mature to be potential game-changers, and given the natural history of metastatic prostate cancer, it seems unlikely that longer follow-up (although crucial, of course) will greatly change the outcomes. Don’t forget the use of these agents early might influence the outcomes of salvage treatment, but there do seem to be a lot of new options in the wings for that phase of treatment.
The other wild card is how to integrate this information with the results obtained a couple of years ago from two important studies of initial taxane-androgen deprivation treatment combination therapy, which showed a clear survival benefit with the combination compared with ADT alone for patients with poor-risk metastatic prostate cancer.9,10 Further follow-up on the STAMPEDE series of trials will help to resolve this question, but for the time being, it seems to me that it is time to give more than standard androgen deprivation treatment for patients with metastatic prostate cancer, maybe with the exception of those likely to suffer lethal toxicity (eg, with an antecedent significant cardiovascular or hepatic disorder).
Real-World Experience Offers Food for Thought
WHEN THE LEVELS of enthusiastic rhetoric from some investigators and pharmaceutical companies become deafening, we should not forget the little retrospective study recently published by Guru Sonpavde and pals. It reflected a real-world experience from the Veterans Administration—a comparison of outcomes from taxanes or novel hormonal agents for castrate-resistant prostate cancer—and showed remarkably little difference.11 Although there may well have been occult case-selection biases in this study, it is food for thought and reminds us that randomized clinical trials of the various innovative approaches will be required to identify the next generation of game-changers in metastatic prostate cancer. Hopefully, the clever work focused on circulating cell-free DNA and other molecular prognosticators, and predictors of response will sharpen our ability to discern real differences. As the U.S. Food and Drug Administration has recently approved some of these new agents for use in castrate-resistant clinically nonmetastatic disease, we can expect another flurry of activity in this space! ■
DISCLOSURE: Dr. Raghavan reported no potential conflicts of interest.
1. de Bono JS, et al: Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364:1995-2005, 2011.
2. Ryan CJ, et al: Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 368:138-148, 2013.
3. Scher H, et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367:1187-1197, 2012.
4. Loriot Y, et al: Enzalutamide in castration-resistant prostate cancer patients with visceral disease in the liver and/or lung. Cancer 123:253-262, 2017.
5. Beer TM, et al: Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 371:424-433, 2014.
6. James ND, et al: Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med 377:338-351, 2017.
7. Fizazi K, et al: Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med 377:352-360, 2017.
8. Rydzewska LHM, et al: Adding abiraterone to androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer. Eur J Cancer 84:88-101, 2017.
9. Sweeney CJ, et al: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 373:737-746, 2015.
10. James ND, et al: Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE). Lancet 387:1163-1177, 2016.
11. Sonpavde G, et al: Taxane chemotherapy versus anti-androgen agents as first-line therapy for metastatic castration-resistant prostate cancer. BJU Int. February 1, 2018 (early release online).