Prostate cancer perspectives after chaarted: Optimizing treatment sequence
Introduction
Prostate cancer is the second most common diagnosed cancer (417.000 estimated cases in 2012, 12.1%), the most frequent cancer amongst men, and the third most common cause of death in men (92,000, 9.5%) in Europe. Rising trends in the incidence of prostate cancer have been reported, but these are mainly attributable to a better detection of the latent disease following the widespread availability of PSA tests (Ferlay et al., 2013). Most cases are diagnosed when tumour is organ-confined, although about 10–20 percent of men with prostate cancer present with metastatic disease at diagnosis and many others will develop metastases during the course of the disease despite treatment (Heidenreich et al., 2014).
Until recently, only two therapeutic options, the hormonal blockage or androgen-deprivation therapy (ADT) in patients without castration-resistant prostate cancer (CRPC), and the treatment with docetaxel when the disease became castration-resistant, provided an overall survival (OS) benefit for metastatic disease. Historically ADT alone has been the standard first-line systemic treatment in advanced disease, and can be accomplished using surgical (orchiectomy) or medical (LHRH agonist/antagonist) castration (Loblaw et al., 2007). Chemotherapy approach used to be initiated when disease became castration-resistant. Two studies provided the first evidence of survival benefit with docetaxel-based chemotherapy (TAX327 and SWOG 9916). In the phase III study TAX 327, two schedules of docetaxel administered with prednisone were compared with mitoxantrone plus prednisone, the standard chemotherapy for CRPC at that time (Heidenreich et al., 2014). The phase III study SWOG 9916 showed that patients who were treated with a combination of docetaxel and estramustine had a significant improvement in median OS and PSA response, compared to mitoxantrone and prednisolone (Petrylak et al., 2004). For the following years, docetaxel plus prednisone was the main option for most patients with CRPC.
More recently new drugs have been developed for CRPC treatment with important advantages in safety and efficacy. Two new agents, abiraterone and enzalutamide, have showed activity both in the post- and pre-docetaxel setting. The COU-AA-301 study with abiraterone prolonged OS in patients with metastatic CRPC who had progressed after docetaxel treatment with a good safety profile (Fizazi et al., 2012). In a phase III study, enzalutamide was tested showing a significantly prolonged survival in men with metastatic CRPC after chemotherapy by a median of 4.8 months and reduced the risk of death from any cause by 37% versus placebo. In a multivariate analysis, the survival benefit was seen in all patient subgroups, including those stratified according to age and ECOG performance status (PS), the geographic location of the study centre, the extent of the disease on diagnostic imaging, and the biochemical measurements that included PSA and lactate dehydrogenase, even after adjustment for baseline factors (Scher et al., 2012). Other three novel agents not acting primarily as anti-androgens but with different mechanisms of action have demonstrated to improve survival in the post-docetaxel setting, i.e. the tubulin-binding chemotherapy (cabazitaxel); immunotherapy (sipuleucel-T) and the radioisotope therapy (radium-223).
The efficacy of these novel therapies in the pre-docetaxel setting has been assessed as part of their clinical development program. The anti-androgen drugs, abiraterone and enzalutamide, have shown a trend toward survival improving OS in asymptomatic or mildly symptomatic patients that have progressed after hormonal blockage, prior to receiving docetaxel (Ryan et al., 2013, Beer et al., 2014). Similarly, radium-223, an α-emitter, has demonstrated a benefit in OS, in docetaxel-naïve and in docetaxel pretreated patients with only bone metastases (Parker et al., 2013a, Vogelzang et al., 2016). With regards to chemotherapy, the FIRSTANA study (NCT01308567) compared the efficacy of cabazitaxel vs. docetaxel as first-line in CRPC chemo-naïve patients (Sartor et al., 2016), showing that cabazitaxel at two different doses was no better than docetaxel with regard to OS or PFS. More details are provided in following sections.
Traditionally, the chemotherapy was initiated once the tumour became resistant to initial ADT for metastatic disease; however the results from the recent CHAARTED study have completely changed, for the first time, the initial treatment approach of metastatic prostate cancer in ADT naïve patients, opening the door to redefine the best sequence for each patient. In this phase III randomized study, patients with metastatic prostate cancer received, at first, complete antiandrogen blockage with 6 cycles of docetaxel, observing a clear benefit on OS in the subgroup of patients with a high-volume disease, defined as visceral metastases and/or four or more bone metastases with at least one beyond the axial skeleton (Sweeney et al., 2015).
Those results are also supported by the data found in the Stampede trial. The Stampede trial was performed as a randomized controlled trial using a multi-arm multi-stage design and comparing standard of care (SOC) versus docetaxel plus/minus zoledronic acid plus SOC versus zoledronic acid plus SOC versus SOC alone for hormone-naïve prostate cancer, to test whether the early use of active therapies may give a larger absolute benefit in OS, as well as whether the addition of zoledronic acid prolongs the time to first Skeletal Related Event (SRE). SOC was hormone therapy for ≥3 years. Stampede results showed a benefit in both survival and time to first SRE (James et al., 2015).
At this point, and in absence of definitive predicting biomarkers of response and of comparative studies between drugs it is essential in clinical practice to define clinical profiles that allow establishing which the optimal treatment sequence is. In the present article we review all the available scientific evidence and, as a novelty, we propose an algorithm of treatment for the metastatic prostatic cancer.
Section snippets
Docetaxel in hormone-sensitive prostate cancer: GETUG-AFU 15 versus CHAARTED
Two studies have tested the role of docetaxel in addition to ADT in patients with hormone-sensitive prostate cancer.
The GETUG-AFU 15 study randomized, between October 2004 and December 2008, up to 385 patients with HSPC to receive ADT or ADT plus docetaxel (75 mg/m2 iv every 3 weeks, up to 9 cycles). A total of 83 patients (22%) were classified as having a poor prognosis according to the Glass criteria (defined as the presence of backbone disease, an ECOG-PS ≥1 and PSA ≥65 ng/mL) (James et al.,
Treatment options after CHAARTED
But starting at this point, after developing progressive disease, how should we treat those patients that have received early docetaxel when develop progressive disease? This question remains unanswered. The knowledge about prostate cancer therapeutics and prognostic-predictive factors has increased and new drugs have been added to the previous available treatments, but there is not a clear algorithm about treatment line choices. We are going to present the main treatment options for these
Conclusions and treatment algorithm
Given the heterogeneity of prostate cancer, it is necessary to stratify different subgroups of patients based on factors that may help to decide the treatment and/or optimal sequence. The progresses made in understanding intricate cancer pathways, leads us into a more complex world for diagnosis and treatment. A deeper knowledge regarding biology of cancer and advances in biotechnology has led to the identification of prognostic and predictive marker for response to different treatments. These
Key issues
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The results from the recent CHAARTED study have completely changed, for the first time, the initial approach of metastatic prostate cancer; now it is time to redefine the optimal sequence for individualized therapy.
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These results were supported by the Stampede trial, which had an increase of 10 months in OS with the combination and also a prolonged time to first skeletal related event.
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With regards to abiraterone and enzalutamide, since there is not a direct comparison between them, treatment
Conflict of interest statement
Funding for this study was provided by Bayer HealthCare. Sonia Maciá (Pivotal SL) provided advice to properly handle and submit the paper. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflicto with the subject matter or materials disccussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or
Financial disclosure
None of the authors has any current or potential conflict of interest including any financial, personal or other relationships with other people or organizations that could inappropriately influence (bias) their work.
References (50)
Overview of nuclides for bone palliation
Appl. Radiat. Isot.
(1998)- et al.
Cancer incidence and mortality patterns in Europe:estimates for 40 countries in 2012
Eur. J. Cancer
(2013) - et al.
Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study
Lancet Oncol.
(2012) - et al.
Effect of abiraterone acetate treatment on the quality of life of patients with metastatic castration-resistant prostate cancer after failure of docetaxel chemotherapy
Eur. J. Cancer
(2013) - et al.
EUA guidelines on prostate cancer Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer
Eur. Urol.
(2014) - et al.
Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial
Lancet Oncol.
(2014) - et al.
Monitoring the clinical outcomes in advanced prostate cancer: what imaging modalities and other markers are reliable?
Semin. Oncol.
(2013) - et al.
Two-year survival follow-up of the randomized, double-blind, placebo-controlled phase II study of radium-223 chloride in patients with castration-resistant prostate cancer and bone metastases
Clin. Genitourin. Cancer
(2013) - et al.
Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial
Lancet Oncol.
(2014) - et al.
Radium-223 dichloride: a new paradigm in the treatment of prostate cancer
Expert Rev. Anticancer Ther.
(2015)
Enzalutamide in metastatic prostate cancer before chemotherapy
N. Engl. J. Med.
Considerations in the selection of radiopharmaceuticals for palliation of bone pain from metastatic osseous lesions
J. Nucl. Med.
Docetaxel rechallenge in patients with castration-resistant prostate cancer – a review
Eur. Oncol. Haematol.
Randomized phase II study of docetaxel and prednisone with or without OGX-011 in patients with metastatic castration-resistant prostate cancer
JCO
A randomized phase 3 study comparing first-line docetaxel/prednisone (DP) to DP plus custirsen in men with metastatic castration-resistant prostate
Ann. Oncol.
Management of patients with advanced prostate cancer: recommendations of the St. Gallen advanced prostate cancer consensus conference (APCCC) 2015
Ann. Oncol.
Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non castrate prostate cancer: impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU 15
Trial Eur. Urol.
Androgen deprivation therapy (ADT) plus docetaxel (D) versus ADT alone for hormone-naïve metastatic prostate cancer (PCa): Long-term analysis of the GETUG-AFU 15 phase III trial
J. Clin. Oncol.
Phase 1/2 dose-escalation study of a GM-CSF-secreting, allogeneic, cellular immunotherapy for metastatic hormone-refractory prostate cancer
Cancer
Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial
Lancet Oncol.
Sipuleucel-T immunotherapy for castration-resistant prostate cancer
N. Engl. J. Med.
Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer
J. Clin. Oncol.
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