Summary

In patients with prostate cancer (PC) who have only biochemically relapsed disease after curative treatment (or some locally advanced PC patients), hormonal therapy remains a de facto standard of care treatment. Adding docetaxel-based chemotherapy to a standard-of-care hormonal therapy has an increased potential to treat prostate cancer cell clones resistant to androgen withdrawal and to possibly shorten the duration of therapy needed to control the disease.

This clinical trial is designed on the basis of an unmet clinical need, as well as other factors including: 1) a consensus among investigators on endpoints for studies of patients with a rising PSA, 2) the ability to identify subjects at high risk for developing radiographic metastases, 3) the fact that hormonal therapy has already been shown to improve survival when applied early in the natural history, and 4) the availability of chemotherapy such as docetaxel that can improve survival in subjects with advanced disease.

It is our hypothesis that a more appropriate group of patients who may benefit from the curative potential of systemic chemo-hormonal modality is that with minimal, but detectable disease who have a high probability of developing metastatic disease, clinical symptoms and eventually death from prostate cancer in a defined time frame. The investigators hypothesize further that the approach is likely to be more effective at a time of minimal tumour burden, resulting in minimization of the overall burden of therapy and better quality of life while on treatment.

This trial will determine whether any benefit is gained by adding chemotherapy to hormonal therapy alone in the population of subjects with a rising PSA. Two therapeutic approaches will be compared in this two-arm randomized clinical trial. The control Arm A provides antiandrogen (bicalutamide 150 mg x 1) alone. The experimental Arm B involves treatment with docetaxel for 8-10 cycles and antiandrogen (bicalutamide 150 mg x 1) treatment. For the schematic representation of study design please see Section 7.3.1.

Subjects with a rising PSA following definitive local curative therapy will be eligible, if their PSA doubling time is < 12 months. Also PC patients planned for anti-.androgen therapy are eligible, with the same criteria. Subjects with radiographic metastases will be excluded. The primary endpoint of the trial is progression-free survival of subjects that do not experience biochemical failure at 60 months from the start of therapy.

Based on the yearly number of prostate cancer patients who undergo definitive local therapies and the estimated probabilities of relapse, upwards of 400 men (if +15% improvement) in the Scandinavian countries are potential candidates for this approach.

Inclusion Criteria:

• Men > 18 and ≤80 years of age.

• WHO/ECOG performance status 0 - 1 (WHO: World Health Organization; ECOG: Eastern Cooperative Oncology Group )

• Histological proven adenocarcinoma of the prostate.

• Patients who are planned to receive antiandrogen (bicalutamide 150 mg x 1) treatment,

• After curative treatment

  • Prostatectomy: PSA > 10 OR PSA DT < 12 months and PSA > 0.5 (PSA doubling time calculation must start at a minimum value of > 0.5)
  • Radiation: PSA > +2.0 above nadir and PSA >10 OR PSA DT < 12 months and PSA > 0.5. (PSA bouncing after radiotherapy should be excluded according to the local traditions, and PSA doubling time calculation must start at a minimum value of > 0.5)

• In locally advanced (or local not suitable for curative therapy) prostate cancer patients, PSA < 100 is required before inclusion AND one of the following

  • PSA DT < 12 months or
  • PSA >20 or
  • Gleason score 8-10

• Previous hormonal therapy in conjunction with radiotherapy is allowed, provided that the total duration of therapy does not exceed 12 months and has to be stopped > 12 months ago.

• Testosterone value > 5 nmol/l

• Adequate haematological-, liver- and kidney function. WBC(white blood cell ) 3.5 x 109/L ANC(absolute neutrophil count ) 1.5 x 109/L Platelet Count 150 x 109/L Haemoglobin > 120 g/L Total bilirubin ≤ ULN (upper limit of normal) unless due to Gilbert's disease Creatinine ≤ 1.5 x ULN or creatinine clearance of 60 cc/min or corresponding Iohexol clearance value ASAT(aspartate aminotransferase )/ALAT(alanine aminotransferase) ≤ 1.5 x ULN ALP (Alkaline phosphatase) < 1.5 x ULN

• Negative bone scan performed no more than 3 months prior to randomisation.

• Additional CT or ultrasound of thorax, abdomen and/or pelvis is optional.

• Written informed consent.

Exclusion Criteria:

• Positive bone scan
• Any distant metastasis detected by CT or ultrasound
• Patients with a history of previous malignant disease. Exceptions should be made for basal cell carcinoma (BCC) and squamous cell carcinoma of the skin. Exceptions should also be made for curatively treated malignant disease, which has been disease free for the past 5 years.
• Previous chemotherapy or randomised in SPCG 12/AdPro or SPCG 13/AdRad (SPCG: Scandinavian Prostate Cancer Group).
• Systemic corticosteroids within 6 months prior to randomisation.
• Unstable cardiovascular disease, including myocardial infarction, within 6 months prior to randomisation.
• Active untreated infectious disease, including tuberculosis, MRSA (Methicillin-resistant Staphylococcus aureus.
• Active gastric ulcer.
• Known hypersensitivity to Polysorbate 80 (an excipient of docetaxel)
• Other serious illness or medical condition
• Symptomatic peripheral neuropathy ≥ CTCAE grade 2.
• Patients who by altered physical or psychological state not are able to co-operate or participate in the trial.