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.     

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.     

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.

     

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.     

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.     

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.     

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.