INTRODUCTION — For men with advanced prostate cancer, androgen deprivation therapy (ADT) 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 (castration-resistant prostate cancer [CRPC]), and typically metastatic.
Prior to the development of the taxanes, cytotoxic chemotherapy was considered to be relatively ineffective in men with CRPC. 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-naïve 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 CRPC will be reviewed here. The use of chemotherapy in combination with ADT for castration-sensitive disease is discussed separately, as are the benefits of treatments for CRPC targeting the androgen pathway, immunotherapy, poly(ADP-ribose) polymerase (PARP) inhibitors for men with homologous recombination repair deficiency, and experimental approaches. An overview of our approach to selecting among the various treatments for CRPC and a discussion about the sequencing of the different treatments (a suggested approach is outlined in the algorithm (algorithm 1)) are presented elsewhere. (See "Overview of systemic treatment for advanced, recurrent and metastatic castration-sensitive prostate cancer and local treatment for patients with metastatic disease" and "Castration-resistant prostate cancer: Treatments targeting the androgen pathway" and "Immunotherapy for castration-resistant prostate cancer" and "Management of advanced prostate cancer with germline or somatic homologous recombination repair deficiency" and "Overview of the treatment of castration-resistant prostate cancer (CRPC)".)
GERMLINE AND TARGETED TUMOR GENOMIC TESTING — Increasingly, biomarker expression is driving therapeutic decision making in patients with advanced refractory cancer, including CRPC. For patients with metastatic CRPC who would be candidates for targeted therapies, both germline genomic testing (if not already known) and somatic genomic testing (gene profiling of tumor tissue using multigene panel-based assays) should be undertaken because of the significant treatment implications, particularly of finding alterations in homologous recombination repair genes [1,2]. (See 'Men with homologous recombination repair gene aberrations' below.)
ASCO has issued a provisional clinical opinion that supports germline and somatic genomic testing in metastatic or advanced cancer when there are genomic biomarker-linked therapies approved by regulatory agencies for their cancer [2]. Given the tissue-agnostic approvals for any advanced cancer with a high tumor mutational burden or DNA mismatch repair deficiency (checkpoint inhibitor immunotherapy), or neurotrophic tyrosine receptor kinase (NTRK) fusions (TRK inhibitors), in principal this provides a rationale for genomic testing of all solid tumors, if the individual would be a candidate for these treatments. Testing should also be considered to determine candidacy for targeted therapies approved for other diseases in patients without approved genomic biomarker-linked therapy; however off-label/off-study use of such therapies is not recommended when a clinical trial is available, or without evidence of meaningful efficacy in clinical trials. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications", section on 'Cancer screening and management' and "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors" and "TRK fusion-positive cancers and TRK inhibitor therapy".)
MEN WITHOUT GERMLINE OR SOMATIC DNA REPAIR GENE ABERRATIONS
Chemotherapy-naïve patients
Castration-resistant disease — For men with chemotherapy-naïve CRPC without neuroendocrine (small cell) features who are candidates for cytotoxic chemotherapy, we recommend docetaxel (75 mg/m2 every three weeks) rather than mitoxantrone. (See 'Docetaxel versus mitoxantrone' below.)
For most men, we generally prefer docetaxel over cabazitaxel as the initial chemotherapy regimen. Cabazitaxel (20 mg/m2) may be preferred in older or frail patients and those at high risk for neutropenia, based on its lower toxicity and equal efficacy compared with docetaxel, despite its higher cost. (See 'Docetaxel versus cabazitaxel' below.)
Another alternative for patients in whom myelosuppression is of particular concern is administration of a lower docetaxel dose (50 mg/m2) every two weeks. (See 'Alternative docetaxel schedules' below.)
Gonadal androgen suppression, but not antiandrogens, should be continued during chemotherapy. (See "Alternative endocrine therapies for castration-resistant prostate cancer", section on 'Continuation of androgen deprivation therapy'.)
The activity of taxanes in men with CRPC was initially suggested by multiple phase II studies in which docetaxel, with or without prednisone, was given on either a weekly or every-three-week 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 CRPC [3].
Docetaxel versus mitoxantrone — In the TAX-327 trial, 1006 men with chemotherapy-naïve metastatic CRPC were randomly assigned to docetaxel 75 mg/m2 every three weeks, docetaxel 30 mg/m2 weekly, or mitoxantrone 12 mg/m2 every three weeks [4]. 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 "Alternative endocrine therapies for castration-resistant prostate cancer", section on 'Continuation of androgen deprivation therapy'.)
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-week schedule of docetaxel plus prednisone persisted for overall survival (median 19.2 versus 17.8 and 16.3 months for the weekly docetaxel and mitoxantrone regimens, respectively) [5]. 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 the docetaxel plus prednisone treatment schedules were associated with a higher PSA response rate than mitoxantrone (45 and 48 versus 32 percent, respectively) 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, 3, and 1 hour(s) 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 [6], at least one study found no benefit from dexamethasone alone [7].
These results established docetaxel (75 mg/m2 every three weeks) plus daily prednisone (5 mg twice a day) as the standard of care for initial systemic chemotherapy for men with CRPC.
Alternative docetaxel schedules — Alternative approaches using docetaxel have been studied in randomized trials, but the every-three-week schedule in conjunction with prednisone remains the standard of care for initial systemic therapy of men with CRPC.
For patients who are unlikely to tolerate docetaxel on an every-three-week 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 [8]. The every-two-week schedule was associated with significantly improved time to treatment failure (5.6 versus 4.9 months) and overall survival compared with the every-three-week 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 on these results, although the three-week schedule is 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 from adding other agents to the docetaxel/prednisone regimen. Agents tested include the following:
●Vascular endothelial growth factor inhibition (bevacizumab [9], aflibercept [10])
●Lenalidomide [11]
●Endothelin receptor antagonists (atrasentan [13], zibotentan [14])
●Calcitriol [15]
Docetaxel-based combinations with older cytotoxic agents (vinorelbine [16], capecitabine [17], epirubicin [18], and carboplatin [19]) have been evaluated in a more limited way in phase II studies, but none of these has an established role.
Docetaxel versus cabazitaxel — Docetaxel is generally preferred over cabazitaxel as the initial chemotherapy regimen for chemotherapy-naïve patients. However, cabazitaxel (20 mg/m2) may be preferred in older or frail patients and those at high risk for neutropenia, based on its lower toxicity and similar efficacy, despite its higher cost. If neutropenia is a problem with docetaxel, the addition of a granulocyte colony-stimulating factor (G-CSF) to docetaxel is another option. (See "Prostate cancer in older males", section on 'Metastatic castration-resistant prostate cancer' and "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".)
Based on its ability to prolong overall survival in patients who had docetaxel-resistant disease, cabazitaxel was compared with docetaxel in chemotherapy-naïve 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 [20]. For each treatment arm, the drug was administered every three weeks in conjunction with prednisone.
●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.
●The incidence of grade 3 or 4 toxicity with cabazitaxel 20 mg/m2, cabazitaxel 25 mg/m2, and docetaxel 75 mg/m2 was 41, 60, and 46 percent, respectively. The incidence of febrile neutropenia was lower with cabazitaxel 20 mg/m2 compared with the other two regimens (2.4 versus 12.0 and 8.3 percent, respectively). Hematuria was more frequent with cabazitaxel, while peripheral neuropathy, edema, alopecia, and nail disorders were more frequent with docetaxel.
Castration-sensitive disease — Docetaxel has been shown to increase overall survival in combination with androgen deprivation therapy (ADT) in patients with high-volume metastatic castration-sensitive prostate cancer. The role of docetaxel plus ADT in this setting is discussed separately.
Men who have received prior docetaxel — For most men who have progressed while receiving a docetaxel-based regimen for CRPC and who can tolerate it, we suggest cabazitaxel rather than other systemic therapy options, including either mitoxantrone or an androgen-signaling-targeted treatment. When cabazitaxel is used, we recommend a dose of 20 mg/m2 rather than 25 mg/m2. Prophylaxis with colony-stimulating factors may be indicated to prevent febrile neutropenia for patients older than 65 years, for those with extensive prior radiation therapy (RT), and in other high-risk groups. In addition, premedication with a glucocorticoid and an H1 as well as H2 receptor antagonist is generally recommended prior to each dose to prevent infusion reactions. (See "Infusion reactions to systemic chemotherapy", section on 'Cabazitaxel'.)
For patients who are not candidates for cabazitaxel, mitoxantrone or platinum-based regimens are appropriate alternatives.
Men with high-volume metastatic castration-sensitive disease who have been treated with concurrent ADT and an 18-week course of docetaxel (based on the results of the CHAARTED and STAMPEDE trials) and who subsequently progress with CRPC and require additional chemotherapy can be treated with cabazitaxel or retreated with docetaxel. Retreatment with docetaxel may be more likely to be effective if the progression occurred a period of time after the initial docetaxel-based chemohormonal therapy; however, neuropathy may be dose limiting.
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. (See "Treatment protocols for castration-resistant prostate cancer", section on 'Cabazitaxel and prednisone'.)
Cabazitaxel versus mitoxantrone — The benefits of cabazitaxel over second-line treatment with mitoxantrone and prednisone were initially shown in the phase III TROPIC trial, in which 755 men progressing on docetaxel were randomly assigned to oral prednisone (10 mg daily) and either cabazitaxel (25 mg/m2 intravenously every three weeks) or mitoxantrone (12 mg/m2 intravenously every three weeks) [21]. Premedication to prevent severe infusion reactions included glucocorticoids and both an H1 and an H2 receptor antagonist.
Men treated with cabazitaxel plus prednisone had 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 who had received >900 mg/m2 versus those who had received <225 mg/m2). With additional follow-up, there was a greater likelihood of surviving two or more years with cabazitaxel (27 versus 16 percent) [22].
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 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 RT, 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".)
Third-line cabazitaxel versus androgen signaling therapy — The superiority of third-line cabazitaxel over androgen-signaling therapy (abiraterone or enzalutamide) in 255 men with metastatic CRPC previously treated with docetaxel who had progression within 12 months while receiving the alternative inhibitor (abiraterone or enzalutamide) was shown in the phase III CARD trial [23]. Cabazitaxel was administered at a dose of 25 mg/m2 every three weeks with daily prednisone and G-CSF support. At a median follow-up of 9.2 months, third-line cabazitaxel improved imaging-based progression or death (74 versus 80 percent), median overall survival (13.6 versus 11 months), PSA response (36 versus 14 percent), and objective tumor response (37 versus 12 percent). Grade ≥3 adverse events occurred in a similar percentage of patients in both groups (56 versus 52 percent), although those that occurred more frequently with cabazitaxel were asthenia/fatigue (4 versus 2.4 percent) and diarrhea, peripheral neuropathy, and febrile neutropenia (for all categories, 3.2 percent versus none).
In a later analysis those who received third-line cabazitaxel rather than enzalutamide or abiraterone also had better pain response rates and time to pain progression, fewer symptomatic skeletal events (19 versus 28 percent), and a longer time to deterioration of FACT-P (Functional Assessment of Cancer Therapy-Prostate) scores [24].
Dose of cabazitaxel — Although cabazitaxel was originally approved at a dose of 25 mg/m2, the preferred dose is 20 mg/m2, based on similar overall survival and decreased toxicity.
In the phase III noninferiority PROSELICA trial, 1200 men who had progressed on docetaxel were randomly assigned to cabazitaxel at 20 or 25 mg/m2 [25]. Patients in both arms were treated every three weeks in conjunction with prednisone for up to 10 cycles. The primary endpoint was overall survival.
●Median overall survival was similar at 20 and 25 mg/m2 (13.4 versus 14.5 months, HR 1.024, upper limit of the 98.8% CI 1.184) and fulfilled the predefined noninferiority conditions in the trial's statistical plan. An upper limit of 1.214 was chosen as the noninferiority margin to maintain at least 50 percent of the 2.4-month survival benefit of cabazitaxel 25 mg/m2 versus mitoxantrone that was observed in the TROPIC trial above. (See 'Cabazitaxel versus mitoxantrone' above.)
●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).
If the 25 mg/m2 dose of cabazitaxel is chosen, the United States Prescribing Information for cabazitaxel recommends primary prophylaxis with granulocyte colony stimulating factors. Prophylaxis with colony-stimulating factors is also indicated to prevent febrile neutropenia for patients older than 65 years, for those with extensive prior RT, and in other high-risk groups, even if they are receiving the 20 mg/m2 dose.
Docetaxel retreatment — Increasingly, men with high-volume metastatic castration-sensitive disease are being offered ADT plus concurrent systemic therapy, often an 18-week course of docetaxel, based on the results of the CHAARTED and STAMPEDE trials.
For men who subsequently progress with CRPC and require additional chemotherapy, retreatment with docetaxel can be an option [26,27]. Retreatment may be more likely to be effective in men who have a docetaxel-free interval of >3 months [26], although cumulative neuropathy may be dose limiting.
Other chemotherapy regimens — There are no chemotherapy regimens that have an established role, based on randomized clinical trials, for patients who have progressed on the standard docetaxel/prednisone regimen and cabazitaxel. However, many of these patients may be candidates for additional chemotherapy when their disease cannot be managed with secondary endocrine therapies. (See "Alternative endocrine therapies for castration-resistant prostate cancer".)
Platinum-based regimens — Platinum agents have some antitumor activity in metastatic CRPC [28]. 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 CRPC in relatively small phase II trials that were conducted prior to the development of the standard docetaxel/prednisone regimen [29-33].
The potential role of carboplatin is illustrated by three contemporary phase II studies limited to patients who had progressed on docetaxel plus prednisone:
●The combination of carboplatin plus paclitaxel was evaluated in 38 patients, 24 of whom had received two or more prior chemotherapy regimens [34]. 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 the 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 [19]. Biochemical responses were observed in 18 percent of cases, median progression-free survival was three months, and median overall survival was 12 months.
Data on combined carboplatin plus cabazitaxel for patients with aggressive variant prostate cancer are discussed below. (See 'Aggressive prostate cancer variants' below.)
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 CRPC [35].
Two subsequent studies have evaluated the combinations using oxaliplatin in men who progressed after docetaxel-based chemotherapy:
●In a study of 47 men, oxaliplatin was combined with pemetrexed [36]. A biochemical (PSA) response was observed in 64 percent of cases, and an objective response was seen in 10 of the 40 men with measurable disease. Median progression-free survival was six months, and median overall survival was 12 months.
●In another phase II study, 14 men were treated with the combination of oxaliplatin plus capecitabine [37]. A PSA response was observed in 8 of 14 cases (57 percent), and median overall survival was 24 weeks.
Cisplatin — Older trials suggested that cisplatin has some activity in combination with either an anthracycline [38] or with estramustine plus ifosfamide [39] in men with CRPC.
In a phase II study, 25 men who had docetaxel-refractory disease were treated with the combination of cisplatin plus prednisone [40]. Biochemical responses were observed in 20 percent of cases, and 3 of the 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 on symptom palliation and not an increase in overall survival in men with CRPC [41-43].
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 [21].
Paclitaxel — The taxane paclitaxel has been less extensively evaluated than docetaxel in men with CRPC. Paclitaxel does not have an established role in these patients but appears to have activity that is schedule dependent [34,44]. Experience in men with docetaxel-refractory disease comes primarily from combinations with platinum compounds. (See 'Platinum-based regimens' above.)
Aggressive prostate cancer variants
Definition — Pure small cell or neuroendocrine carcinomas of the prostate are rare at initial diagnosis (≤2 percent of cases [45]), and they have a dismal prognosis, with most patients dying within one year, despite their sensitivity to platinum-based cytotoxic chemotherapy. They are treated in a manner similar to other extrapulmonary small cell cancers. (See "Interpretation of prostate biopsy", section on 'Neuroendocrine neoplasms' and "Localized prostate cancer: Risk stratification and choice of initial treatment", section on 'High-grade, low-PSA prostate cancer' and "Extrapulmonary small cell cancer", section on 'Treatment'.)
More commonly, neuroendocrine differentiation may also emerge in men who have previously had ADT for prostate adenocarcinoma. Autopsy series demonstrate the presence of neuroendocrine differentiation in 10 to 20 percent of men dying of CRPC [46-48]. These tumors, sometimes called treatment-related neuroendocrine prostate cancers or aggressive-variant prostate cancers (AVPCs), are increasingly recognized in the castration-resistant phases of disease progression.
The underlying biology evolves due to the selective pressure of hormone therapy, especially with potent androgen receptor pathway inhibitors, with loss of dependence on androgen receptor signaling. These tumors can be androgen receptor negative, have a varying degree of small cell carcinoma morphology (or mixed small cell and adenocarcinoma), and can express markers of neuroendocrine differentiation (eg, chromogranin, synaptophysin) [49-51]. In addition, they can be associated with low PSA production and with an aggressive clinical course with atypical clinical manifestations, and they are relatively resistant to androgen-signaling inhibitors.
Investigators from MD Anderson Cancer Center utilized a series of 114 patients to prospectively develop seven clinical criteria to identify AVPC (table 1) [52].
These investigators also showed that the presence of at least one of these clinical features in a man with CRPC was associated with a high response rate to carboplatin and docetaxel, irrespective of morphology. (See 'Treatment' below.)
Molecular characterization of tumor tissues (and circulating tumor DNA) from patients who met the clinical criteria for AVPC revealed defects in one or more of the tumor suppressors TP53 (tumor protein 53), RB1 (retinoblastoma 1), PTEN (phosphatase and tensin homolog) [53-55]. The biologic significance of this molecular signature is supported by its association with lineage plasticity and androgen indifference in preclinical studies [56-58].
Treatment — The optimal way to manage patients with AVPC is not established. We prefer that patients be enrolled in clinical trials testing new strategies. If trial participation is not available or is declined, we have used cabazitaxel in combination with carboplatin (if cabazitaxel was not previously used). Another approach is to use the drugs sequentially rather than in combination. Others have shown benefit with docetaxel plus carboplatin.
There are few randomized trials to guide management of patients with aggressive-variant CRPC, and clinical studies are sparse. Patients with tumors that contain essentially neuroendocrine features (for instance, pure primary small cell cancers) can respond to chemotherapy regimens that are used for small cell cancer involving the lung (eg, platinum/etoposide combinations), with response rates that vary from 10 to 50 percent [52,59,60]. (See "Extensive-stage small cell lung cancer: Initial management".)
Guidelines from the National Comprehensive Cancer Network (NCCN) suggest a combination of etoposide with either cisplatin or carboplatin in patients with pure small cell carcinoma of the prostate. To what extent this recommendation is applicable to treatment-emergent (post-ADT, with or without prior taxane treatment) AVPC with a neuroendocrine-differentiated component is not clear.
At times, we have used cabazitaxel in combination with carboplatin in this setting, and there is some preliminary evidence to support the efficacy of this combination. One randomized phase II trial directly compared cabazitaxel alone versus cabazitaxel plus carboplatin in 160 men with CRPC (87 of whom met at least one of the clinicopathologic criteria for AVPC (table 1)) [61]. In the entire cohort, median progression-free survival (the primary endpoint) was significantly greater with combined therapy (7.3 versus 4.5 months, HR 0.69, 95% CI 0.5-0.95), and the partial response rate was also higher (57 versus 23 percent). The incidence of serious adverse events was also higher with combined therapy (40 versus 22 percent, mostly fatigue, nausea, dehydration, and myelosuppression). In a prespecified subgroup analysis based on stratification factors at baseline, the benefit of combined therapy was greater in men with AVPC (HR 0.58, 95% CI 0.37-0.89), but the test for interaction was not statistically significant in the intent-to-treat population.
Given the toxicity of the combination regimen and the limited progression-free survival benefit, another approach is to use these drugs sequentially rather than in combination. Others have used docetaxel plus carboplatin [52]. We urge clinical trial participation if feasible (eg, NCT03263650, NCT03582475).
Overall, prognosis is poor, with a median survival of only 9 to 17 months [45,60,62-64]. Molecular phenotyping for various potentially targetable alterations is emerging as a therapeutic approach in these patients. (See "Management of advanced prostate cancer with germline or somatic homologous recombination repair deficiency" and "Immunotherapy for castration-resistant prostate cancer".)
MEN WITH HOMOLOGOUS RECOMBINATION REPAIR GENE ABERRATIONS — A proportion of men with advanced prostate cancer can harbor deleterious germline or somatic mutations in homologous recombination repair (HRR) genes. As an example, analyses of clinical cohorts of men have revealed germline DNA repair mutations in approximately 12 percent of those with metastatic prostate cancer [65]. (See "Genetic risk factors for prostate cancer", section on 'Heritable factors'.)
The identification of a germline mutation in BRCA2 (breast cancer susceptibility 2) or in other DNA repair genes (BRCA1 [breast cancer susceptibility 1], ATM [ataxia telangiectasia mutated], PALB2 [partner and localizer of BRCA2], RAD51 or RAD54, CHEK2 [checkpoint kinase 2]), or of a somatic mutation in these genes that is found using next-generation sequencing of tumor tissue has implications for chemotherapy treatment in men with metastatic prostate cancer.
●Platinum-based chemotherapy – Platinum agents lead to DNA interstrand crosslinks, which can often be processed by homologous recombination. However, BRCA-mutant tumors are defective in DNA repair by homologous recombination (ie, they are HRR deficient), leading to a unique sensitivity to platinum agents.
Retrospective data suggest a high probability of response to platinum-based chemotherapy in metastatic CRPC with HRR deficiency, similar to breast, ovarian, and pancreatic cancer.
Patients with metastatic CRPC who have pathogenic or likely pathogenic variants in HRR genes such as BRCA, ATM, PALB2, FANCA (Fanconi anemia complementation group A), RAD51D, and CHEK2 to be candidates for early use of platinum-based chemotherapy. This subject is discussed in detail elsewhere. (See "Management of advanced prostate cancer with germline or somatic homologous recombination repair deficiency", section on 'Platinum-containing chemotherapy'.)
●PARP inhibitors – Poly(ADP-ribose) polymerase (PARP) inhibitors block the repair of DNA single-strand breaks, and as tumors associated with BRCA mutations become more dependent on single-strand DNA repair pathways, PARP inhibitors lead to cell death due to the inefficiencies in cell repair mechanisms in such tumors.
PARP inhibitors have demonstrated activity in men who have metastatic CRPC and pathogenic or likely pathogenic germline or somatic variants in DNA repair genes leading to HRR deficiency (especially BRCA2). Two of these agents are now approved for advanced CRPC with HRR deficiency and are discussed in more detail elsewhere. (See "Management of advanced prostate cancer with germline or somatic homologous recombination repair deficiency", section on 'Benefit of PARP inhibitors'.)
MEN WITH DEFICIENT DNA MISMATCH REPAIR OR HIGH LEVELS OF TUMOR MUTATIONAL BURDEN — Patients whose tumors harbor a loss of one of the DNA mismatch repair enzymes (ie, MLH1, PMS2, MSH2 or MSH6) or demonstrate high levels of TMB (≥10 mutations per megabase [mut/Mb]) may be candidates for checkpoint inhibitor immunotherapy. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)
ASSESSMENT DURING TREATMENT — For men with CRPC who are undergoing chemotherapy, periodic assessment should be geared toward identifying signs and symptoms of disease progression, as well as the side effects of treatment. Serial evaluation of serum prostate-specific antigen (PSA) is the mainstay of testing. Consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) recommend testing PSA every three to six months during treatment for advanced prostate cancer [66]. Most clinicians make decisions about the need for radiographic evaluation based on changes in PSA values and/or the development of new symptoms. Therapeutic changes are usually not made based on a rising PSA alone.
Assessment strategies during treatment for CRPC are discussed in more detail separately. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)", section on 'Assessment during treatment'.)
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas with persistently high rates of viral transmission include balancing the risk from delaying cancer treatment versus harm from COVID-19, minimizing immunosuppressive cancer treatments whenever possible, mitigating the negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These and other recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of prostate cancer".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topic (see "Patient education: Treatment for advanced prostate cancer (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Germline and somatic genomic testing – For patients with metastatic CRPC who may be potential candidates for targeted therapies, both germline genomic testing (if not already known) and somatic genomic testing should be undertaken because of the significant treatment implications, particularly of finding alterations in homologous recombination repair (HRR) genes. (See 'Germline and targeted tumor genomic testing' above.)
●Men without neuroendocrine features or DNA repair abnormalities
•For men with chemotherapy-naïve castration-resistant prostate cancer (CRPC) without neuroendocrine (small cell) features or alterations in a HRR gene who are candidates for cytotoxic chemotherapy, we suggest docetaxel plus oral prednisone (table 2) rather than mitoxantrone plus prednisone (Grade 2A).
Another reasonable option is cabazitaxel. Although we generally prefer docetaxel over cabazitaxel as the initial chemotherapy regimen for CRPC, cabazitaxel (table 3) may be preferred in older or frail patients and those at high risk for neutropenia, based on its lower toxicity and similar efficacy, despite its higher cost. (See 'Docetaxel versus cabazitaxel' above.)
Another alternative for patients in whom myelosuppression is of particular concern is administration of a lower docetaxel dose (50 mg/m2) every two weeks or the addition of a granulocyte colony-stimulating factor (G-CSF) to standard every-three-week docetaxel. (See 'Alternative docetaxel schedules' above.)
•Gonadal androgen suppression, but not antiandrogens, should be continued during chemotherapy. (See "Alternative endocrine therapies for castration-resistant prostate cancer", section on 'Continuation of androgen deprivation therapy'.)
•For patients with CRPC that has progressed on treatment with docetaxel plus prednisone, a number of treatment options have been shown to prolong overall survival (table 4). (See 'Men who have received prior docetaxel' above and "Overview of the treatment of castration-resistant prostate cancer (CRPC)".)
-For most men who can tolerate it, we suggest cabazitaxel (table 3) over other systemic therapy options, including mitoxantrone and androgen-signaling-targeted therapies (Grade 2C). (See 'Cabazitaxel versus mitoxantrone' above and 'Third-line cabazitaxel versus androgen signaling therapy' above.)
-For patients who are not candidates for cabazitaxel, mitoxantrone plus prednisone or platinum-based regimens are appropriate alternatives. (See 'Other agents' above.)
-Men with high-volume metastatic castration-sensitive disease who have been treated with concurrent androgen deprivation therapy (ADT) and an 18-week course of docetaxel (based on the results of the CHAARTED and STAMPEDE trials) and who subsequently progress to CRPC and require additional chemotherapy can be treated with cabazitaxel or retreated with docetaxel. Retreatment with docetaxel may be more likely to be effective if the progression occurred a period of time after the initial docetaxel-based chemohormonal therapy. (See 'Docetaxel retreatment' above.)
-For men who are treated with an androgen-signaling-targeted therapy rather than cabazitaxel after progression on first-line docetaxel, third-line cabazitaxel is an option. (See 'Third-line cabazitaxel versus androgen signaling therapy' above.)
●Small cell neuroendocrine tumors – Neuroendocrine differentiation may emerge in men who have previously had ADT for prostate adenocarcinoma (aggressive-variant prostate cancer [AVPC]). The best regimen for tumors that have some features of neuroendocrine differentiation but are not pure small cell cancers (eg, AVPC) is not established. Some patients may benefit from a taxane/platinum combination. (See 'Aggressive prostate cancer variants' above.)
●Men with HRR gene alterations
•Men who have metastatic CRPC and either a germline or somatic mutation in a DNA repair gene (eg, BRCA [breast cancer susceptibility], PALB2 [partner and localizer of BRCA2], or ATM [ataxia telangiectasia mutated]) are appropriate candidates for early use of a PARP inhibitor and/or a platinum-based chemotherapy regimen. (See 'Men with homologous recombination repair gene aberrations' above.)
●Men with deficient mismatch repair or high TMB – Patients whose tumors harbor a loss of one of the DNA mismatch repair enzymes (ie, MLH1, PMS2, MSH2 or MSH6) or high levels of tumor mutational burden (TMB, ≥10 mutations per megabase [mut/Mb]) may be candidates for checkpoint inhibitor immunotherapy. Specific recommendations are provided separately. (See "Immunotherapy for castration-resistant prostate cancer", section on 'PD-1 pathway inhibition'.)
ACKNOWLEDGMENT — We are saddened by the death of Nicholas Vogelzang, MD, who passed away in September 2022. UpToDate gratefully acknowledges Dr. Vogelzang's role as Section Editor on this topic, and his dedicated and longstanding involvement with the UpToDate program.
