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.     

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.     

New developments in the treatment of castration resistant prostate cancer

In the past 5 years, the treatment and understanding of metastatic castrate resistant prostate cancer （CRPC） have improved dramatically. Our understanding of the mechanisms of castration resistance has allowed for the development of new drugs to target prostate cancer, and our understanding of genetic mutations may give us new tools with which to more accurately diagnose and be able to predict the course of this heterogeneous disease. This article summarizes the recent advances in the understanding of the development of CRPC, as well as the new drugs and targets, which have evolved from this basic research.     

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.     

KDM5D predicts response to docetaxel chemotherapy in metastatic castration resistant prostate cancer patients

BackgroundThe administration of docetaxel chemotherapy is one therapeutic option to delay disease progression and increase overall survival in metastatic castration resistant prostate cancer (mCRPC). However, about 15% of patients are primary resistant to chemotherapy and hence would benefit from an alternative mCRPC treatment. Despite intensive research, there are no robust clinical validated biomarkers to predict mCRPC therapy response. Thus, the aim of the study was to determine KDM5D expression in archival radical prostatectomy specimens of patients medicated with docetaxel at time of mCRPC development in order to correlate KMD5D expression with treatment response.MethodsWe used in situ hybridization (ISH) (RNA scope 2.5 HD) to determine KDM5D expression in tissue samples of 28 prostate cancer patients. KDM5D status was correlated to chemotherapy response (PSA and radiographic response).ResultsData revealed that KDM5D is significantly overexpressed in tumor cells (P<0.0001) but also in benign cells (P<0.02) of those patients who responded to chemotherapy compared to non-responders.ConclusionsTo summarize, KDM5D is a promising novel biomarker predicting response to docetaxel chemotherapy already at the time of localized disease and thus potentially avoiding metastatic biopsies in the mCRPC stage of disease.     

抗雄激素撤退治疗去势抵抗性前列腺癌的疗效分析

目的 观察抗雄激素撤退治疗去势抵抗性前列腺癌(CRPC)的疗效,并分析影响疗效的预测因素.方法 对经持续性最大限度雄激素阻断疗法治疗后前列腺特异抗原(PSA)进行性升高的前列腺癌患者48例采用抗雄激素撤退治疗,氟他胺停用4周,比卡鲁胺停用8周.以血清PSA的变化作为主要观察指标,观察治疗前后患者血清PSA的变化情况.结果 抗雄激素撤退治疗后,共12例(25％)患者出现PSA下降≥50％,疾病缓解的中位有效时间为(4.0±2.0)个月.抗雄激素撤退治疗是否有效与治疗前患者一般特征无关.结论 抗雄激素撤退治疗对部分CRPC患者有效.     

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.     

去势抵抗性前列腺癌治疗进展

大部分前列腺癌经过治疗终将进展为临床难治的去势抵抗性前列腺癌,目前的治疗手段均难以提高其2~3年的生存期。近年来通过不同作用机制治疗去势抵抗性前列腺癌的许多新型有效的药物投入临床或进入临床试验。本文就这方面的研究进展作一综述。