Castration Resistant Prostate Cancer: Role of Chemotherapy

Mitoxantrone

Mitoxantrone is a DNA-intercalating derivative of an anthracenedione antibiotic, which binds to topoisomerase II, thus causing inhibition of DNA and RNA replication. Based on the encouraging early phase trials, a phase III trial enrolled 161 patients with symptomatic mCRPC to mitoxantrone 12 mg/m ² IV every-3-weeks plus prednisone arm and to prednisone alone arm. Mitoxantrone with prednisone significantly improved pain control compared to prednisone alone (29% vs. 12%) with the median duration of response of 7.6 versus 2.1 months ( p = 0.0009). No significant improvement in OS was reported. Another phase III trial (CALGB 9182) randomized 244 mCRPC patients to mitoxantrone plus hydrocortisone arm and to hydrocortisone alone. This study also showed improvement in pain control with no significant survival advantage (12.3 vs. 12.6 months, p = 0.3298). Mitoxantrone was approved by the FDA in 1996 for the palliative treatment of mCRPC. Mitoxantrone is generally well-tolerated. Cardiotoxicity was observed in 5.5% of patients (defined as any decrease in left ventricle ejection fraction below the normal range, congestive heart failure, or myocardial ischemia), while secondary leukemia was reported in 1% of the treated patients. Today, mitoxantrone is used with the goal of improving quality of life and pain control as second- or third-line chemotherapy.

Docetaxel

Docetaxel is a taxane derivate, which prevents androgen receptor (AR) nuclear translocation by binding to microtubules and causing apoptosis through Bcl-2 phosphorylation. Single-agent docetaxel or in combination with estramustine demonstrated objective response rates (ORR) in up to 38% patients, PSA decline >50% in up to 69% patients with a median OS between 20 months and 23 months. These exciting findings prompted two phase III trials (TAK 327 and SWOG 99-16) that independently confirmed that docetaxel chemotherapy improved OS in mCRPC.

The TAX 327 study randomized 1006 mCRPC patients to three arms (all with daily oral prednisone): (1) mitoxantrone 12 mg/m ² IV every 3 weeks, (2) docetaxel 30 mg/m ² IV weekly, and (3) docetaxel 75 mg/m ² IV every 3 weeks. Eight milligrams of dexamethasone was prescribed 12, 3, and 1 h prior treatment in order to minimize toxicity. Only the docetaxel every-3-weeks arm showed significant median OS advantage compared with weekly docetaxel and mitoxantrone (19.2 vs. 17.8 vs. 16.3 months, respectively), with additional improvement in pain and quality of life. Subset analyses confirmed survival advantage in all subgroups. Docetaxel toxicity was acceptable. The most common toxicity in the docetaxel every-3-weeks group was grade 3/4 neutropenia compared with weekly docetaxel and mitoxantrone group (32% vs. 2% vs. 22%). Neutropenic infections were rare (3% vs. 0% vs. 2%, respectively). Treatment discontinuation due to side effects was relatively uncommon in all arms (11% vs. 16% vs. 10%, respectively). This trial has established docetaxel (75 mg/m ² every-3-weeks) plus daily prednisone (5 mg twice a day) as the standard treatment option for mCRPC and was approved by the FDA in 2004.

The SWOG 99-16 phase III trial enrolled 770 mCRPC patients to two arms: (1) docetaxel (60 mg/m ² IV every-3-weeks) plus estramustine (280 mg PO TID days 1–5) and (2) mitoxantrone (12 mg/m ² IV every-3-weeks) plus prednisone (5 mg BID). The docetaxel plus estramustine arm demonstrated improvement in median OS (17.5 vs. 15.6 months, p = 0.02). Pain improvement was similar in both groups. Grade 3/4 toxicity (gastrointestinal, cardiovascular/thromboembolic events, infections, pain, and neuropathy) was significantly higher and was reported in 54% patients (compared to 34% on mitoxantrone and prednisone arm); however, study discontinuation due to toxicities and treatment-related deaths (2% vs. 1%) were similar in both groups. Despite demonstrated survival advantage, the combination of docetaxel plus estramustine is rarely used due to significant toxicity of the regimen.

Docetaxel Combinations

It is a widely accepted rule in oncology that chemotherapy drugs are most effective when given in combination since using agents that work by different mechanisms can improve the treatment effect while decreasing the risk of resistance development. Several large phase III studies have combined docetaxel plus prednisone with different agents such as bevacizumab, aflibercept, lenalidomide, dasatinib, atrasentan, zibotentan, and calcitriol. Surprisingly, none of the combinations were superior. The majority of combination studies demonstrated significant toxicities requiring docetaxel dose reduction and delays as well as potentially compromising survival. Several ongoing phase II and III studies are testing the combination of docetaxel with other agents; however, none of them have established a role yet ( Table 54.1 ).