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Chemotherapy in castration-resistant prostate cancer
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Chemotherapy in castration-resistant prostate cancer
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Jul 20, 2016.

INTRODUCTION — For men with advanced prostate cancer, androgen deprivation therapy usually can provide disease control for a substantial period of time. However, the vast majority of men eventually develop progressive disease that is resistant to further hormonal treatment.

Prior to the development of the taxanes, cytotoxic chemotherapy was considered to be relatively ineffective in men with castration-resistant prostate cancer. In early trials, objective response rates were 10 to 20 percent, and median survival generally did not exceed 12 months.

However, taxane-based regimens have been associated with higher rates of objective tumor regression and biochemical (prostate-specific antigen [PSA]) response, as well as longer overall survival. As discussed below, docetaxel has an established role in chemotherapy-naive patients, and a second-generation taxane, cabazitaxel, is active in patients who have received prior docetaxel.

The use of cytotoxic chemotherapy for the treatment of castration-resistant prostate cancer will be reviewed here. The use of chemotherapy in combination with androgen deprivation therapy for castration-sensitive disease is discussed separately, as are experimental approaches. (See "Overview of the treatment of disseminated prostate cancer" and "Investigational approaches for the treatment of advanced prostate cancer".)

CHEMOTHERAPY-NAIVE PATIENTS — For patients with castration-resistant prostate cancer who have not received prior chemotherapy, docetaxel given every three weeks in conjunction with prednisone remains the preferred approach to systemic chemotherapy. Alternative schedules and combinations, and the second-generation taxane cabazitaxel have been studied in randomized trials, but none has proven superior. However, in two large randomized trials, cabazitaxel was noninferior to docetaxel and was significantly less toxic, particularly at a dose of 20 mg/m². (See 'Docetaxel versus cabazitaxel' below and 'Dose of cabazitaxel' below.)

The activity of taxanes in men with castration-resistant prostate cancer was initially suggested by multiple phase II studies in which docetaxel, with or without prednisone, was given on either a weekly or every-three-weeks schedule. These trials led to the evaluation of docetaxel in a number of combinations, including a phase III comparison with mitoxantrone, which established the combination of docetaxel plus prednisone as the standard of care for initial chemotherapy in men with castration-resistant prostate cancer [1].

Docetaxel versus mitoxantrone — In the TAX-327 trial, 1006 men with chemotherapy-naive metastatic castration-resistant prostate cancer were randomly assigned to docetaxel (75 mg/m2 every three weeks), docetaxel (30 mg/m2 weekly), or mitoxantrone (12 mg/m2 every three weeks) [2]. All patients received prednisone 5 mg orally twice a day. Patients were continued on maintenance gonadal androgen suppression, but antiandrogens were discontinued at least four weeks prior to chemotherapy. Overall survival was the primary endpoint of the trial. (See "Secondary endocrine therapies for castration resistant prostate cancer", section on 'Continuation of ADT'.)

Key results from the trial included the following:

With an extended follow-up that included death of 86 percent of the patients, the benefit of the every-three-weeks schedule of docetaxel plus prednisone has persisted for overall survival (median 19.2 versus 17.8 and 16.3 months for the weekly docetaxel and mitoxantrone regimens, respectively) [3]. The three-year survival rates were higher in those treated with the two docetaxel schedules (18.6 and 16.6 versus 13.5 percent with mitoxantrone, respectively). Crossover to the alternative chemotherapy agent was permitted and may have influenced overall survival.

In subset analyses, survival benefits were present in those older and younger than 65 years of age, in those with and without pain at baseline, and in those whose baseline prostate-specific antigen (PSA) was greater than or less than the median (115 ng/mL).

Both docetaxel plus prednisone treatment schedules were associated with a higher PSA response rate than with mitoxantrone (45 and 48 versus 32 percent) and a higher pain response rate (35 and 31 versus 22 percent, respectively).

Grade 3 or 4 neutropenia was most common with docetaxel every three weeks compared with weekly docetaxel and mitoxantrone (32 versus 2 and 22 percent). Neutropenic infection was uncommon with all three regimens (3, 0, and 2 percent, respectively). Discontinuation of treatment due to adverse effects was uncommon with all three regimens (11, 16, and 10 percent, respectively).

Dexamethasone (8 mg) was administered 12, three, and one hour prior to infusion with docetaxel to minimize toxicity. Although some have speculated that the dexamethasone, rather than the docetaxel, may be responsible for the activity of this combination [4], at least one study found no benefit from dexamethasone alone [5].

These results established docetaxel (75 mg/m2 every three weeks) plus daily prednisone (5 mg twice a day) as the standard of care for the initial systemic chemotherapy for men with castration-resistant prostate cancer.

Alternative docetaxel schedules — Alternative approaches using docetaxel have been studied in randomized trials, but the every-three-weeks schedule in conjunction with prednisone remains the standard of care for the initial systemic therapy of men with castration-resistant prostate cancer.

For patients who are unlikely to tolerate docetaxel on an every-three-weeks schedule, more frequent administration of docetaxel may offer a less myelosuppressive alternative. In a phase III trial, 361 patients were randomly assigned to docetaxel 50 mg/m2 every two weeks or to docetaxel 75 mg/m2 every three weeks, both given with prednisone [6]. The every-two-weeks schedule was associated with a significantly improved time to treatment failure (5.6 versus 4.9 months) and overall survival compared with the every-three-weeks schedule (19.5 versus 17.0 months), and there was a decrease in the incidence of severe neutropenia (53 versus 36 percent) and febrile neutropenia (14 versus 4 percent). Based upon these results, although the three-week schedule was well-established and more convenient, docetaxel every two weeks at the reduced dose could be an alternative for patients in whom myelosuppression is of particular concern.

Other docetaxel combinations — Multiple large phase III trials have failed to demonstrate an improvement in overall survival by adding other agents to the docetaxel prednisone regimen. Agents tested include the following:

Vascular growth factor inhibition (bevacizumab [7], aflibercept [8])

Lenalidomide [9]

Dasatinib [10]

Endothelin receptor antagonists (atrasentan [11], zibotentan [12])

Calcitriol [13]

Docetaxel-based combinations with older cytotoxic agents have been evaluated in a more limited way in phase II studies, but none of these have an established role. These include combinations with vinorelbine [14], capecitabine [15], epirubicin [16], and carboplatin [17].

Docetaxel versus cabazitaxel — Based upon its ability to prolong overall survival in patients who had docetaxel-resistant disease, cabazitaxel was compared with docetaxel in chemotherapy-naive patients. (See 'Cabazitaxel' below.)

In a phase III trial, 1168 men with castration-resistant disease were randomly assigned to one of three treatment arms: cabazitaxel 20 mg/m2, cabazitaxel 25 mg/m2, or docetaxel 75 mg/m2 [18]. On each treatment arm, the drug was administered every three weeks in conjunction with prednisone. Preliminary results were presented at the 2016 American Society of Clinical Oncology meeting.

There were no statistically significant differences in overall survival, the primary endpoint of the study, between the three treatment arms (median 24.5 months for cabazitaxel 20 mg/m2, 25.2 months for cabazitaxel 25 mg/m2, and 24.3 months for docetaxel).

Although the tumor response rate was significantly higher with cabazitaxel 25 mg/m2 compared with docetaxel (42 versus 31 percent), there was no significant difference between the three treatment arms in progression-free survival.

There were decreased incidences of grade 3 or 4 neutropenia and febrile neutropenia with the cabazitaxel 20 mg/m² regimen compared with docetaxel, as well as significantly less neuropathy, edema, and alopecia of any grade.

PRIOR DOCETAXEL — Cabazitaxel has been shown to prolong survival in patients who have progressed on docetaxel, compared with mitoxantrone, and is indicated for use in combination with prednisone for patients who have previously been treated with a docetaxel-containing regimen.

Patients with high-volume castration-sensitive metastatic disease may be treated with concurrent androgen deprivation therapy and docetaxel based upon the results of the CHAARTED and STAMPEDE trials. If they subsequently progress, develop castration-resistant prostate cancer, and require additional chemotherapy, then they can be treated with cabazitaxel or potentially be retreated with docetaxel, particularly if the progression occurred after a period of time from the initial docetaxel-based chemohormonal therapy. (See "Initial systemic therapy for castration sensitive prostate cancer", section on 'Chemohormonal therapy'.)

Other agents, including mitoxantrone and platinums, may have a role in patients who are no longer responsive to taxane chemotherapy.

Cabazitaxel — Cabazitaxel is a semisynthetic taxane derivative that was developed for its activity in patients with resistance to docetaxel and is the preferred chemotherapy agent for patients previously treated with docetaxel.

Cabazitaxel versus mitoxantrone — In the phase III TROPIC trial, 755 men, all of whom had progressed on docetaxel, were randomly assigned to oral prednisone (10 mg/day) plus either cabazitaxel (25 mg/m2 as an intravenous infusion every three weeks) or mitoxantrone (12 mg/m2 every three weeks) [19]. Premedication to prevent severe hypersensitivity reactions included antihistamines, steroids, and an H2 antagonist. Antiemetic prophylaxis was recommended and was given either orally or intravenously as needed.

Men treated with cabazitaxel plus prednisone had an increased overall survival compared with those treated with mitoxantrone plus prednisone (hazard ratio [HR] 0.70, 95% CI 0.59-0.83, median survival 15.1 versus 12.7 months). Progression-free survival was also significantly prolonged (2.8 versus 1.4 months, HR 0.74, 95% CI 0.64-0.86). On subset analysis, the survival benefit was greater in patients who had been most heavily exposed to docetaxel compared with those with the lowest exposure (HR 0.51 versus 0.96 for those with >900 mg/m2 compared with those who had received <225 mg/m2). With additional follow-up, the two-year estimated survival was greater than two years in 27 percent of patients treated with cabazitaxel versus 16 percent of those treated with mitoxantrone [20].

The cabazitaxel regimen was significantly more toxic than mitoxantrone. Potential treatment-related deaths were more frequent in the 30 days after last treatment for cabazitaxel compared with mitoxantrone (4.9 versus 2.4 percent). Grade 3 or greater neutropenia was observed in 82 percent of patients with cabazitaxel, and febrile neutropenia was seen in 8 percent. In addition, diarrhea was reported in 47 percent of patients and was greater than or equal to grade 3 in 6 percent.

Prophylaxis with colony-stimulating factors is indicated to prevent febrile neutropenia for patients older than 65 years and for those with extensive prior radiation therapy, as well as in other high-risk groups. In addition, prophylaxis to prevent infusion reactions is recommended. (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation" and "Infusion reactions to systemic chemotherapy".)

Dose of cabazitaxel — Although cabazitaxel was originally approved at a dose of 25 mg/m2, the preferred dose is 20 mg/m2, based upon similar overall survival and decreased toxicity.

In a phase III noninferiority trial, 1200 men who had progressed on docetaxel were randomly assigned to cabazitaxel at 20 mg/m2 or cabazitaxel at 25 mg/m2 [21]. Both arms were treated every three weeks in conjunction with prednisone for up to 10 cycles. The primary endpoint was overall survival.

Preliminary results were presented at the 2016 American Society of Clinical Oncology meeting.

The median overall survival was similar at 20 mg/m2 and 25 mg/m2 (13.4 versus 14.5 months, HR 1.024), and fulfilled the predefined noninferiority conditions in the trial's statistical plan.

The overall incidence of grade 3/4 adverse events was significantly decreased at the 20 mg/m2 dose level (39.7 versus 54.5 percent). Similarly, the incidence of grade 4 neutropenia was decreased (21.3 versus 48.6 percent), as was the incidence of neutropenic sepsis and infection (2.2 versus 6.1 percent).

Other chemotherapy regimens — There are no chemotherapy regimens that have an established role based upon randomized clinical trials for patients who have progressed on the standard docetaxel prednisone regimen and with cabazitaxel. However, many of these patients may be candidates for additional chemotherapy when their disease cannot be managed with secondary endocrine therapies. (See "Secondary endocrine therapies for castration resistant prostate cancer".)

Platinum-based regimens — Platinum agents have some antitumor activity in metastatic prostate cancer [22]. The most widely used contemporary regimens for docetaxel-resistant disease incorporate a platinum compound (carboplatin, oxaliplatin, cisplatin), often in conjunction with estramustine, capecitabine, or paclitaxel.

Carboplatin — Carboplatin had some clinical activity against castration-resistant prostate cancer in relatively small phase II trials that were conducted prior to the development of the standard docetaxel prednisone regimen [23-27].

The potential role of carboplatin is illustrated by three contemporary phase II studies limited to patients who had progressed on docetaxel prednisone:

The combination of carboplatin plus paclitaxel was evaluated in 38 patients, 24 of whom had received two or more prior chemotherapy regimens [28]. A clinical and/or biochemical response was seen in 26 percent of cases, and an additional 34 percent had stable disease. The median duration of response and median time to progression were 6 and 3.6 months, respectively, and the median overall survival was 10 months.

In a second phase II study, carboplatin was given in combination with docetaxel to 34 men who had progressed during or within 45 days after the completion of docetaxel-based chemotherapy [17]. Biochemical responses were observed in 18 percent of cases, the median progression-free survival was three months, and median overall survival was 12 months.

In a phase II trial, 149 patients were randomly assigned to cabazitaxel or cabazitaxel plus carboplatin [29]. Progression-free survival (the primary endpoint) was increased with the combination (5.7 versus 4.0 months). Partial responses in those with measurable disease were also more frequent with the combination (17 of 33 [52 percent]) versus 5 of 35 [14 percent]).

Oxaliplatin — The clinical activity of oxaliplatin was initially suggested in a phase II study in which oxaliplatin was combined with infusional fluorouracil in men with castration-resistant prostate cancer [30].

Two subsequent studies have evaluated the combinations using oxaliplatin in men who had progressed after docetaxel-based chemotherapy:

In a study in 47 men, oxaliplatin was combined with pemetrexed [31]. A biochemical (prostate-specific antigen [PSA]) response was observed in 64 percent of cases, and an objective response was seen in 10 of the 40 men with measurable disease. The median progression-free survival was six months, and median overall survival was 12 months.

In another phase II, 14 men were treated with the combination of oxaliplatin plus capecitabine [32]. A PSA response was observed in 8 of 14 cases (57 percent), and the median overall survival was 24 weeks.

Cisplatin — Older trials suggested that cisplatin had some activity in combination with either an anthracycline [33] or with estramustine plus ifosfamide [34] in men with castration-resistant prostate cancer.

In a phase II study, 25 men who had docetaxel-refractory disease were treated with the combination of cisplatin plus prednisone [35]. Biochemical responses were observed in 20 percent of cases, and 3 of 13 patients with measurable disease had a partial response. Median progression-free survival was six months, and median overall survival was 55 weeks.

Other agents

Mitoxantrone — Although mitoxantrone is approved for the treatment of men with advanced prostate cancer, the approval was based upon symptom palliation and not an increase in overall survival in patients who had castration-resistant disease [36-38].

Mitoxantrone retains some activity in patients who have progressed on docetaxel, although the availability of cabazitaxel and other agents that prolong survival minimizes its role in this setting. In the phase III trial comparing cabazitaxel with mitoxantrone in patients who had previously been treated with docetaxel, mitoxantrone had a 4 percent objective response rate and an 18 percent PSA response rate [19]. (See "Overview of the treatment of disseminated prostate cancer", section on 'Castration resistant disease'.)

Estramustine — Estramustine, either as single-agent or in combination therapy, has a minimal, if any, role in the overall management of metastatic castration-resistant prostate cancer.

Estramustine is a conjugate of an alkylating agent to estradiol. Although estramustine has some activity as a single agent in men with castration-resistant prostate cancer [39-43], its use is complicated by an increased risk of arterial and venous thromboembolic events [44]. Although daily aspirin and low-dose warfarin have been proposed as prophylaxis, a decrease in thromboembolic complications using these strategies has not been demonstrated.

Although the combination of estramustine plus docetaxel improved overall survival in a phase III trial compared with mitoxantrone plus prednisone [45], this combination was associated with excessive toxicity and does not have an established role.

Paclitaxel — The taxane paclitaxel has been less extensively evaluated than docetaxel in men with castration-resistant prostate cancer. Paclitaxel does not have an established role in these patients but appears to have activity that is schedule dependent [28,46]. Experience in men with docetaxel-refractory disease comes primarily from combinations with platinum compounds. (See 'Platinum-based regimens' above.)

PARP inhibitors — Poly-ADP ribose polymerase (PARP) inhibitors have demonstrated some activity in patients with mutations in the BRCA2 gene. However these agents are not approved for advanced prostate cancer. (See "Investigational approaches for the treatment of advanced prostate cancer", section on 'PARP inhibitors'.)

Miscellaneous agents — A number of other drugs have been evaluated and showed evidence of at least limited activity. These included antimetabolites (fluorouracil, gemcitabine), cyclophosphamide, ixabepilone, and topoisomerase I inhibitors alone or in various combinations [47-56]. Objective response rates were generally 10 to 20 percent or less, and the use of these agents has been supplanted by the development of taxanes and platinum compounds.

PROSTATE CANCER WITH LOW PSA PRODUCTION — Some men with aggressive metastatic prostate cancer have low serum prostate-specific antigen (PSA) values [57-59]. These patients are more likely to have visceral and osteolytic metastases rather than osteoblastic bone lesions. In this setting, serum PSA cannot be used as a marker to assess the response to treatment.

There are no randomized trials to guide management of patients with castration-resistant prostate cancer and a low serum PSA. Our approach to treatment in these patients varies depending upon the histology:

Patients with tumors that contain neuroendocrine (small cell) features are relatively sensitive to chemotherapy regimens that are used for small cell cancer involving the lung (eg, platinum/etoposide combinations), with response rates of over 50 percent. Nevertheless, the optimal treatment regimen is unknown, and clinical studies are sparse. (See "Extensive stage small cell lung cancer: Initial management" and "Extrapulmonary small cell cancer", section on 'Prostate ESCC'.)

Patients with poorly differentiated adenocarcinoma tend to have a clinically aggressive course. Although a combination of paclitaxel, estramustine, and carboplatin may be useful in those without neuroendocrine features [23,24], there are no data demonstrating that this is more effective than docetaxel plus prednisone.

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Beyond the Basics topics (see "Patient education: Treatment for advanced prostate cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

For chemotherapy-naive men with castration-resistant prostate cancer without neuroendocrine (small cell) features who are candidates for cytotoxic chemotherapy, we recommend docetaxel (75 mg/m2 every three weeks) plus oral prednisone (5 mg twice a day) rather than mitoxantrone (Grade 1A). We suggest this same regimen of docetaxel rather than cabazitaxel (Grade 2A). (See 'Docetaxel versus mitoxantrone' above and 'Docetaxel versus cabazitaxel' above.)

Gonadal androgen suppression, but not antiandrogens, should be continued during chemotherapy. (See "Secondary endocrine therapies for castration resistant prostate cancer", section on 'Continuation of ADT'.)

For patients with castration-resistant prostate cancer who have progressed on treatment with docetaxel plus prednisone, there are a number of treatment options that have been shown to prolong overall survival (table 1).

For those who are candidates for second-line cytotoxic chemotherapy, we recommend cabazitaxel (Grade 1B). Cabazitaxel plus prednisone significantly increased overall survival compared with mitoxantrone plus prednisone. For patients who are treated with cabazitaxel, we suggest a dose of 20 mg/m2 rather than 25 mg/m2 (Grade 2B). (See 'Cabazitaxel' above.)

For patients who are not candidates for cabazitaxel, mitoxantrone or platinum-based regimens may have useful activity. (See 'Other agents' above.)

Patients with castration-resistant prostate cancer and a low serum prostate-specific antigen (PSA) are more likely to have aggressive disease, including the presence of visceral metastases rather than bone metastases. There are no randomized trials to guide therapy in this setting:

For patients with poorly differentiated adenocarcinoma without neuroendocrine features, we suggest a combination of docetaxel plus prednisone (Grade 2C). A combination of paclitaxel, estramustine, and carboplatin may be an alternative. (See 'Prostate cancer with low PSA production' above.)

Those patients whose tumors have a substantial component with neuroendocrine features may benefit from treatment with a chemotherapy regimen similar to that used for patients with small cell lung cancer. (See "Extensive stage small cell lung cancer: Initial management" and "Extrapulmonary small cell cancer", section on 'Prostate ESCC'.)

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