Androgen deprivation therapy as backbone therapy in the management of prostate cancer

Introduction

The androgen sensitivity of prostate cancer (PCa) is well established,¹ and androgen deprivation therapy (ADT) has become a cornerstone of treatment, with the potential to halt, or at least slow, the disease progression.² Surgical castration remains the gold standard for ADT, but its effects are permanent, continuous and irreversible.³ Nonsurgical treatments have become a more popular choice for ADT, because they allow intermittent therapy and have a lower psychological impact than surgical castration. The National Comprehensive Cancer Network (NCCN) now states that medical castration is as effective as bilateral orchiectomy.⁴

ADT can delay metastatic PCa (mPCa) progression for around 2 years on average, but most patients will eventually develop castration-resistant PCa (CRPC).⁵ PCa growth remains dependent on androgen receptor (AR) signaling, even after the development of CRPC, highlighting the need to maintain ADT.⁶

This review outlines the importance of ADT as backbone therapy in CRPC and considers its continued use with existing and new treatment modalities in CRPC.

Treatment guidelines

There is a clear consensus on the role of ADT, among current treatment guidelines published by the European Association of Urology, the American Urological Association and the NCCN.^3,7–9 ADT is recommended in addition to radiotherapy (intermediate and high-risk disease) and for selected patients with biochemical failure (defined as rising prostate-specific antigen [PSA] values).^3,6–8 Guidelines agree that ADT is the gold standard treatment for mPCa and that hormone therapy should remain a backbone of treatment following the transition from castration-sensitive disease to CRPC.^3,6–8

Adherence to guidelines

Despite consistent guidance to maintain backbone ADT in CRPC, there is a wide variation in actual clinical practice (Figure 1).⁵ Cross-sectional survey data from 3,477 patients with CRPC in five countries (France, Germany, Italy, Spain and the UK) revealed that between 19% and 45% (in the UK and Italy, respectively) of patients received chemotherapy alone with no ADT (Figure 1). The reasons for this divergence between guidelines and clinical practice are unclear, and this study reported no consistent link between years of practice and likelihood of continuing ADT in CRPC.⁵ However, this apparent tendency for some clinicians to overlook the need for continued ADT may expose patients to unnecessary risk.

Figure 1 Treatment patterns across Europe for patients with mCRPC receiving their first chemotherapy regimen. Note: Reproduced from Sternberg CN, Baskin-Bey ES, Watson M, Worsfold A, Rider A, Tombal B. Treatment patterns and characteristics of European patients with castration-resistant prostate cancer. BMC Urol. 2013;13:58. © Sternberg et al; licensee BioMed Central Ltd. 2013.5 Abbreviations: AA, antiandrogen; C, chemotherapy; LHRH, luteinizing hormone-releasing hormone; mCRPC, metastatic castration-resistant prostate cancer.

Defining medical castration with ADT

In defining ADT, regulatory authorities recommend the historical castration cutoff value of <1.7 nmol/L (<50 ng/dL) testosterone, based on early tests that could only detect testosterone above this level. However, modern assays, with improved sensitivity, have revealed that the mean testosterone level following bilateral orchiectomy is 0.5 nmol/L (15 ng/dL), and a lower cutoff at <0.7 nmol/L testosterone may be beneficial.¹⁰ A 6-month retrospective study of 73 men with non-mPCa found that any recorded testosterone peak above 1.1 nmol/L (32 ng/dL) was associated with significantly impaired survival free of androgen independent progression (88 months [95% CI, 55–121] versus 137 months [95% CI, 104–170], respectively; P<0.03).¹¹ In addition, rising PSA levels are commonly used to diagnose CRPC in the clinic, with a minority of oncologists or urologists citing testosterone levels as an additional marker, according to a European survey.⁵ Clinical trials have continued to use the <1.7 nmol/L testosterone cutoff, although some studies are starting to explore lower cutoff values.¹² A recent trial found that gonadotropin-releasing hormone agonist therapy was associated with a 90.0% probability of maintaining serum testosterone levels of <0.7 nmol/L up to 26 weeks, compared with a 96.0% probability of testosterone levels of <1.7 nmol/L (95% CI, 85.0–95.0 and 92.0–99.0, respectively).¹²

Data from 626 patients with PCa with baseline serum testosterone levels above 5.0 nmol/L, more than 12 months after completing definitive radiotherapy in the PR-7 trial, have shown that testosterone values below 0.7 nmol/L are associated with delayed progression to CRPC and cancer-related death, compared with values above 0.7 nmol/L.¹³ Patients whose testosterone values reached a nadir below 0.7 nmol/L had a median time to CRPC of 10 years, versus 7.21 years and 3.62 years with testosterone nadirs between 0.7 nmol/L and 1.7 nmol/L, and >1.7 nmol/L, respectively (hazard ratio [HR], 1.62 and 1.90; P≤0.015).¹³ Median and maximum testosterone levels below 0.7 nmol/L were also associated with significantly longer times to CRPC, compared with testosterone levels between 0.7 nmol/L and 1.7 nmol/L, and >1.7 nmol/L.¹³ Similarly, patients with minimum or maximum testosterone levels of >1.7 nmol/L had significantly shorter times to death due to PCa than patients with minimum or maximum testosterone values of <0.7 nmol/L (HR, 2.93 and 2.08 for nadir and maximum value comparisons, respectively; P=0.02).¹³

This link between very low testosterone levels and improved outcomes corresponds to the observation that lower PSA levels predict longer survival, even to the point of any detectable PSA being linked to worsened outcomes.¹⁴

Optimizing treatment regimens in hormone-sensitive PCa

The optimal timing of ADT, whether as monotherapy or in combination with other agents, remains a subject of debate, and research is ongoing to optimize ADT regimens (Tables 1–3).² Studies have tested androgen blockade using different agents alone or in combination, and whether adding chemotherapy to backbone ADT before transition to CRPC can improve the overall survival (OS) for patients with mPCa (Table 1).^15,16

Table 1 Completed studies with ADT as backbone therapy in PCa Abbreviations: ADT, androgen deprivation therapy; mPCa, metastatic PCa; PCa, prostate cancer.

Table 2 Summary of ongoing Phase II clinical studies with ADT as backbone therapy in PCa Abbreviations: ADT, androgen deprivation therapy; CRPC, castration-resistant PCa; LH, luteinizing hormone; LHRH, LH-releasing hormone; PCa, prostate cancer; PFS, progression-free survival; PSA, prostate-specific antigen; Pts, patients; QoL, quality of life.

Table 3 Summary of ongoing Phase III (and IV) clinical studies with ADT as backbone therapy in PCa Abbreviations: ADT, androgen deprivation therapy; BPI-SF, Brief Pain Inventory Short Form; CRPC, castration-resistant PCa; EQ-5D-5L, EuroQol5 dimension 5 level health state utility index – 5L; FACT-P, Functional Assessment of Cancer Therapy – Prostate; GnRH, gonadotropin-releasing hormone; LHRH, luteinizing hormone-releasing hormone; LHRHA, luteinizing hormone-releasing hormone analog; mCRPC, metastatic CRPC; MFS, metastasis-free survival; mPCa, metastatic PCa; NSAA, nonsteroidal anti-androgen; OS, overall survival; PCa, prostate cancer; PFS, progression-free survival; PSA, prostate-specific antigen; Pts, patients; QoL, quality of life; rPFS, radiographic PFS; SRE, skeletal-related event; SSE, symptomatic skeletal event; TTF, time to treatment failure.

Intense androgen blockade for hormone-sensitive mPCa

The European Organization for Research and Treatment of Cancer (EORTC) conducted two Phase III studies using intense androgen blockade in mPCa, with apparently conflicting results.^17–20 The EORTC GU Group Trial 30843 compared maximal androgen blockade using a luteinizing hormone-releasing hormone (LHRH) agonist plus cyproterone acetate versus standard LHRH monotherapy or bilateral orchiectomy.^19,20 Investigators reported no significant difference between survival times, response rates or times to progression in all three treatment groups.¹⁹ In contrast, the EORTC Phase III trial 30853 found that an intensive androgen-blocking regimen using LHRH plus flutamide was associated with significantly improved outcomes compared with bilateral orchiectomy.^17,18 Time to death due to malignant disease, time to first progression, progression-free survival (PFS) and duration of survival were significantly better in patients receiving intense androgen blockade compared with bilateral orchiectomy (P=0.008, P=0.009, P=0.02, and P=0.04, respectively).¹⁷ The HR for overall mortality in the intense androgen blockade group was 0.73 (95% CI, 0.53–0.95).¹⁸

A subgroup analysis of both trials suggested that intense androgen blockade might be more beneficial for patients with good prognoses compared with those whose prognoses were poor.²⁰ There were very few patients with a good prognosis in trial 30843 (n=93) to allow a comprehensive analysis, but the investigators concluded that intense androgen blockade only improved outcomes for patients with a good prognosis.²⁰ Most patients in trial 30843 had a poor prognosis (72%), and the average prognosis of participants in this trial was worse than in trial 30853, which was consistent with this explanation.²⁰ Overall median survival was 2.1 years in trial 30843 versus 2.5 years in trial 30853, but there was no significant difference between outcomes in the control groups (orchiectomy) in the two trials.²⁰

Ongoing Phase III trials such as the Study of Abiraterone Acetate Plus Low-Dose Prednisone Plus Androgen Deprivation Therapy (ADT) versus ADT Alone in Newly Diagnosed Participants With High-Risk, Metastatic Hormone-Naive Prostate Cancer (LATITUDE), Study of JNJ-56021927 (ARN-509) Plus Androgen Deprivation Therapy (ADT) versus ADT in Participants With Low-Volume mHSPC (TITAN), Phase III of ADT ± Local RT ± Abiraterone Acetate in Metastatic Hormone-naïve Prostate Cancer (PEACE-1) and Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) are assessing the impact of different androgen deprivation regimens, using new forms of androgen deprivation and AR target drugs, such as abiraterone acetate and enzalutamide, on OS in patients with hormone-sensitive mPCa (Table 3).

Intense androgen blockade with novel agents for localized PCa

Other trials are investigating the benefit of combining agents that target androgen activity via different mechanisms to maximize androgen blockade and potentially improve clinical outcomes in localized PCa (ClinicalTrials.gov: NCT01547299, NCT00924469).²⁸ A Phase II study comparing neoadjuvant therapy with the AR inhibitor enzalutamide as monotherapy or in combination with ADT plus the dihydrotestosterone blocker dutasteride found lower tissue testosterone levels and a higher rate of pathologically complete response after 6-month combination therapy including ADT, compared with enzalutamide alone (Table 1).²⁸ Another Phase II trial found that intense ADT plus abiraterone acetate was more effective than intense ADT alone in patients with localized PCa (Table 1).²⁸

Two Phase III trials are also investigating intense androgen blockade for patients with hormone-sensitive non-mPCa: Enzalutamide in Androgen Deprivation Therapy With Radiation Therapy for High Risk, Clinically Localized, Prostate Cancer (ENZARAD; ClinicalTrials.gov: NCT02446444) and Safety and Efficacy Study of Enzalutamide Plus Leuprolide in Patients With Nonmetastatic Prostate Cancer (EMBARK; NCT02319837).

Chemotherapy in metastatic hormone-sensitive PCa

An increasing body of evidence suggests that adding chemotherapy to ADT may improve survival in patients with hormone-sensitive mPCa. Studies have generated apparently conflicting results, and these trials, such as the intensive androgen blockade studies described earlier, have also identified subsets of patients who seem most likely to benefit from this treatment approach.

The CHAARTED trial

The Eastern Cooperative Oncology Group ChemoHormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (ECOG-CHAARTED) demonstrated a significant survival benefit for patients who received six cycles of docetaxel at the start of ADT compared with ADT alone (Figure 2).¹⁶ A significant OS survival benefit was seen in patients with high-volume disease (defined as having visceral metastases or ≥4 bone lesions, including at least one outside the vertebrae and pelvis): median OS was 49.2 months versus 32.2 months, respectively, for combined treatment or ADT monotherapy; HR for death, 0.60; 95% CI, 0.45–0.81; P<0.001.¹⁷ It is interesting that there was such a strong survival advantage for adding docetaxel to ADT in early phase mPCa, even though 147 of the 287 patients who progressed to CRPC in the ADT-only group subsequently received docetaxel.¹⁶ The frequency of Grade 3 or higher adverse events in the combined therapy group was comparable with frequencies reported in the docetaxel summary of product characteristics.^16,21

Figure 2 Kaplan–Meier estimates of OS following six cycles of docetaxel at the start of ADT versus ADT alone in the CHAARTED study. Notes: The median duration of follow-up was 28.9 months among all patients. From N Engl J Med. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. 373(8):737–746. Copyright © 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.16 Abbreviations: ADT, androgen deprivation therapy; CHAARTED, Androgen Ablation Therapy with or without Chemotherapy in Treating Patients with Metastatic Prostate Cancer; HR, hazard ratio; OS, overall survival.

The GETUG-AFU 15 trial

In contrast, investigators on the smaller androgen deprivation therapy alone or with docetaxel in non-castrate mPCa (GETUG-AFU 15) trial concluded that docetaxel should not be used in the first-line treatment regimens for patients with hormone-sensitive mPCa.^15,22 PFS was significantly longer in the ADT-plus-docetaxel group, versus ADT alone: 22.9 months versus 12.9 months; HR, 0.72; P=0.005 (biological PFS; clinical PFS was also significantly different), but there was no significant OS advantage for combination therapy (Table 1).^15,22 Common toxic effects in the ADT plus docetaxel group included neutropenia (50% vs 3% on ADT monotherapy), anemia (72% vs 22% on ADT monotherapy), sensory neuropathy (29% vs 4% on ADT monotherapy) and fatigue (74% vs 20% on ADT monotherapy).¹⁵ Mean quality of life scores were also significantly poorer on combined therapy compared with ADT alone, at both 3- and 6-month follow-up.¹⁵

These contrasting results have stimulated debate on the value of adding docetaxel to ADT in hormone-sensitive mPCa, and the GETUG-AFU 15 investigators performed a subset analysis, at a mean follow-up of 82.9 months, to assess whether the different outcomes were due to different case mixes in their patient populations.^16,22 This new analysis found no significant difference in OS between groups receiving ADT plus docetaxel, or ADT alone, neither for the whole study population nor for the subgroup of high-volume disease (using the same definitions as the CHAARTED study), although the authors noted that their subsets were underpowered for this retrospective analysis.²²

The STAMPEDE trial

The ongoing Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) trial is already generating clear evidence on whether to add docetaxel – or other agents – to ADT in early/hormone-naïve PCa.^23,24 STAMPEDE is comparing ADT monotherapy versus ADT plus chemotherapy, anti-androgen treatment and/or radiotherapy, and has recruited more than 7,000 patients to date (Table 3).^23,25,26 Results are now available for 2,962 patients randomized to four arms (control/ADT monotherapy, ADT plus six cycles of 75 mg/m² docetaxel [with 10 mg prednisolone], ADT plus zoledronic acid, or ADT plus docetaxel and zoledronic acid).^26,27 Adding docetaxel (but not zoledronic acid) to ADT significantly improved OS, with a 10-month extension in median survival from 71 months on ADT alone to 81 months on ADT plus docetaxel (Table 4).²⁶ There was no benefit for zoledronic acid on either survival or skeletal-related events, despite good compliance with therapy.²⁶

Table 4 Survival outcomes in STAMPEDE trial Note: Copyright © James et al. Adapted from James ND, Sydes MR, Clarke NW, et al; STAMPEDE Investigators. 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. 2016;387(10024):1163–1177.26 Abbreviations: HR, hazard ratio; OS, overall survival.

Conclusion from STAMPEDE and CHAARTED trials for patients with high-risk PCa

The result of STAMPEDE is consistent with the findings of the CHAARTED study, but, interestingly, STAMPEDE data suggest that docetaxel may be of benefit in both metastatic and non-mPCa.^16,26 The investigators reported that estimated treatment effects of docetaxel in both PCa-specific survival and failure-free survival were comparable in both patient groups, although the relatively low population size and smaller number of deaths (compared with men who presented with metastatic disease) meant that the non-metastatic subgroup was underpowered to demonstrate improved survival.²⁶ STAMPEDE will generate long-term data on these four arms.²⁶ The authors concluded that “Standard of care should be updated to include docetaxel chemotherapy in suitable patients with metastatic disease, and docetaxel may be considered for men with high-risk non-metastatic prostate cancer with or without radiotherapy.”²⁶

Future STAMPEDE publications will also report on similar comparisons for celecoxib, abiraterone, combination therapy using enzalutamide plus abiraterone and prostate radiotherapy.²⁶

It is interesting to note that an earlier study of 589 men with advanced PCa, of whom 46% had locally advanced T3 or T4 disease and 52% had metastatic disease, also found a similar benefit of intensive androgen blockade in both groups.²⁶ The authors reported a nonsignificant improvement in survival when they added flutamide to LHRH therapy in patients who were hormone naïve.²⁷

Optimizing therapy in CRPC

A number of clinical studies have investigated the benefit of combining ADT with various other agents, including enzalutamide, abiraterone acetate, chemotherapy, radium-223 and novel agents, following the development of CRPC (Table 1 and Figure 3).^29–37 Figure 3 shows the findings of Phase III trial in patients with previously untreated mPCa that tested hypothesis that three 8-week cycles of ketoconazole and doxorubicin alternating with vinblastine and estramustine, given in addition to standard androgen deprivation, would delay the appearance of castration-resistant disease.

Figure 3 TPP with standard androgen ablation therapy versus three cycles of systemic chemotherapy in a Phase III trial in advanced PCa. Notes: (A) TTP by assigned treatment. (B) TTP by treatment, stratified by disease volume at entry. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Millikan RE, Wen S, Pagliaro LC, et al. Phase III trial of androgen ablation with or without three cycles of systemic chemotherapy for advanced prostate cancer. J Clin Oncol. 2008;26(36):5936–5942.29 Abbreviations: PCa, prostate cancer; PFS, progression-free survival; TTP, time to progression.

ADT during radium-223

Radium-223 has been associated with significantly improved survival, versus placebo: in an interim analysis (n=809) of a Phase III trial of men with metastatic CRPC (mCRPC), the median OS was 14.0 months versus 11.2 months on placebo; HR 0.70 (95% CI, 0.58–0.83); P=0.002.³⁸ This study applied a pragmatic approach, allowing clinicians to prescribe best standard of care, at their own discretion, throughout the study, meaning that the results may be more applicable to clinical practice than other trials.³⁸ It is unclear how many of these patients received ADT during the study, although they were required to continue their maintenance treatment.³⁸

Abiraterone acetate

Abiraterone acetate has demonstrated the efficacy in Phase III trials when added to ADT for men with progressive mCRPC, both before and after receiving chemotherapy.^33,35

The COU-AA-301 study revealed a significant survival benefit of abiraterone acetate in 1,195 men with mCRPC, which had progressed following docetaxel.³³ Median OS was 15.8 months in the abiraterone acetate plus prednisone group versus 11.2 months on prednisone plus placebo, after a median follow-up of 20.2 months (HR, 0.74; 95% CI, 0.64–0.86; P<0.0001).³⁴ This OS benefit was consistent across subgroups (according to prespecified analyses).³³ Median radiographic PFS (rPFS) was 5.6 months and 3.6 months on abiraterone acetate and placebo, respectively (HR, 0.66; 95% CI, 0.58–0.76; P<0.0001).³³

In the COU-AA-302 study, abiraterone acetate (with prednisone) was linked with significantly improved survival versus placebo (plus prednisone) in 1,088 patients with mCRPC who were asymptomatic or minimally symptomatic and had received no prior chemotherapy.³⁵ There were 147 deaths in the abiraterone-treated group (n=546; 27%) and 186 deaths in the prednisone-only group (n=542; 34%), at a median follow-up of 22.2 months.³⁵ HRs for OS and rPFS were 0.75 (95% CI, 0.61–0.93; P=0.01) and 0.53 (95% CI, 0.45–0.62; P<0.001), respectively.³⁵ Abiraterone showed a consistent benefit across subgroups.³⁵

Enzalutamide

Adding the oral AR inhibitor enzalutamide to ongoing ADT also significantly improves survival in CRPC, according to two large Phase III studies.^34,39 Both trials (Safety and Efficacy Study of MDV3100 in Patients With Castration-Resistant Prostate Cancer Who Have Been Previously Treated With Docetaxel-based Chemotherapy [AFFIRM] and Safety and Efficacy Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer [PREVAIL]) included patients with progressive mCRPC, and serum testosterone levels of 1.7 nmol/L (50 ng/dL) or less, maintained with regular hormonal ADT (unless they had previously undergone orchiectomy).^34,39 The AFFIRM study investigators recruited patients who had previously received docetaxel, while the PREVAIL trial included patients who had not received chemotherapy.^34,39 Both studies were stopped after interim analyses that revealed significant survival benefits of treatment.^34,39

AFFIRM included 1,199 patients who were randomized to receive either enzalutamide (n=800) or placebo (n=399) with backbone ADT and bisphosphonate therapy.³⁴ Median OS was 18.4 months in the enzalutamide group versus 13.6 months on placebo (HR, 0.63; 95% CI, 0.53–0.75; P<0.001).³⁴ All secondary end points also showed significant improvements on enzalutamide, including time to PSA progression (HR, 0.25; 95% CI, 0.20–0.30; P<0.001) and rPFS (HR, 0.40; 95% CI, 0.45–0.47; P<0.001).³⁴ Adverse event rates were similar in the enzalutamide and placebo groups, even though the observation period for enzalutamide was more than double that of the placebo group.³⁴

Chemotherapy-naïve patients entering the PREVAIL study were also randomized to receive either enzalutamide (n=872) or placebo (n=845) in combination with ongoing ADT.³⁹ Enzalutamide-treated men had better OS than controls, with an estimated median survival time of 32.4 months versus 30.2 months on placebo (HR, 0.71; 95% CI, 0.60–0.84; P<0.001).^36,39 The HR for rPFS was 0.19 (95% CI, 0.15–0.23; P<0.001).³⁹ Several ongoing Phase III trials are comparing different therapeutic approaches to mCRPC, as summarized in Table 3.

Non-mCRPC

Optimizing management of non-mCRPC could dramatically improve survival for many thousands of men with PCa. A recent large-scale data analysis reported a total PCa prevalence of 2,219,280 in the USA in 2009, with an annual all-cause mortality of 168,290.⁴⁰ The authors estimated an mCRPC incidence of only 36,100 (1.6%), but this group contributed 34,525 annual deaths (20.5% of total deaths in men with PCa).⁴⁰ Optimal treatment at the non-mCPRC stage could delay progression to metastatic disease, in which this model predicted to be 34% each year.⁴⁰ Annual all-cause mortality in mCPRC was 56%, and 86% of mCPRC had progressed from non-mCPRC.⁴⁰ Reducing annual progression from non-mCPRC to mCPRC by 11.5% could prevent 3,694 deaths per year, according to this model.⁴⁰

Results of four large-scale Phase III trials with a total planned population over 5,800 patients with non-mCRPC are due to become available over the next 1–10 years (Table 3). Tables 2 and 3 summarize some key ongoing Phase II and III randomized clinical trials investigating the efficacy and safety of abiraterone, enzalutamide or ARN-509, with or without ADT and other treatments, in both metastatic and non-mPCa.

Future developments

Accumulating evidence for the benefits of combining ADT with chemotherapy, at least using docetaxel, may encourage many clinicians to adopt this approach. This could substantially increase OS in a large population of men with PCa. Enzalutamide or abiraterone acetate may potentially be used before CRPC develops, either as an alternative to ADT or in combination with ADT (Tables 2 and 3).

The optimal approach to treating patients with non-mCRPC remains an open question. Limited data availability and the small number of ongoing studies (notably PROSPER, SPARTAN and ARAMIS; Table 3) means these decisions may remain uncertain, although there are encouraging preliminary results from the ongoing STAMPEDE trial. There is a clear need for more research in this area, to allow clinicians to make informed decisions for this group of patients, which could transform outcomes in PCa. Increased numbers of reliable biomarkers and genetic profiling may help to determine which patients to treat, with which type of treatment and by when. Personalized/individualized medicine in PCa will become a reality as more treatment options/combinations that include ADT become available which are supported by clinical data.

Conclusion

Clinical studies to date have shown the benefit of maintaining ADT as backbone therapy in combination with other treatment modalities in mPCa, but data are limited. Further studies are needed to determine the most appropriate use of backbone ADT therapy in CRPC. The safety and tolerability of chemotherapy regimens are not markedly changed by continuing ADT as backbone treatment. The key question is whether continuing ADT following the development of CRPC, irrespective of the additional treatments given, prolongs survival for patients with an acceptable level of side effects.

Acknowledgments

Editorial assistance was provided by Shari Barber-Bailey and Catherine Amey for Touch Medical Media, funded by Ipsen.

Disclosure

ASM is the advisor and speaker for Bayer, Astellas, Janssen, TEVA, Novartis, BMS, Ipsen, Medac, Pfizer, GSK, Takeda, Astra Zeneca and Merck. CAvK is the advisor and/or speaker for Janssen, TEVA, Novartis, BMS, Astellas, Galil Medical, Bayer and Sennewald. AA is the lecturer for Astellas, Olympus, Janssen, Sanofi and Ipsen. The authors report no other conflicts of interest in this work.

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