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.     

Androgen receptor splice variant 7 in castration‐resistant prostate cancer: Clinical considerations

Constitutively‐active ligand‐independent splice variants of the androgen receptor are an adaptive response by prostate cancer cells to escape androgen deprivation therapy and novel androgen receptor‐directed treatments. Androgen receptor splice variant 7 is the most common splice variant detected in clinical biospecimens, and emerging data now suggest that the presence of tumoral androgen receptor splice variant 7 might be indicative of primary and acquired resistance to next‐generation androgen pathway inhibitors, such as abiraterone and enzalutamide. At the same time, taxane chemotherapy might retain its efficacy regardless of androgen receptor splice variant 7 status, thus suggesting the potential for a predictive biomarker guiding treatment selection in men with metastatic castration‐resistant prostate cancer. Herein, we review the preclinical data elucidating the structure and function of androgen receptor splice variant 7, we describe the existing clinical data using this biomarker in metastatic castration‐resistant prostate cancer, and we highlight potential therapeutic strategies to target androgen receptor splice variant 7‐expressing prostate cancer.     

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.     

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.     

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.     

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.     

Safety of enzalutamide in patients with metastatic castration‐resistant prostate cancer previously treated with docetaxel: Expanded access in North America

BACKGROUND

The open‐label, single‐arm enzalutamide expanded access program (EAP) in the United States and Canada evaluated the safety of enzalutamide in patients with metastatic castration‐resistant prostate cancer (mCRPC) who had previously received docetaxel.

METHODS

Patients (n = 507) received enzalutamide 160 mg/day until disease progression, intolerable adverse events (AEs), or commercial availability occurred. AEs and other safety variables were assessed on day 1, weeks 4 and 12, and every 12 weeks thereafter. Data following transition to commercial drug were not collected.

RESULTS

Median age was 71 years (range 43–97); 426 patients (83.9%) had a baseline ECOG score of ≤1. In addition to docetaxel, the majority of patients had received prior prostate cancer treatments such as abiraterone (76.1%) or cabazitaxel (28.6%). Median study treatment duration was 2.6 months (range 0.03–9.07). The most frequently reported reasons for discontinuation were commercial availability of enzalutamide (46.7%) and progressive disease (33.7%). A total of 88.2% of patients experienced AEs; 45.4% experienced AEs with a maximum grade of 1 or 2. Fatigue (39.1%), nausea (22.7%), and anorexia (14.8%) were the most commonly reported AEs. Seizure was reported in four patients (0.8%). The most commonly reported event leading to death was progression of metastatic prostate cancer (7.7%).

CONCLUSION

In this heavily pretreated EAP population with progressive mCRPC, enzalutamide was well tolerated and the safety profile was consistent with that of the AFFIRM trial. Prostate 75: 836–844, 2015. © 2015 The Authors. The Prostate, published by Wiley Periodicals, Inc.