Since the establishment of docetaxel as first-line chemotherapy for metastatic castration-resistant prostate cancer significant advancements have been made in the management of this disease. Clinical trials have investigated agents for use prior to docetaxel, in combination with docetaxel and agents for second-line treatment for patients who have progressed despite docetaxel. In addition, several new agents have been developed and clinically investigated in the fields of hormonal, cytotoxic, targeted and immune therapy, providing options either side of first-line chemotherapy. As a result of this considerable research activity, three new therapies; cabazitaxel, sipuleucel-T and abiraterone acetate, have each demonstrated improvement in overall survival in phase III trials and have been approved by the US Food and Drug Administration. With so many new therapies now available and in the pipeline, the management of metastatic castration-resistant prostate cancer is undergoing a significant and positive change. This article discusses current and future options for second-line therapy in metastatic castration-resistant prostate cancer, providing insight into the potential roles of these new treatment options in the Australian clinical setting.
Prostate cancer is the most common cancer and the second most common cause of cancer deaths in Australian men; recent statistics confirm close to 20 000 diagnosed cases and more than 3300 deaths annually.1 Through early detection and improved local therapies a large number of men with prostate cancer will be cured.2 However, for those individuals who are diagnosed with, or who go on to develop, metastatic prostate cancer the current treatment options remain limited.
For many years androgen deprivation therapy (ADT) has been accepted as the standard treatment for patients with metastatic prostate cancer. Prostate cancer typically responds well to ADT; however the response is often short-lived with malignant cells becoming resistant to hormonal therapy within a median of 12 to 18 months of treatment initiation.3
Prostate cancer that becomes resistant to hormone therapy has traditionally been referred to as hormone-refractory prostate cancer (HRPC) or androgen-independent prostate cancer. Most recently, investigators have begun using the term castration (or castrate)-refractory (or resistant) prostate cancer (CRPC), because research has shown that even HRPC may respond to certain types of second-line hormone therapy as a consequence of continued androgen receptor signaling, even in late-stage disease. The current, and preferred, definition of progression of metastatic disease despite castrate levels of serum androgen is metastatic castration-resistant prostate cancer (mCRPC). This terminology has been used throughout this article, although it should be borne in mind that many of the studies discussed used the earlier definition (mHRPC).
Until relatively recently, mCRPC was considered resistant to chemotherapy and treatment was considered palliative. Agents were studied in unfocused phase II trials that typically lacked a specific primary end-point and frequently did not accrue statistically significant groups of participants.4 In a review of 26 trials published between 1987 and 1991, treatment with single-agent chemotherapy was associated with very low rates of clinical response (8.7%).5 In the late 1990s a randomized control trial demonstrated that mitoxantrone plus low-dose prednisone conferred greater improvement in quality of life than prednisone alone.6 Shortly thereafter, a second study that examined hydrocortisone with or without mitoxantrone established the quality of life benefit as a valid clinical trial end-point.7 Although neither of these two studies showed an improvement in survival, the results were considered a milestone in the treatment of mCRPC. Subsequently, the combination of mitoxantrone and low-dose prednisone became the palliative standard of care.
It was not until 5 years later that two large phase III randomized trials changed the landscape for mCRPC chemotherapy. The phase III Southwest Oncology 9916 (SWOG 9916) study (evaluating estramustine/docetaxel vs mitoxantrone/prednisone)8 and the TAX 327 trial (investigating docetaxel/prednisone vs mitoxantrone/prednisone)9 both demonstrated a significant 2-month overall survival benefit for docetaxel-treated patients. The median overall survival associated with docetaxel every three weeks was significantly greater than that associated with mitoxantrone plus prednisone: SWOG 9916 Trial 17.6 versus 15.6 months (hazard ratio [HR] = 0.80) and TAX 327 trial 18.9 versus 16.5 months (HR = 0.76). These results established docetaxel every three weeks as the standard of care in mCRPC. Analysis of secondary end-points in the TAX 327 trial revealed that, overall, docetaxel patients had better pain control and quality of life and more frequent prostate-specific antigen (PSA) responses than did those in the mitoxantrone group.9
Since the establishment of docetaxel as first-line chemotherapy clinical trials have been designed in three different contexts – agents for use prior to docetaxel, agents for use in combination with docetaxel and agents for second-line treatment for patients who have progressed despite docetaxel.10 In recent years several new agents with promising activity and favorable toxicity profiles have been developed and clinically investigated in the fields of hormonal, cytotoxic, targeted and immune therapy.11
In 2010 the US Food and Drug Administration approved two new treatment options for prostate cancer, cabazitaxel and sipuleucel-T. This was followed, in April 2011, by the approval of a third agent, abiraterone acetate. On the basis of these new developments, the prostate cancer treatment landscape has begun to evolve, providing options either side of first-line chemotherapy.12 Indeed, based on the results of their respective phase III randomized controlled trials, both sipuleucel-T13 and cabazitaxel14 have been adopted as category 1 recommendations in the National Comprehensive Cancer Network guidelines for prostate cancer, albeit in vastly different patient groups.15 We are now entering the next era in the management of prostate cancer. This article discusses current and future options for second-line therapy in mCRPC.
Sipuleucel-T is an autologous cellular vaccine. Two early phase III trials (D9901 and D99902A) showed a trend toward increased survival with sipuleucel-T; however, neither study demonstrated an improvement in time to disease progression, the primary end-point of both trials.16,17 An integrated analysis of both trials showed a trend towards a delay in time to disease progression.17
In the phase III IMPACT trial the median overall survival associated with sipuleucel-T was 4.1 months longer than with placebo (25.8 vs 21.7 months).13 The study group was a largely chemotherapy-naive cohort of patients with mCRPC.13 On this basis, sipuleucel-T is approved in the USA for the treatment of men with asymptomatic or minimally symptomatic mCRPC.
The optimal sequence of the therapies to enhance survival (sipuleucel-T followed by chemotherapy, or chemotherapy followed by sipuleucel-T) has yet to be prospectively determined in a large, randomized study. The high cost (estimated to be ∼US$ 90 00018) and clinical complexity associated with the use sipuleucel-T are likely to limit its use in Australia.
SECOND-LINE CHEMOTHERAPY FOLLOWING DOCETAXEL IN mCRPC
Docetaxel remains the current standard of care for first-line chemotherapy in patients with mCRPC. Despite the demonstrated survival benefit with this drug in mCRPC, patients inevitably progress and require additional treatment. Thus, a need exists for an effective and well-tolerated treatment for patients with mCRPC who experience progression after initial chemotherapy.
Re-treatment with docetaxel (also referred to as a docetaxel rechallenge) may be considered in those patients who have not shown definitive evidence of disease progression on prior docetaxel therapy. However, the currently available data are limited to phase II (evidence level 2) evaluations.19–23
Data from Europe suggest that up to 80% of patients with docetaxel-resistant mCRPC receive second-line chemotherapy, primarily via clinical trials or open access programs.24 In Australia it is estimated that this figure is closer to 50%, with some variation between states. Although published data are available from 44 phase II trials of chemotherapy in docetaxel-resistant mCRPC, the results of many of these trials have been disappointing.24 There are only two phase III randomized controlled studies of cytotoxic agents in this setting (Table 1) – SPARC25 and TROPIC.14
Table 1. Published phase III clinical trials of second-line chemotherapy in metastatic castration-resistant prostate cancer patients
*Statistically significant. †Prostate-specific antigen (PSA) response was defined as a 50% or more reduction in serum PSA concentration, established at baseline and confirmed by a repeat PSA measurement after at least 3 weeks. CBZ, cabazitaxel; MXN, mitoxantrone; PDN, prednisone; SPT, satraplatin.
In the SPARC study patients with mCRPC (only half of whom were docetaxel pretreated) were allocated to receive either satraplatin and prednisone (n = 635) or placebo and prednisone (n = 315).25 Although satraplatin delayed disease progression (progression-free survival: 11.0 vs 9.7 weeks; HR 0.67; 95% CI 0.57–0.77, P < 0.001) and was associated with a higher pain response, it did not confer a survival benefit (overall survival: 61.3 vs 61.4 weeks; HR 0.98; 95% CI 0.84–1.15, P = 0.80). Further confirmatory trials are needed before the true role of satraplatin in advanced prostate cancer can be established.
Cabazitaxel is an i.v.-administered semi-synthetic tubulin-binding taxane, developed to overcome the emergence of multidrug resistance that can occur with existing taxanes.26 Preclinical studies have shown that cabazitaxel has equal or greater antitumor activity than docetaxel, including activity in cancer cells that are resistant to docetaxel.27 In the TROPIC study, cabazitaxel was associated with a 30% reduced risk of death, prolonging survival from 12.7 to 15.1 months (HR 0.70; 95% CI 0.59–0.83, P < 0.0001).14
Prior to enrolment into the TROPIC trial patients in the cabazitaxel arm had received a median total docetaxel dose of 576.6 mg/m2 (range 408.4–761.2 mg/m2) and disease progression occurred in 72% of patients during or within 3 months of their last docetaxel dose. In all, 25% had visceral metastases, 53% had measurable disease and 46% had pain at baseline. An intention-to-treat analysis of overall survival in subgroups defined by prognostic factors favored cabazitaxel, even in patients who had disease progression during docetaxel treatment (n = 219; HR 0.65; 95% CI 0.47–0.90) and in those who had received high cumulative doses of docetaxel (n = 134; HR 0.51; 95% CI 0.33–0.79).
Post hoc subgroup analysis of the TROPIC trial shows that a similar proportion of patients discontinued prior docetaxel due to disease progression (63 and 61% in the cabazitaxel and mitoxantrone arms, respectively).28 In this subgroup of patients, median overall survival was greater with cabazitaxel than with mitoxantrone (13.8 vs 10.9 months; HR 0.70; 95% CI 0.57–0.87). Survival benefit with cabazitaxel was also evident among patients who had discontinued prior docetaxel for reasons other than disease progression (18.0 vs 15.6 months; HR 0.63; 95% CI 0.46–0.85). This suggests that the survival benefit of cabazitaxel over mitoxantrone is maintained irrespective of whether prior docetaxel treatment was discontinued due to disease progression.28
In the TROPIC trial patients were initiated at 25 mg/m2 and, as was anticipated from the phase I29 and II30 data, the most common toxicity associated with cabazitaxel was neutropenia. Grade ≥ 3 neutropenia occurred in 82% of patients and 8% developed febrile neutropenia (vs 58 and 1% of patients, respectively, in the mitoxantrone group).14 Diarrhea was the most common non-hematological adverse event with cabazitaxel; with 47% of patients experiencing some diarrhea and in 6.2% this toxicity was grade 3 (the corresponding figures in the mitoxantrone group were 11% and <1%, respectively). Neuropathy was relatively infrequent. In the cabazitaxel group 18 (5%) patients died within 30 days of the last dose of the study drug. Neutropenia and its clinical consequences was the most frequent cause, being attributed to seven (2%) of these deaths.
Several factors may have influenced these toxicity findings. A subgroup analysis reported the incidence of neutropenia to be significantly higher in older men (17.6% in men aged < vs 24.2% in those aged ≥65; P < 0.1) and lower in European study centers (16.1%) than those in North America (25.7%) or other regions (35.1%). Similarly, the incidence of diarrhea (all grades) was statistically significantly (P < 0.1) higher in older (≥75 years) patients and in those who had had prior radiotherapy.
Potential risk-mitigation strategies include dose reduction to 20 mg/m2 in selected high-risk patients (aged >65 years, extensive prior radiation, poor nutrition, previous febrile neutropenia, poor performance status and other serious medical comorbidities) or primary prophylaxis with granulocyte colony stimulating factor and secondary prophylaxis with growth factors, or dose delays prior to subsequent cycles, or both. An open-label, randomized phase III study to evaluate the non-inferiority and safety of cabazitaxel 20 mg/m2 versus 25 mg/m2 has been initiated, with results due in late 2017 (Table 2).31 Combining proactive patient education (to ensure that patients understand what to do in the event that they develop fever or diarrhea) with vigilant adherence to established management protocols is also warranted. Indeed, it is noteworthy that after the safety board's advice to all centers to adhere to the American Society of Clinical Oncology's (or comparable) guidelines no further adverse event-related deaths occurred in the TROPIC study.
Table 2. Cabazitaxel: current phase III clinical trials in prostate cancer
End date = estimated primary completion date and denotes final data collection date for primary outcome measure. CBZ, cabazitaxel; DOC, docetaxel; mCRPC, metastatic castration-resistant prostate cancer; PDN, prednisone.
To date, cabazitaxel is the only cytotoxic agent to have been associated with a significant survival advantage compared to mitoxantrone when used in combination with prednisone for the treatment of mCRPC that has progressed following docetaxel therapy. Several studies are underway evaluating the efficacy and safety of cabazitaxel both alone and in combination with other agents,12 and a phase III study to compare the efficacy of cabazitaxel/prednisone as first-line chemotherapy to that of docetaxel/prednisone began recruiting in May 2011 (Table 2).32
Androgen receptor signaling remains essential for many prostate cancers that have progressed despite ADT. After medical or surgical castration, persistent, although not insignificant, low levels of androgens are produced from extragonadal sources such as the adrenal glands. Some CRPR acquire the ability to convert adrenal steroids to androgens, maintaining levels sufficient to activate androgen receptor. The inhibition of persistent androgen production and androgen receptor mediated signaling are relevant therapeutic strategies for mCRPC.33
Abiraterone acetate is a selective inhibitor of androgen biosynthesis that potently blocks cytochrome P450 c17 (CYP17). Phase II clinical trials with abiraterone acetate have yielded promising results,34,35 which have now been corroborated in a randomized, double-blind, placebo controlled phase III trial of abiraterone acetate plus low-dose prednisone in patients with mCRPC who had progressed after docetaxel-based chemotherapy.36
The results from this phase III study demonstrate that patients treated with abiraterone acetate plus low-dose prednisone/prednisolone showed a significant improvement in overall survival compared to patients treated with prednisone/prednisolone plus placebo. After a median follow up of 12.8 months, overall survival was 14.8 versus 10.9 months; (HR = 0.65; 95% CI: 0.54–0.77; P < 0.001). All secondary end-points also favored the abiraterone treatment group. Subgroup analysis for overall survival has also been conducted; demonstrating that significantly prolonged overall survival across multiple patient subgroups (HR range 0.52–0.81) was consistent with the survival benefit for the overall study group.36
The toxicity profile of abiraterone acetate is dependent upon its mechanism of action. Although CYP17 regulates the conversion of pregnenolone and related steroids into androgens and is relatively specific for androgen production, there is a compensatory rise in adrenocorticotropic hormone mediated by a hypothalamic response to partial adrenal inhibition. This can cause increased adrenal mineralocorticoid production, which can lead to hypertension and hypokalemia.
In the phase III trial, mineralocorticoid-related adverse events were more common in the abiraterone acetate arm than in the placebo arm, including fluid retention (31 vs 22%) and hypokalemia (17 vs 8%). However, grade 3/4 hypokalemia (3 vs 1%), and grade 3/4 hypertension (1 vs 0.1%) were infrequent. As a result of a report of a grade 4 elevation in aminotransferase levels early in the study, frequent monitoring of liver function tests occurred during the first 12 weeks of treatment. Overall abnormal liver function tests occurred with similar frequency in the abiraterone and the placebo groups (all grades: 10 vs 8%). A similar trial in the pre-chemotherapy setting has completed accrual and is undergoing analysis.37Table 3 provides an overview of current phase III studies.
Table 3. Abiraterone acetate: current phase III clinical trials in prostate cancer
End date = estimated primary completion date and denotes final data collection date for primary outcome measure. AA, abiraterone acetate; DOC, docetaxel; LHRH, luteinizing hormone-releasing hormone; mCRPC, metastatic castration-resistant prostate cancer; PDN, prednisone.
AA + leuprolide acetate + PDN vs leuprolide acetate alone
Phase II open label, randomized, multi-center
Localized high risk prostate cancer
Serum and prostate tissue androgen levels
Start: Sep 2009
End: Dec 2011
BONE COMPLICATIONS IN mCRPC
Bone metastases are a substantial burden to men with advanced prostate cancer, causing considerable pain. In addition, treatment-related osteoporosis is associated with increased susceptibility to fractures and spinal cord compression. Several bisphosphonates have been shown to improve bone mineral density in men receiving ADT, zoledronic acid has been standard of care for CRPR with bone metastases as it reduces the risk for skeletal-related events.46
The receptor activator of nuclear factor-κB ligand (RANKL) is a key mediator of osteoclast formation, function, and survival. RANKL plays a critical role in the formation and activation of osteoclasts. The effects of RANKL are physiologically counterbalanced by the decoy receptor osteoprotegerin (OPG). Skeletal malignancies enhance the ratio of RANKL to OPG, thereby promoting osteoclastogenesis, accelerating bone resorption, and inducing bone loss. In animal models, the inhibition of RANKL has prevented bone loss caused by malignant tumours and has, therefore, has the target of pharmaceutical development.47 Denosumab is a fully human monoclonal antibody of the immunoglobulin G2 subclass, possessing a high specificity and affinity for RANKL. It acts by mimicking the effects of OPG, binding RANKL and thereby reducing osteoclast formation and action.46
The efficacy of denosumab in preventing ADT-induced bone loss and fracture in non-metastatic48 prostate cancer as well as disease-related skeletal events in men metastatic disease49 has been investigated in two phase III studies. Among men with non-metastatic prostate cancer undergoing ADT, those receiving denosumab had an increase of 5.6% in the bone mineral density of the lumbar spine in the denosumab group as compared with a loss of 1.0% in the placebo group (P < 0.001) at 24 months.48 The incidence of new vertebral fractures at 36 months was significantly lower in those patients who had received denosumab (1.5 vs 3.9%; relative risk, 0.38; 95% CI, 0.19 to 0.78; P = 0.006). Similarly, among men with mCRPC, the median time to a first on-study skeletal event was 20.7 months (95% CI 18.8–24.9) with denosumab compared with 17.1 months (15.0–19.4) with zoledronic acid (HR = 0.82, 95% CI 0.71–0.95; P = 0.0002 for non-inferiority; P = 0.008 for superiority).49
Denosumab is currently the only RANKL targeted therapy available. It has been approved in the USA for the prevention of skeletal-related events in men with mCRPC and in the USA, Europe and Australia for the treatment of bone loss associated with hormone ablation in men with non-metastatic prostate cancer.
Radiopharmaceutical therapy is used palliatively in metastatic prostate cancer and can provide a number of advantages over conventional external beam radiotherapy, such as i.v. administration and the potential to cause fewer side effects. Two radiopharmaceuticals, strontium-89 and samarium-153, are approved for use in Australia.
Radium-223 is a first-in-class alpha-pharmaceutical developed to target bone metastases with high energy alpha particles in very short range (<100 µm). The first clinical experience showed radium-223 to be well tolerated at therapeutically relevant dosages.50 In a phase II study, radium-223 was well tolerated and had a significant positive effect on bone-alkaline phosphatase concentration.51 Favourable effects on median time to PSA progression, time to first skeletal-related event and median overall survival were also observed prompting the need for a larger clinical trial.
Most recently it has been shown to improve overall survival in men with mCRPC.52 The phase III randomized ALSYMPCA study compared radium-223 combined with best standard of care versus placebo plus best standard of care in patients with symptomatic prostate cancer and at least two bone metastases. The trial was largely in the post-docetaxel setting although some patients received radium-223 without prior chemotherapy since they were deemed to be unfit for docetaxel. In a pre-planned interim analysis, overall survival was 14.0 versus 11.2 months; (HR = 0.695; 95% CI: 0.552–0.875; P = 0.002) and time to first skeletal-related event was 13.6 versus 8.4 months (HR = 0.610; 95% CI 0.461–0.807; P = 0.00046). The trial was stopped early due to this evidence of significant treatment benefit.
To date, radium-223 is the only bone-targeting agent to show a survival benefit in advanced stage prostate cancer. These positive results coupled with the low toxicity and high tolerability of this treatment suggests that radium-223 may provide a new standard of care in the treatment of CRPC patients with bone metastases. A phase I/II dose-escalation study designed to establish the recommended dose of radium-223 to be used in conjunction with docetaxel is currently recruiting, with results anticipated in June 2012.53
Other investigational agents, which are in various stages of ongoing clinical trials for the treatment and prevention of bone metastases in prostate cancer, include zibotentan (endothelin-A receptor antagonism), dasatinib, saracatinib and bosutinib (proto-oncogene tyrosine-protein kinase inhibition) and cabozantinib hepatocyte growth factor receptor (MET/vascular endothelial growth factor receptor 2 inhibition).
OTHER EMERGING THERAPIES
Immunotherapies have been sought as treatments for prostate cancer for some time, but for the most part these efforts have been unsuccessful. In addition to sipuleucel-T (discussed earlier) other immune-based therapies are currently at various stages of development.
Ipilimumab is an anti-CTLA-4 monoclonal antibody for which preliminary phase II data in advanced prostate cancer patients are available.54,55 Data from a randomized phase II trial of ipilimumab plus ADT versus ADT alone in patients with advanced disease suggest that ipilimumab may act synergistically with ADT.54
Two randomized, double-blinded, phase III trials comparing ipilimumab with placebo following radiotherapy in men with mCRPC are underway. One is in the post-docetaxel setting and the other in chemotherapy-naive patients (Table 4). In addition, a phase II trial investigating ipilimumab in combination with leuprolide acetate in the neoadjuvant setting is also recruiting at the time of writing.56
Table 4. Ipilimumab: current phase III clinical trials in prostate cancer
GVAX immunotherapy for prostate cancer comprises two prostate tumor cell lines that have been modified to secrete granulocyte-macrophage colony-stimulating factor. It reached phase III testing, but both the VITAl-1 trial (comparing GVAX immunotherapy with docetaxel and prednisone chemotherapy in men with asymptomatic prostate cancer) and the VITAL-2 trial (comparing the combination of GVAX immunotherapy plus docetaxel (minus prednisone) with standard docetaxel and prednisone in men with symptomatic disease trials were terminated early in 2008 due to unfavorable results:59
• A routine safety review of VITAL-2 revealed an imbalance of deaths (47 in the docetaxel and prednisone arm and 67 in the GVAX immunotherapy and docetaxel combination arm).
• While no safety concerns were raised for VITAl-1, efficacy concerns prompted a futility analysis, which revealed that the trial had only a 30% chance of meeting an improved survival end-point.
Bio Sante Pharmaceuticals acquired GVAX immunotherapy for prostate cancer when it bought Cell Genesys in 2009. Ongoing discussions with the Food and Drug Administration since that time have resulted in a recent lift on the prior hold over clinical trials for this product. In June 2011 the company announced that a new phase II trial was being planned in the USA.
MDV3100 is a novel androgen receptor blocker, shown in preclinical studies to block testosterone binding to the androgen receptor, impede the movement of the androgen receptor to the nucleus of prostate cancer cells and inhibit binding to DNA.60 In a phase I/II multicenter, dose-finding trial for MDV3100 investigators noted antitumor activity at all doses administered, including a PSA reductions of ≥50% in 56% of patients.61
A phase III trial (AFFIRM) was designed to compare the efficacy and safety of MDV3100 versus placebo in patients with mCRPC previously treated with docetaxel-based chemotherapy.62 This study was stopped early when a pre-planned interim analysis showed a significant (P < 0.0001) overall survival benefit in the MDV3100 arm: median overall survival was 18.4 versus 13.6 months in the placebo arm. A full analysis of the AFFIRM results, including safety data, is still to be published.In addition to two further phase II studies (Table 5), the PREVAIL trial is underway at the time of writing and will evaluate the utility of this agent in chemotherapy-naive mCRPC patients.63
Table 5. MDV3100: current clinical trials in prostate cancer
Phase III, randomized, parallel group, double blind, placebo-controlled, multi-center
Overall survival, progression-free survival
Start: Sep 2010
End: Sep 2014
Like abiraterone, TAK-700 is a selective inhibitor of androgen biosynthesis. In preclinical studies TAK-700 has been shown to bind to and inhibit the enzyme 17,20-lyase 1 offering potent inhibition of androgen synthesis.33 Phase II and III studies are currently recruiting men with mCRPC in both the pre-docetaxel and post-docetaxel settings (Table 6).
Table 6. Orteronel : current clinical trials in prostate cancer
With the many new therapies now available and in the pipeline, the management of mCRPC is undergoing a significant and positive change (Fig. 1). Currently available evidence demonstrates a survival benefit with cabazitaxel, radium-223, MDV3100 and abiraterone in patients with mCRPC who have progressed beyond docetaxel. In the meantime, we await the full results of a recently completed AFFIRM study62 in the same patient setting as well as the results of trials with abiraterone acetate,37 MDV310063 and orteronel66 in mCRPC chemotherapy-naive patients. These studies, as well as those currently recruiting, will aid in future refinements of the relative position of these new therapeutic options.
Much progress has been made in developing new therapies and treatment regimens. Whereas in the past treatment focused on the sequential use of limited treatments, clinicians and their patients now face the more positive prospect of having a choice of drugs to use. Further work is required to determine the optimum sequence of these new agents but, regardless of the outcome of these studies, we can be assured that the lives of patients with mCRPC will be improved.
This work has been carried out with financial support from Sanofi Australia. The authors acknowledge editorial assistance provided by Hazel Palmer of Scius Solutions. Ms Palmer's contribution was funded by Sanofi Australia. The authors have received reimbursement from Sanofi as follows: Dr Parente, for participation in an Australian Advisory Board and for involvement in ongoing clinical trials with Sanofi oncology products; Dr Parnis, for participation in an Australian Advisory Board and also for involvement in ongoing clinical trials with Sanofi oncology products; and Dr Gurney, for participation in an Australian Advisory Board.