Urologists and oncologists: adapting to a new treatment paradigm in castration-resistant prostate cancer (CRPC)

The treatment landscape for men with castration-resistant prostate cancer (CRPC) is undergoing significant changes; a redefinition of the respective roles of oncologists and urologists will probably occur. In addition, the advent of the multidisciplinary team or coordinated-care approach, which has been gathering momentum over the last decade, will become not simply a preference but a clear necessity. In the present review, we explore the current wave of new treatments and describe the possibility of more complex approaches to combined therapy. New treatment options include abiraterone acetate, cabazitaxel, MDV3100 (in development), radium-223 (in development) and sipuleucel-T. We also present the traditional roles of the urologist and oncologist in caring for patients with CRPC and discuss how these may change. Compounding the new potential for treatment success, as well as the complexity of therapeutic strategies, is the emergence of novel biomarkers to evaluate treatment efficacy and to assist in patient prognosis. The prospects for successful treatment of patients with CRPC have developed considerably so that these patients may soon have a reasonable expectation of therapeutic efficacy and meaningful extension of their lives.     

The role of docetaxel based therapy for prostate cancer in the era of targeted medicine

Docetaxel based chemotherapy has been shown to modestly extend life, relieve pain and improve the quality of life in patients with metastatic castration‐resistant prostate cancer. Current trials are attempting to build on the backbone of docetaxel by combining it with novel biological agents. Trials are also investigating the role of docetaxel for earlier stages of prostate cancer. No standard second‐line systemic therapy exists and such patients are candidates for clinical trials. The increased understanding of the mechanisms of progressive castration‐resistant prostate cancer is being translated into an increasing pipeline of novel therapies.     

Low dose of ketoconazole in patients with prostate adenocarcinoma resistant to pharmacological castration

Study Type – Therapy (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? Ketoconazole is an inhibitor of adrenal androgen synthesis which carries on the anti‐tumour activity by interfering with different enzymes, cytochrome P450 14‐α‐demethylase, C 17,20 lyase and C 17 α‐hydroxylase. Some studies have shown an anti‐tumour activity of ketoconazole employed at different dose levels following the failure of androgen‐suppressive therapies. Patients refractory to pharmacological castration and/or chemotherapy could have an additional benefit in terms of disease control from the use of low dose of ketoconazole. The safety profile was good.

OBJECTIVE

• ? To assess the efficacy of ketoconazole in patients with castration‐resistant prostate cancer (CRPC).

PATIENTS AND METHODS

• ? From April 2008 to November 2009, 37 patients with CRPC have been treated with ketoconazole. The primary endpoint was the prostate‐specific antigen (PSA) response; the secondary endpoints were progression‐free survival and safety profile.
• ? Ketoconazole was administered by oral route at a dose of 200 mg every 8 h continuous dosing until the onset of serious adverse events or disease progression.
• ? The study was based on a two‐step design with an interim efficacy analysis carried out on the first 12 patients accrued.

RESULTS

• ? Main characteristics of population were: median age 75 years (range 60–88); baseline mean PSA 28.8 ng/mL (4.3–1000); 30 patients previously challenged with at least two lines of hormone therapy; 15 patients previously treated with chemotherapy.
• ? Biochemical responses accounted for: two complete responses (5%), six partial responses (16%), 13 patients with stable disease (35%), and 14 with progressive disease (38%). Of 15 patients resistant to chemotherapy, overall disease control (complete plus partial responses plus stable disease) was recorded in seven of them.
• ? Treatment was feasible without inducing grade 3–4 adverse events. The most common grade 1–2 adverse events were asthenia (27%), vomiting (8%) and abdominal pain (8%).

CONCLUSION

• ? Treatment with low‐dose ketoconazole is feasible and well tolerated. The efficacy was satisfactory in patients previously treated with chemotherapy.

     

Germline BRCA mutation does not prevent response to taxane-based therapy for the treatment of castration-resistant prostate cancer

Study Type – Prognosis (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? In the preclinical setting BRCA mutations appear to modulate response to chemotherapy, increasing sensitivity to platinums and increasing resistance to taxanes. Clinical data supports a greater platinum sensitivity among BRCA mutation carriers. This study suggests that BRCA mutation carriers may also respond to taxanes.

OBJECTIVE

? To investigate the relationship between BRCA mutation status and response to taxane‐based chemotherapy, since BRCA mutation carriers with prostate cancer appear to have worse survival than non‐carriers and docetaxel improves survival in patients with castration‐resistant prostate cancer.

PATIENTS AND METHODS

? We determined BRCA mutation prevalence in 158 Ashkenazi Jewish (AJ) men with castration‐resistant prostate cancer. Clinical data were collected as part of an institutional prostate cancer research database and through additional medical record review. ? Clinical records and DNA samples were linked through a unique identifier, anonymizing the samples before genetic testing for the AJ BRCA1/2 founder mutations. ? Response to taxane‐based therapy was defined by the prostate‐specific antigen nadir within 12 weeks of therapy.

RESULTS

? In all, 88 men received taxane‐based treatment, seven of whom were BRCA carriers (three BRCA1, four BRCA2; 8%). Initial response to taxane was available for all seven BRCA carriers and for 69 non‐carriers. ? Overall, 71% (54/76) of patients responded to treatment, with no significant difference between carriers (57%) and non‐carriers (72%) (absolute difference 15%; 95% confidence interval –23% to 53%; P= 0.4). ? Among patients with an initial response, the median change in prostate‐specific antigen was similar for BRCA carriers (?63%, interquartile range ?71% to ?57%) and non‐carriers (?60%, interquartile range ?78% to ?35%) (P= 0.6). ? At last follow‐up, all seven BRCA carriers and 49 non‐carriers had died from prostate cancer. One BRCA2 carrier treated with docetaxel plus platinum survived 37 months.

CONCLUSION

? In this small, hypothesis‐generating study approximately half of BRCA carriers had a prostate‐specific antigen response to taxane‐based chemotherapy, suggesting that it is an active therapy in these individuals.     

Phase II study of docetaxel re‐treatment in docetaxel‐pretreated castration‐resistant prostate cancer

Study Type – Therapy (cohort)
Level of Evidence 2b What’s known on the subject? and What does the study add? We show that (i) docetaxel re‐treatment, after a treatment‐free interval, preserves activity; (ii) the treatment is especially well tolerated in patients who were effectively pretreated with docetaxel; and (iii) it could be speculated that combining docetaxel with other agents in this setting might be safe and result in greater activity.

OBJECTIVE

To determine the activity and tolerability of docetaxel re‐treatment after first‐line therapy with docetaxel in castration‐resistant prostate cancer (CRPC).

PATIENTS AND METHODS

Between November 2005 and January 2009, 45 patients initially responding to docetaxel and then experiencing disease progression after a period of biochemical remission of at least 5 months were enrolled in a prospective multicenter study and re‐treated with docetaxel. The primary endpoint was the biochemical response (biochemical partial response defined as >50% prostate‐specific antigen [PSA] decline); secondary endpoints were objective response, toxicity, progression‐free survival (PFS) and overall survival (OS).

RESULTS

Partial PSA responses were observed in 11 patients (24.5%), 4 (25%) of whom also had an objective response. The treatment was well tolerated, with grade 1–2 neutropenia, thrombocytopenia, vomiting and peripheral neuropathy noted in 18 (40%), 11 (24.5%), 8 (17.8%), and 6 (13.3%) patients, respectively. The most common grade 3 toxicity was neutropenia, which was observed in 8 patients (17.8%). Median PFS was 5 months and median OS was 13 months.

CONCLUSIONS

Docetaxel re‐treatment preserves anti‐tumour activity and is well tolerated in a selected population of pretreated patients with CRPC. Further randomized trials are needed to confirm our preliminary results.     

Prostate-specific antigen response to deferred combined androgen blockade therapy using bicalutamide predicts survival after subsequent oestrogen and docetaxel therapies in patients with castration-resistant prostate cancer

Study Type – Prognosis (retrospective cohort analysis) Level of Evidence 2b What's known on the subject? and What does the study add? The additional use of anti‐androgen (deferred combined androgen blockade [CAB] therapy) for patients with castration‐resistant prostate cancer (CRPC) initially treated with androgen deprivation monotherapy (ADMT) can provide a clinical response, although the reported response rates vary widely. Our previous study, which reported a response rate of 66% to deferred CAB therapy, suggested that deferred CAB responders would also respond better to subsequent therapies than non‐responders because the difference in cancer‐specific survival between the deferred CAB responders and the non‐responders was much larger than the progression‐free survival rates for the responders. The present study showed that PSA response to deferred CAB therapy predicts clinical outcomes after subsequent oestrogen and docetaxel therapy. We propose that PSA response to deferred CAB be used for planning individualized treatment that includes secondary hormonal therapy and chemotherapy.

OBJECTIVE

• ? To evaluate whether there is any association between prostate‐specific antigen (PSA) response to deferred combined androgen blockade (CAB) therapy using bicalutamide in patients with castration‐resistant prostate cancer (CRPC), initially treated with castration monotherapy, and the clinical outcomes after subsequent oestrogen and docetaxel therapies.

PATIENTS AND METHODS

• ? Fifty‐six patients with advanced prostate cancer, who were refractory to both initial castration monotherapy and subsequent deferred CAB, received oestrogen therapy (estramustine phosphate 140 or 280 mg/day in 50 patients, diethylstilbestrol diphosphate 100 mg/day orally in six patients). Of the 56 patients, 33 underwent docetaxel therapy (median dose 55 mg/m², every 4–8 weeks, median 6 courses) when they became refractory to oestrogen therapy.
• ? A deferred CAB response was defined as a decrease of >50% in PSA levels after the addition of bicalutamide. The difference in cancer‐specific survival (CSS) after confirmation of resistance to initial castration monotherapy between the deferred CAB responders and the non‐responders was evaluated, and outcomes after oestrogen and docetaxel therapies were also compared between the two groups.

RESULTS

• ? A response to deferred CAB was observed in 27 (48%) of the 56 patients. There was no significant difference between the responders and the non‐responders in pretreatment clinical variables, including Gleason score, metastatic sites, PSA level at diagnosis, and PSA nadir during castration monotherapy.
• ? A deferred CAB response was a significant predictor of CSS after confirmation of resistance to initial castration monotherapy.
• ? The deferred CAB responders had significantly longer progression‐free survival (PFS) (median 3.2 months in the responders, 2.1 month in the non‐responders, P= 0.04) and CSS (median 3.0 years in the responders, 1.5 years in the non‐responders, P= 0.04) after oestrogen therapy. Likewise, PFS (median 8.2 months in the responders, 2.2 months in the non‐responders, P < 0.01) and CSS (median not reached in the responders, 1.4 years in the non‐responders, P < 0.01) after docetaxel therapy was significantly longer in the deferred CAB responders.

CONCLUSION

• ? PSA response to deferred CAB predicts clinical outcomes after subsequent oestrogen and docetaxel therapies in patients with CRPC, and provides useful information for planning individualized optimum treatment courses that include secondary hormonal therapy and chemotherapy.

     

Influence of prior oral ethinylestradiol use on the efficacy of enzalutamide for the treatment of castration‐resistant prostate cancer in men

Objective

To elucidate the effect of prior use of ethinylestradiol on enzalutamide treatment for men with castration‐resistant prostate cancer.

Methods

We retrospectively analyzed data from 99 consecutive patients (median age 72 years, range 50–88 years) treated with enzalutamide for castration‐resistant prostate cancer between May 2014 and November 2015 after receiving several lines of hormonal therapy.

Results

A total of 45 patients were given ethinylestradiol before enzalutamide. The prostate‐specific antigen response rate (decline in prostate‐specific antigen >50% from baseline) of patients receiving ethinylestradiol and enzalutamide were 51.1% and 41.4%, respectively. Cross‐resistance between ethinylestradiol and enzalutamide was clearly observed in the setting of pre‐docetaxel. In multivariate analysis, the T stage and number of therapies before enzalutamide were the only significant predictors of prostate‐specific antigen response to enzalutamide. However, in patients treated pre‐docetaxel use, prior use of ethinylestradiol was a significant predictor of prostate‐specific antigen response to enzalutamide, whereas ethinylestradiol did not affect the overall survival of these patients.

Conclusions

Cross‐resistance between ethinylestradiol and enzalutamide in the setting of pre‐docetaxel therapy seems to be evident. Therefore, ethinylestradiol should be used prudently before enzalutamide in this setting.     

Current treatment strategies for advanced prostate cancer

During the past decade, treatment strategies for patients with advanced prostate cancer involving stage IV (T4N0M0, N1M0 or M1) hormone‐sensitive prostate cancer and recurrent prostate cancer after treatment with curative intent, as well as castration‐resistant prostate cancer, have extensively evolved with the introduction and approval of several new agents including sipuleucel‐T, radium‐223, abiraterone, enzalutamide and cabazitaxel, all of which have shown significant improvement on overall survival. The appropriate use of these agents and the proper sequencing of these agents are still not optimized. The results of several recently reported randomized controlled trials and retrospective studies could assist in developing a treatment strategy for advanced prostate cancer. In addition, prospective studies and molecular characterization of tumors to address these issues are ongoing.     

Docetaxel reintroduction in patients with metastatic castration‐resistant docetaxel‐sensitive prostate cancer: a retrospective multicentre study

OBJECTIVE

To investigate the potential benefit of reintroducing docetaxel chemotherapy in patients with progressive metastatic castration‐resistant prostate cancer (mCRPC) who had initially responded to first‐line docetaxel‐based regimen.

PATIENTS AND METHODS

Records were evaluated retrospectively from French patients with mCRPC who had been included in seven controlled clinical studies of docetaxel as first‐line treatment. We identified patients who were confirmed as responders to first‐line treatment, discontinued for reasons other than disease progression or unacceptable toxicity, and who received further docetaxel chemotherapy for disease progression. The primary objective was to assess efficacy in terms of the prostate‐specific antigen (PSA) response after resuming a docetaxel‐based chemotherapy. Secondary objectives were overall survival and tolerance.

RESULTS

Of the 148 patients who responded to first‐line docetaxel, 50 received further therapy with docetaxel and were analysed. The median (range) response duration to first‐line docetaxel was 10.3 (4.6–45.7) months and the median docetaxel‐free interval was 18.4 (5.0–46.7) months. Docetaxel was reintroduced as second‐line therapy in 52% of patients and as further lines in 48%. After docetaxel reintroduction, 24 patients (48%) had a 50% decrease in PSA level (95% confidence interval, CI, 34.1–61.8%). The median (95% CI) overall survival from docetaxel reintroduction was 16 (13–20) months. Re‐treatment was well tolerated (6% of grade 3–4 haemotoxicity).

CONCLUSION

Docetaxel reintroduction appears to be effective, with favourable tolerance profiles, in patients with mCRPC having responded to first‐line docetaxel, and should be prospectively assessed in clinical trials against alternative therapies or investigational agents given alone or in combination, to define further management.     

Current paradigms and evolving concepts in metastatic castration-resistant prostate cancer

Until recently, docetaxel-based therapy represented the only therapy shown to prolong survival in patients with metastatic castration-resistant prostate cancer (mCRPC). The past year and a half has been marked by unprecedented progress in treatments for this disease. Three positive phase III clinical trials have emerged, each evaluating agents (sipuleucel-T, cabazitaxel and abiraterone) with distinct mechanisms of action. Herein, the three pivotal trials are described alongside both past and current large phase III studies conducted in this mCRPC. The overall survival for patients with mCRPC treated in current clinical trials is considerably longer than noted in the past. We note that more recent trials with older agents have also shown improved survival and discuss potential non-therapeutic biases that influence this critical measure of outcome. The necessity for utilizing randomized trials when evaluating new therapeutics is emphasized given the changing prognosis in this mCRPC.     

Cytotoxic chemotherapy in the contemporary management of metastatic castration‐resistant prostate cancer (mCRPC)

For several years, docetaxel was the only treatment shown to improve survival of patients with metastatic castration‐resistant prostate cancer (mCRPC). There are now several novel agents available, although chemotherapy with docetaxel and cabazitaxel continues to play an important role. However, the increasing number of available agents will inevitably affect the timing of chemotherapy and therefore it may be important to offer this approach before declining performance status renders patients ineligible for chemotherapy. Patient selection is also important to optimise treatment benefit. The role of predictive biomarkers has assumed greater importance due to the development of multiple agents and resistance to available agents. In addition, the optimal sequence of treatments remains undefined and requires further study in order to maximize long‐term outcomes. We provide an overview of the clinical data supporting the role of chemotherapy in the treatment of mCRPC and the emerging role in metastatic castration‐sensitive prostate cancer. We review the key issues in the management of patients including selection of patients for chemotherapy, when to start chemotherapy, and how best to sequence treatments to maximise outcomes. In addition, we briefly summarise the promising new chemotherapeutic agents in development in the context of emerging therapies.