Docetaxel Improves Survival in Metastatic Androgen-Independent Prostate Cancer

R esearch in Brief Docetaxel Improves Survival in Metastatic Androgen-Independent Prostate Cancer Rationale • The median survival of patients with symptomatic hormone-refractory prostate cancer (HRPC) with evidence of metastases has typically been reported in the 912 month range.1,2 Chemotherapy in HRPC has not previously shown a survival benefit. Mitoxantrone and prednisone provide some palliative relief in HRPC, but no survival benefit has been demonstrated. • Several phase II trials have been conducted to assess the activity of singleagent docetaxel in HRPC.3-5 Biochemical response, defined as a ≥ 50% decrease in prostate-specific antigen (PSA) from baseline, was reported in 41%-46% of patients, and partial responses were seen in 24%-33% of patients with measurable disease. Other phase II trials used docetaxel in combination with estramustine in HRPC,6-11 with PSA responses of 45%-78%.12 Docetaxel-associated neutropenia was the major grade 3/4 hematologic toxicity in both single-agent and combination trials when docetaxel was given in an every-3-week regimen. • The high PSA responses observed in the phase II studies led to 2 separate phase III multicenter, randomized trials of docetaxel compared with mitoxantrone in HRPC. Both trials were powered to assess a 33% difference in survival. Based on survival data from these trials, docetaxel received approval by the Food and Drug Administration (FDA) as a treatment for HRPC in May 2004. The results of the TAX 327 and Southwestern Oncology Group (SWOG) 9916 trials were presented as plenary lectures at the 40th Annual Meeting of the American Society of Clinical Oncology in June 2004.13,14 Prepared by: Nancy Price, PhD Reviewed by: Vinay K. Jain, MD, Oliver Sartor, MD

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Figure 1: TAX 327 Treatment Schema

Patients with metastatic HRPC were stratified on the basis of Karnofsky PS and pain

R A N D O M I Z E

Arm A Mitoxantrone 12 mg/m2 every 3 weeks with Prednisone 5 mg p.o. b.i.d. Arm B Docetaxel 30 mg/m2 weekly with Prednisone 5 mg p.o. b.i.d. Arm C Docetaxel 75 mg/m2 every 3 weeks with Prednisone 5 mg p.o. b.i.d.

Abbreviations: HRPC = hormone-refractory prostate cancer; PS = performance status

Single-Agent Docetaxel in Androgen-Independent Prostate Cancer TAX 327 TAX 327 compared 2 different schedules of docetaxel to mitoxantrone and prednisone, the current standard treatment for HRPC.13 Docetaxel given every 3

weeks can cause significant neutropenia with its attendant risks. Weekly administration of docetaxel can decrease the degree of myelosuppression, but it is unclear how the weekly docetaxel schedule compares with the more standard every-3-week dosing schedule with respect to efficacy. The primary endpoint of TAX 327 was overall survival, with secondary

Table 1: Efficacy Data for TAX 327 Mitoxantrone 12 mg/m2 (n = 337)

Docetaxel 30 mg/m2 Weekly (n = 334)

Docetaxel 75 mg/m2 P Value* Every 3 Weeks (n = 335)

Median Survival

16.5 Months

17.4 Months

0.3

18.9 Months

0.009

HR* (95% CI)

NA

0.91 (0.75-1.11)

–

0.76 (0.62-0.94)

–

Pain Response

22% (n = 157)

31% (n = 154)

0.07

35% (n = 153)

0.01

PSA Response (> 50 Decline)

32% (n = 300)

48% (n = 282)

< 0.0001

45% (n = 291)

0.0005

Measurable Tumor Response

7% (n = 137)

8% (n = 134)

0.5

12% (n = 141)

0.1

P Value*

*Compared to mitoxantrone. Mitoxantrone 12 mg/m2 was given every 21 days; docetaxel 30 mg/m2 weekly; docetaxel 75 mg/m2 every 21 days. Abbreviations: HR = hazard ratio; NA = not applicable; PSA = prostate-specific antigen

June 2004

Table 2: Grade 3/4 Toxicities for TAX 327 Mitoxantrone 12 mg/m2 (n = 337)

Docetaxel 30 mg/m2 Weekly (n = 334)

Docetaxel 75 mg/m2 Every 3 Weeks (n = 335)

34.6%

43%

45.8%

Neutropenia

22%

1.5%

32%

Neutropenic infection

0.9%

0

3%

Febrile neutropenia

1.8%

0

2.7%

2%

5%

5%

Bone pain

9.9%

7.3%

7.8%

Nausea

1.5%

2.4%

2.7%

Fatigue

5.1%

5.5%

4.5%

Diarrhea

1.2%

4.8%

2.1%

Toxicity Overall Hematologic

Anemia Nonhematologic

Mitoxantrone was given every 21 days; docetaxel 30 mg/m2 weekly; docetaxel 75 mg/m2 every 21 days.

endpoints being PSA response (≥ 50% decrease), measurable response, and improvement in pain and quality of life. Eligible patients had clinical and/or biochemical (PSA) progression due to metastatic HRPC, testosterone < 50 ng/dL, and no prior chemotherapy. Prior treatment with estramustine was permitted. Antiandrogen therapy was withdrawn 6 weeks prior to initiation of chemotherapy. Patients were stratified based on Karnofsky performance scores and pain, then randomized into 1 of the 3 treatment arms. TAX 327 compared arm A, mitox-

antrone 12 mg/m2 and prednisone 5 mg orally twice daily to either arm B, consisting of weekly docetaxel 30 mg/m2 every 5 of 6 weeks plus prednisone 5 mg orally twice daily, or to arm C, consisting of docetaxel 75 mg/m2 every 3 weeks plus prednisone 5 mg orally twice daily to patients with HRPC (Figure 1). Patients treated with docetaxel were also pretreated with dexamethasone to diminish allergic reactions. Of the 1006 patients accrued into the trial, 337 were randomized into arm A, 334 into arm B, and 335 into arm C. Patients randomized into the 3 treatment arms had similar baseline characteristics.

Figure 2: Treatment Schema for SWOG 9916

Patients with metastatic HRPC were stratified according to disease status

R A N D O M I Z E

Arm A Estramustine 280 mg t.i.d. on days 1-5 Docetaxel 60 mg/m2 I.V. over 1 hour on day 2 of each 3-week cycle

Arm B Mitoxantrone 12 mg/m2 on day 1 with Prednisone 5 mg b.i.d. on days 1-21 of a 3-week cycle

Abbreviations: HRPC = hormone-refractory prostate cancer; SWOG = Southwest Oncology Group

The median follow-up was 20.7 months. Planned treatments were delivered to 99%, 96%, and 98% of patients in treatment arms A, B, and C, respectively. Patients randomized to the every-3week docetaxel arm had a statistically significant prolongation of median survival at 18.9 months compared with 16.5 months median survival for patients on the mitoxantrone/prednisone arm (P = 0.009). Patients randomized to the every-3-week docetaxel arm had a 35% pain response (P = 0.01) and a 45% PSA response (P = 0.0005). Patients on the weekly docetaxel arm had a median survival of 17.4 months, which was not statistically superior to the mitoxantrone arm (P = 0.3). The efficacy data are summarized in Table 1. Overall, the docetaxel treatments were well tolerated. The every-3-week docetaxel arm had a 32% incidence of grade 3/4 neutropenia, although only 2.7% of the patients developed febrile neutropenia. This was not distinct from the 1.8% rate of febrile neutropenia seen on the mitoxantrone arm. Other toxicities included pain, infection, fatigue, and diarrhea (Table 2).

SWOG 9916 The objectives of SWOG 9916 were to compare the overall survival and progression-free survival in patients with HRPC who were treated with either docetaxel/estramustine or mitoxantrone/prednisone.14 Secondary objectives included toxicity and quality-of-life assessments, including palliation of metastatic bone pain. Patients were stratified according to disease status—measurable or evaluable disease progression versus rising PSA only. SWOG 9916 compared docetaxel (starting at 60 mg/m2 but allowing dose escalation to 70 mg/m2) plus estramustine (280 mg orally 3 times daily days 15) to mitoxantrone (12 mg/m2 but allowing dose escalation to 14 mg/m2) plus prednisone (5 mg orally twice daily). In the absence of unacceptable toxicity or disease progression, treatment in both arms was repeated every 3 weeks for a maximum of 12 courses (Figure 2). A total of 770 patients with progressive HRPC were accrued in the study. Of the eligible patients, 338 patients were

Clinical Prostate Cancer

June 2004 •

19

R esearch in Brief Table 3: Efficacy for SWOG 9916 Mitoxantrone/ Prednisone

Docetaxel/ Estramustine

P Value

Median Overall Survival

16 Months

18 Months

0.01

Median PFS

3 Months

6 Months

< 0.0001

Measurable Disease Response

11% (n = 93)

17% (n = 103)

0.15

PSA Response

27% (n = 303)

50% (n = 303)

< 0.0001

Abbreviatons: PFS = progression-free survival; PSA = prostate-specific antigen; SWOG = Southwest Oncology Group

randomized to the docetaxel arm and 336 patients to the mitoxantrone arm. The patient characteristics were well balanced between the 2 treatment arms with respect to age, race, performance status, PSA, and symptoms. In January 2001, because of the high incidence of thromboembolic events in the docetaxel/estramustine arm, the protocol was amended to include anticoagulant prophylaxis with warfarin 2 mg and acetylsalicyclic acid 325 mg orally daily. Interestingly, the rate of thromboembolic events apparently did not decrease after initiation of routine warfarin/acetylsalicyclic acid prophylaxis. Median survival in the docetaxel arm was 18 months, which was significantly higher than that seen in the mitoxantrone arm at 16 months (P = 0.01). Time to progression was significantly longer in the docetaxel arm at 6 months compared with 3 months in the mitoxantrone arm (P < 0.0001). The measurable disease responses in the docetaxel and mitoxantrone arms were 17% and 11%, respectively (P = 0.15). The efficacy data are summarized in Table 3. Overall, grade 3/4 toxicities occurred in 54% of patients in the docetaxel arm and in 34% of patients in the mitox-

antrone arm (Table 4). Higher incidence of gastrointestinal and cardiovascular events occurred in the docetaxel/estramustine arm. No significant difference in toxic deaths was observed between the 2 arms, with 7 deaths in the docetaxel arm and 4 deaths in the mitoxantrone arm.

Clinical Relevance Docetaxel is the first chemotherapy agent to show an improvement in survival in patients with HRPC, and the FDA has now approved the combination of docetaxel 75 mg/m2 every 3 weeks plus prednisone in this setting. The clinical activity of docetaxel in HRPC represents an important treatment breakthrough in a disease where chemotherapy was formerly considered ineffective in prolonging survival. TAX 327 demonstrated superiority of every-3-week docetaxel compared to mitoxantrone. It also suggested that the every-3-week schedule of docetaxel is better than the weekly schedule commonly used to treat prostate cancer in the United States. The addition of estramustine to every-3-week docetaxel in the SWOG 9916 trial did not result in an increase in median survival compared to historical data with single-agent docetaxel, suggesting that most of the benefit was due to sin-

Table 4: Toxicities for SWOG 9916 Mitoxantrone/Prednisone

Docetaxel/Estramustine

109 (34%)

175 (54%)

Gastrointestinal

21

63

Cardiovascular

20

44

4 (1%)

7 (2%)

Toxicity Grade 3/4 Toxicity

Toxic Deaths

Abbreviation: SWOG = Southwest Oncology Group

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June 2004

gle-agent docetaxel. Trials are ongoing to determine whether the combination of docetaxel with newer targeted agents will further improve the outcome of patients with prostate cancer.

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