Abstract
Simple SummaryCurrently, a combination therapy of standard androgen deprivation therapy (ADT) plus docetaxel or androgen receptor-axis-targeted therapy is the gold standard for metastatic hormone-sensitive prostate cancer (mHSPC) treatment. Compared to ADT monotherapy, combination treatment prolongs overall survival by at least 18 months. The latest data has shown that triple treatment with standard ADT plus docetaxel plus abiraterone is superior to standard ADT plus docetaxel. Ongoing clinical trials are investigating triple therapy protocols by affecting diverse signaling pathways that are pivotal in prostate cancer. In this review, we will explore if triple therapy has the potential to be the new standard for mHSPC treatment in the near future.For decades, mono androgen deprivation therapy (ADT) has been the gold standard for metastatic hormone-sensitive prostate cancer (mHSPC) treatment. Several studies have been published within the last seven years demonstrating a significant survival advantage by combination treatment with standard ADT plus docetaxel or androgen receptor-axis-targeted therapy (ARAT) compared to ADT monotherapy. As a result, overall survival can be prolonged by at least 18 months. Recently published congress data of the PEACE-1 study suggests that in the future, triple therapy might be the new gold standard. In addition to this study, which has shown that triple treatment with standard ADT plus docetaxel plus abiraterone is superior to standard ADT plus docetaxel, several other phase III triple therapy studies are currently ongoing. The different modes of action that are investigated reach from AR-targeting over mitotic inhibition and immunotherapy to PARP and AKT inhibition. In this review we will explore if triple therapy has the potential to be the new standard for mHSPC treatment in the near future.
Highlights
Single androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) agonists or LHRH antagonists was the standard treatment for patients with metastatic hormone-sensitive prostate cancer
The largest study investigating the additional effect of flutamide, including 1387 patients, was published by Eisenberger and colleagues in 1998 and found an increased rate of diarrhea and anemia caused by the first-generation antiandrogen but no impact on overall survival [18]
Combining docetaxel with standard ADT significantly improved overall survival by a median of 10.4 months compared to standard ADT (HR 0.72; 95% CI, 0.59–0.89; p = 0.0018) [29,38]
Summary
Single androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) agonists or LHRH antagonists was the standard treatment for patients with metastatic hormone-sensitive prostate cancer (mHSPC). Treating 87 mHSPC patients with ADT plus the first-generation antiandrogen flutamide, continuing response and survival at 2 years was 91% [16] Despite these promising initial results, prospectively randomized, double-blind, placebo-controlled trials failed to show a significant improvement by adding flutamide to standard ADT [17]. Novel insights in targeting androgenreceptor (AR) and AR-independent pathways have led to the development of promising new compounds at the beginning of the 21st century [23,24,25,26] After showing their highly potent antitumoral effects in castration-resistant state, the effect of these compounds has been extensively investigated in combination with standard ADT in mHSPC patients over the last decade [27]. We will discuss the options of intensifying systemic treatment by triple therapy approaches targeting the same or different cell signaling pathways
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