Adaptation and clonal selection models of castration‐resistant prostate cancer: Current perspective

Prostate cancer is a leading cause of cancer deaths in men worldwide. Management of the disease has remained a great challenge and even more so is the aggressive advanced stage with castration‐resistant behavior. The mechanisms and timing of development of castration‐resistant prostate cancer are unclear and remain debatable. Progression to castration‐resistant prostate cancer is undoubtedly multifactorial, with a number of molecular‐genetic aberrations implicated. However, a key question that remains unanswered is: when in the evolution of prostate cancer do the changes that confer castration resistance occur? Earlier attempts to address this question led to two proposed models: the “adaptation” and the “clonal selection” models. Although the prevailing hypothesis is the adaptation model, there is recent evidence in favor of the clonal selection model. Clarification of the model development of castration‐resistant prostate cancer might significantly alter our diagnostic and therapeutic strategies, and potentially lead to improved outcome of management of this daunting condition. Here we review existing knowledge and current research findings addressing the timing of events in the course of prostate cancer progression to castration‐resistant prostate cancer.     

Targeting the androgen receptor signalling axis in castration‐resistant prostate cancer (CRPC)

What's known on the subject? and What does the study add? Castration resistance has been appreciated for decades, and several mechanisms theorising on this effect have been proposed. A rich pipeline of novel agents, including abiraterone and MDV3100, have provided proof of principle that novel agents targeting the AR signalling pathway with superior selectivity and activity than predecessors have yielded significant clinical benefit for patients with metastatic castration‐resistant prostate cancer. Our review provides an update in the development of several novel agents targeting the AR signalling pathway now in clinical testing, as well as review novel therapies in development with distinct mechanisms of action showing promising preclinical activity.

• ? Despite undergoing local therapy with curative intent, 20–30% of patients with prostate cancer will ultimately development metastatic disease, leading to morbidity and mortality.
• ? Androgen‐deprivation therapy (ADT) for men with metastatic prostate cancer results in transient clinical benefit, but ultimately, cancers progress despite castrate levels of serum testosterone, a clinical state classically referred to as ‘hormone refractory’ disease.
• ? In this review, we examine mechanisms of resistance to ADT that have redefined our understanding of the more appropriately termed ‘castration resistant’ disease, and have paved the way for a new generation of therapeutics targeting the androgen signalling axis in advanced prostate cancer.

     

Alternative antiandrogen therapy in patients with castration‐resistant prostate cancer: A single‐center experience

Outcomes of alternative (second‐line) antiandrogen therapy in 112 patients with relapsing prostate cancer after first‐line hormonal therapy were analyzed. A good response (prostate‐specific antigen [PSA] decrease ≥50%) and a partial response (PSA decrease of 0–50%) by switching from bicalutamide (BCL) to flutamide (FLT) and from FLT to BCL were achieved in 35.4% (28/79) and 30.4% (24/79), and in 45.0% (9/20) and 20.0% (4/20) of cases, respectively. A good response and a partial response with the change from chlormadinone acetate (CMA) to a non‐steroidal antiandrogen (FLT or BCL) and from a non‐steroidal antiandrogen to CMA were obtained in 25.0% (2/8) and 37.5% (3/8), and in 20.0% (1/5) and 0% (0/5) of cases, respectively. In multivariate analyses, a second‐line good response was significantly predictive of cause‐specific survival from first therapy relapse to cancer death in all patients. Patients (52/112, 46.4%) with ≥30% decrease in PSA levels were associated with significantly better cause‐specific survival as measured from the start of first‐line treatment and first‐line relapse.     

Chemotherapy for metastatic castration‐sensitive prostate cancer

Incorporation of docetaxel into metastatic castration‐sensitive prostate cancer treatment has added a new treatment option to a disease state that had previously not seen change for decades. Early attempts of a chemo‐hormonal approach for castration‐sensitive prostate cancer were not successful. With the demonstration of survival benefits using docetaxel in patients with metastatic castration‐resistant prostate cancer, this encouraged continued research with docetaxel given earlier in the disease course. Three randomized phase III trials have defined the benefits of docetaxel in the metastatic castration‐sensitive prostate cancer setting; however, there remain questions and controversies on the appropriate and optimal patient selection.     

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.     

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.     

Phase II trial of RAD001 and bicalutamide for castration‐resistant prostate cancer

Study Type – Therapy (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Despite expanding treatment options for castration‐resistant prostate cancer (CRPC), therapies with long response duration remain intangible due to prostate cancer cells’ natural ability to develop iterative resistance. Androgen receptor (AR) signaling has been shown to play a critical role in CRPC and its expression is regulated by the PI3K‐Akt pathway. Thus inhibition of AR signalling and PI3K‐Akt‐mTOR (a downstream mediator of the PI3K‐Akt pathway) pathway is a logical combination in CRPC and we report a phase II trial of RAD001 and bicalutamide. Our study is the first clinical trial report of an AR inhibitor of PI3K‐Akt‐mTOR. The AR pathway and the PI3K‐Akt‐mTOR pathway are two of the most relevant growth pathway for CRPC. Despite low efficacy results from our trial there will be significant interest in the field for these data (dose, schedule, response, toxicity, trial design) as newer generations of both AR inhibitors and PI3K‐Akt‐mTOR inhibitors are in development and likely will be tested in combination in CRPC.

OBJECTIVES

• ? To determine best overall response and duration of response of RAD001, a selective inhibitor of mammalian target of rapamycin, in combination with bicalutamide in castration‐resistant prostate cancer (CRPC).
• ? To characterize the toxicity profile of RAD001 in combination with bicalutamide in patients with CRPC.

PATIENTS AND METHODS

• ? A phase II study was conducted to explore the efficacy and tolerability of RAD001 (10 mg daily) in combination with bicalutamide (50 mg daily) in men with progressive CRPC.
• ? The primary endpoint was a composite of prostate‐specific antigen (PSA) level and measurable disease response by standard criteria.
• ? This single‐stage trial with a sample size of 38 eligible patients provided 90% power to differentiate a response rate of ≥40% from a response rate of ≤20%, as expected for bicalutamide alone (α= 0.10, power = 0.90).

RESULTS

• ? In total, 36 men were enrolled, with a median (range) age of 68 (60–72) years and median (range) baseline PSA level of 22.2 (8.4–121.3) ng/mL, and 89% had metastatic disease.
• ? There were 31 (86%) patients had previously used bicalutamide for a median duration of 7.4 months.
• ? There were two patients with a confirmed PSA level decline ≥50%.
• ? The median (interquartile range) time to progression was 8.7 (7.9–15.9) weeks.
• ? The most common toxicity was grade 1/2 mucositis, which was observed in 20 (56%) patients.

CONCLUSION

• ? The combination of RAD001 and bicalutamide in men with CRPC was well tolerated but had low activity and failed to achieve the primary endpoint of improved response compared to the results previously achieved for bicalutamide alone in this population.

     

Activity of ketoconazole after taxane‐based chemotherapy in castration‐resistant prostate cancer

Study Type – Therapy (case series)Level of Evidence 4

OBJECTIVE

To assess the efficacy of the androgen‐synthesis inhibitor ketoconazole as a secondary hormonal therapy in patients with castration‐resistant prostate cancer (CRPC) previously treated with chemotherapy, as persistent androgens appear to play a role in the development and maintenance of CRPC.

PATIENTS AND METHODS

We retrospectively identified 34 patients with CRPC who were treated with ketoconazole as a secondary hormonal therapy after paclitaxel‐ or docetaxel‐based chemotherapy for CRPC. They were treated with ketoconazole 200–400 mg three times daily with or without hydrocortisone. Patients with previous use of ketoconazole were excluded. Half the patients had received estramustine as part of their chemotherapy regimen. The primary endpoint was the proportion of patients with a decline of ≥50% in their prostate‐specific antigen (PSA) level. PSA progression was defined by the PSA Working Group 1 Criteria.

RESULTS

Eight of the 32 evaluable patients (25%) had a PSA decline of ≥50%. The median time to progression (TTP) was 3 months (95% confidence interval, 1.2–5.4). A history of previous response to taxane‐based chemotherapy was not associated with the response to ketoconazole. However, previous use of oestrogens for CRPC was significantly associated with a shorter TTP on ketoconazole (1.5 vs 10.2 months; P = 0.03).

CONCLUSIONS

Ketoconazole has moderate activity as secondary hormonal therapy in patients with CRPC previously treated with taxane‐based chemotherapy, although the TTP was short. Previous treatment with oestrogenic therapy is associated with a shorter TTP.     

Final analysis of a phase II trial using sorafenib for metastatic castration‐resistant prostate cancer

OBJECTIVE

To determine if sorafenib is associated with an improved 4‐month probability of progression‐free survival, using radiographic and clinical criteria alone, in patients with metastatic castration‐resistant prostate cancer. Secondary endpoints included pharmacokinetics, toxicity analysis and overall survival.

PATIENTS AND METHODS

The study was an open‐label, phase II, two‐stage design, focusing on the results from the second stage, as criteria for progression were modified after completing the first stage. Sorafenib was given at a dose of 400 mg orally twice daily in 28‐day cycles. Clinical and laboratory assessments were done every 4 weeks, and radiographic scans were obtained every 8 weeks.

RESULTS

Twenty‐four patients were accrued in the second stage; the median (range) age was 66 (49–85) years, the on‐study prostate‐specific antigen level was 68.45 (5.8–995) ng/mL, the Gleason score 8 (6–9) and Eastern Cooperative Oncology Group status 1 (in 17 patients). Of the 24 patients, 21 had previous chemotherapy with docetaxel. All patients had bony metastases, either alone (in 11) or with soft‐tissue disease (in 13). One patient had a partial response; 10 patients had stable disease (median duration 18 weeks, range 15–48). At a median potential follow‐up of 27.2 months, the median progression‐free survival was 3.7 months and the median overall survival was 18.0 months. For the whole trial of 46 patients the median survival was 18.3 months. Most frequent toxicities included hand‐foot skin reaction (grade 2 in nine patients, grade 3 in three), rash, abnormalities in liver function tests, and fatigue.

CONCLUSIONS

Sorafenib has moderate activity as a second‐line treatment for metastatic castration‐resistant prostate cancer.     

Enzalutamide: targeting the androgen signalling pathway in metastatic castration‐resistant prostate cancer

Significant progress has been made in the understanding of the underlying cancer biology of castration‐resistant prostate cancer (CRPC) with the androgen receptor (AR) signalling pathway remaining implicated throughout the prostate cancer disease continuum. Reactivation of the AR signalling pathway is considered to be a key driver of CRPC progression and, as such, the AR is a logical target for therapy in CRPC. The objective of this review was to understand the importance of AR signalling in the treatment of patients with metastatic CRPC (mCRPC) and to discuss the clinical benefits associated with inhibition of the AR signalling pathway. A search was conducted to identify articles relating to the role of AR signalling in CRPC and therapies that inhibit the AR signalling pathway. Current understanding of prostate cancer has identified the AR signalling pathway as a logical target for the treatment of CRPC. Available therapies that inhibit the AR signalling pathway include AR blockers, androgen biosynthesis inhibitors, and AR signalling inhibitors. Enzalutamide, the first approved AR signalling inhibitor, has a novel mode of action targeting AR signalling at three key stages. The direct mode of action of enzalutamide has been shown to translate into clinical responses in patients with mCRPC. In conclusion, the targeting of the AR signalling pathway in patients with mCRPC results in numerous clinical benefits. As the number of treatment options increase, more trials evaluating the sequencing and combination of treatments are required. This review highlights the continued importance of targeting a key driver in the progression of CRPC, AR signalling, and the clinical benefits associated with inhibition of the AR signalling pathway in the treatment of patients with CRPC.