• Adverse event profile (Safety) [ Time Frame: Evaluation of all adverse events during the complete study treatment until 28 days after the last intake, using the CTCAE v5.0 grading system ]
  The hematological and non-hematological safety profile of ModraDoc006/r will be assessed by clinical and laboratory evaluations according to CTCAE v5.0.
• PSA Response Rate [ Time Frame: From baseline through study completion, an average of 1 year ]
  PSA decline of >30% and >50% decline from baseline with confirmatory read ≥4 weeks later without clinical / imaging progressive disease (PD) based on the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) recommendations
• PFS at 6 months [ Time Frame: Landmark analysis after last patient progressed or survived for 6 months after randomization ]
  Progression free survival (PFS) at 6 months based on RECIST v1.1
• PSA-PFS [ Time Frame: From baseline through study completion, an average of 1 year ]
  PSA-PFS according to PCWG3 criteria
• Time to PSA progression [ Time Frame: From baseline through study completion, an average of 1 year ]
  Time from randomization to the time when the PSA increases by 50% above the nadir
• Time to first skeletal event [ Time Frame: From baseline through study completion, an average of 1 year ]
  Time to first skeletal event, defined as the time from randomisation to the occurrence of the first skeletal-related event (i.e. radiation therapy or surgery to bone, clinically apparent pathological bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain).
• Duration of response (DOR) [ Time Frame: From baseline through study completion, an average of 1 year ]
  Duration of response (DOR) based on RECIST v1.1
• Time to progression (TTP) [ Time Frame: From baseline through study completion, an average of 1 year ]
  Time to progression (TTP) based on RECIST v1.1, incorporating the bone metastatic variable according to PCWG3
• Disease control rate (DCR) [ Time Frame: From baseline through study completion, an average of 1 year ]
  Disease control rate DCR) based on RECIST v1.1

• FACT Global (Functional Assessment of Chronic Illness Therapy) - Global Scale [ Time Frame: From baseline through study completion, an average of 1 year ]
  The FACT-G is a 27-item HRQOL questionnaire that assesses health status in terms of 4 HRQOL dimensions: physical well-being, emotional well-being, social well-being, and functional well-being. HRQoL response is defined as a 10-point or greater increase in the global FACT score at a post-baseline assessment compared with baseline. Improvements in individual HRQoL domains will be investigated with weekly ModraDoc006/r as compared to the standard treatment with i.v. docetaxel. Improvements that are considered significant are in subscales of FACT:

  • ≥3 for physical wellbeing (7 items; score range 0-28)
  • ≥3 for social or family wellbeing (7 items; score range 0-28)
  • ≥3 for emotional wellbeing (6 items; score range 0-24)
  • ≥3 for functional wellbeing (7 items; score range 0-28)
• FACT Prostate (Functional Assessment of Chronic Illness Therapy) - Prostate scale [ Time Frame: From baseline through study completion, an average of 1 year ]
  The FACT - Prostate is a 12-item HRQOL questionnaire that assesses health status related to prostate cancer symptoms. HRQoL response is defined as a 10-point or greater increase in the prostate FACT score at a post-baseline assessment compared with baseline. Improvements in individual HRQoL domains will be investigated with weekly ModraDoc006/r as compared to the standard treatment with i.v. docetaxel. Improvements that are considered significant are in subscales of FACT - P: ≥3 for prostate cancer subscale (12 items; score range 0-48)
• FACT Taxane (Functional Assessment of Chronic Illness Therapy) - Taxane treatment scale [ Time Frame: From baseline through study completion, an average of 1 year ]
  The FACT-Taxane is a 16-item HRQOL questionnaire that assesses health status related to anti-cancer treatment with a taxane. HRQoL response is defined as a 10-point or greater increase in the FACT score at a post-baseline assessment compared with baseline. Improvements in individual HRQoL domains will be investigated with weekly ModraDoc006/r as compared to the standard treatment with IV docetaxel. Improvements that are considered significant are in subscales of FACT - P: ≥3 for taxane treatment subscale (16 items; score range 0-64)
• Treatment Satisfaction Questionnaire for Medication (TSQM) [ Time Frame: From the first visit after start of treatment until study completion, an average of 1 year. ]
  The Treatment Satisfaction Questionnaire for Medication (TSQM) Version 1.4 is a 14-item questionnaire to assess patients' satisfaction with medication, providing scores on four scales - side effects, effectiveness, convenience and global satisfaction. TSQM scores have a range of 0 to 100, with higher scores indicating higher satisfaction.
• EuroQoL-5D (EQ-5D) [ Time Frame: From baseline through study completion, an average of 1 year ]
  The EQ-5D is a standardized instrument for measuring generic health status. It has two components: health state description and evaluation. In the description part, health status is measured in terms of five dimensions (5D); mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Mobility dimension asks about the person's walking ability. Self-care dimension asks about the ability to wash or dress by oneself, and usual activities dimension measures performance in "work, study, housework, family or leisure activities". In pain/discomfort dimension, it asks how much pain or discomfort they have, and in anxiety/depression dimension, it asks how anxious or depressed they are. The respondents self-rate their level of severity for each dimension using three-level (EQ-5D-3L) or five-level (EQ-5D-5L) scale. In the evaluation part, the respondents evaluate their overall health status using the visual analogue scale (EQ-VAS).

• Prostate Cancer Metastatic
• Castration-resistant Prostate Cancer

• Drug: Docetaxel in Parenteral Dosage Form
  Treatment with IV docetaxel at 75 mg/m2 given as a one-hour infusion on day 1 every 21 days plus 5 mg oral prednisone twice daily
  Other Name: Taxotere
• Drug: ModraDoc006/r
  Treatment with twice daily once weekly (BIDW) ModraDoc006 (oral docetaxel) 10mg tablets in combination with ritonavir 100mg tablets
  Other Name: oral docetaxel formulation

• Active Comparator: Docetaxel IV
  This study arm will receive docetaxel at 75 mg/m2 given i.v. as a one-hour infusion on day 1 every 21 days plus 5 mg oral prednisone twice daily.
  Intervention: Drug: Docetaxel in Parenteral Dosage Form
• Experimental: ModraDoc006/r
  This cohort will receive ModraDoc006/r 30 mg oral docetaxel in combination with 200 mg ritonavir in the morning and 20 mg oral docetaxel in combination with 100 mg ritonavir in the evening (7-12 hours after the morning dose), on Day 1, 8 and 15 of a 21-day cycle, plus 5 mg oral prednisone twice daily.
  Intervention: Drug: ModraDoc006/r

Inclusion Criteria:

1. Age ≥ 18 years

2. Histologically or cytologically proven prostate cancer with evidence of progressive mCRPC, defined as:

   1. Castrate levels of testosterone, defined as ≤ 50 ng/dL (or ≤ 0.50 ng/mL or 1.73 nmol/L)
   2. Evidence of progressive metastatic disease as defined by radiographic disease progression or PSA progression
   3. With an indication for systemic treatment with docetaxel according to the standard of care
3. Measurable tumour lesions, defined as pelvic and/or extra-pelvic nodal lesions ≥1.5 cm in the short axis or visceral lesions ≥1.0 cm in the longest dimensions and measurable according to RECIST v1.1, bone metastasis as evaluated with 99mTc-methylene diphosphonate (MDP) radionuclide bone scintigraphy
4. Resolution of toxicity of prior therapy to < grade 2 (except for alopecia), as defined by CTCAE v5.0

5. Adequate haematological, renal and hepatic functions:

   1. Hemoglobin ≥ 6.0 mmol/l (>9.6 g/dL)
   2. ANC ≥ 1.5 x 109 /L
   3. Platelet count ≥ 100 x 109 /L
   4. Hepatic function defined by serum bilirubin ≤ ULN, ALAT and ASAT ≤ 1.5 x ULN concomitant with alkaline phosphatase ≤ 2.5 × ULN.
   5. Renal function defined by serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 ml/min (by Cockcroft-Gault formula, or MDRD).
6. WHO performance status of 0-2
7. Estimated life expectancy of at least 12 weeks
8. Able and willing to swallow oral medication
9. Able and willing to undergo radiologic scans (CT scan)
10. Able and willing to give written informed consent according to local guidelines

Exclusion Criteria:

1. Any treatment with investigational drugs, chemotherapy or immunotherapy within 4 weeks prior to receiving the first dose of investigational treatment. Palliative radiotherapy (1x8 Gy dose) is allowed before and during the study, but not in the week prior to start of study treatment.
2. Subjects who have had prior treatment with taxanes.
3. Subjects with symptomatic brain metastases. Subjects asymptomatic in the absence of corticosteroids and anticonvulsant therapy for ≥6 weeks are eligible. Radiotherapy for brain metastasis must have been completed ≥6 weeks prior to start of trial. Brain metastasis must be stable with verification by imaging (e.g. brain MRI or CT completed at screening, demonstrating no current evidence of progressive brain metastases). Subjects are not permitted to receive anti-epileptic drugs or corticosteroid treatment indicated for brain metastasis. Subjects with a history of leptomeningeal metastases are not eligible.
4. Current malignancies other than mCRPC with exception of adequately treated basal or squamous cell carcinoma of the skin, or adequately treated non-muscular invasive bladder cancer.
5. Absence of highly effective method of contraception as of cycle one day one (C1D1). Men enrolled in this trial must agree to use a highly effective contraceptive method throughout the study.
6. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg)
7. Unresolved (>grade 0 as defined by CTCAE version 5.0) gastrointestinal toxicities (pre-existing mucositis, diarrhea or nausea/vomiting)
8. Grade ≥ 2 motor ≥ 2 motor or sensory neuropathy symptoms (as defined by CTCAE version 5.0)
9. Known hypersensitivity to any of the study drugs or excipients or taxanes
10. Concomitant use of P-glycoprotein (P-gp , MDR), CYP3A, OATP1B1, OATP1B3 and MRP2 modulating drugs such as Ca+- entry blockers (verapamil, dihydropyridines), cyclosporine, quinidine and grapefruit juice, concomitant use of HIV medications, other protease inhibitors, (non) nucleoside analogues, or St. John's wort
11. Bowel obstruction or motility disorder that may influence the resorption of drugs as judged by the treating physician
12. Major surgical procedures within 21 days prior to providing informed consent
13. Active acute or chronic infection, which is not controlled by appropriate medication (at the discretion of the treating physician)
14. Known positivity for Human Immunodeficiency Virus HIV-1 or HIV-2 type
15. Patients with known active infection of hepatitis B, C, or E (patients who are anti-HBC positive but HBsAg negative are eligible to participate in this study)
16. Clinically significant (i.e. active) cardiovascular disease defined as stroke, transient ischemic attack (TIA), myocardial infarction, unstable angina, or congestive heart failure within ≤ 6 months prior to first trial treatment
17. Evidence of any other medical conditions (such as treatment-resistant peptic ulcer disease, erosive oesophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, or pulmonary embolism within 4 weeks of randomization, or psychiatric illness, drug or alcohol abuse, physical examination or laboratory findings) that may interfere with the planned treatment, affect subject compliance or place the subject at high risk of treatment-related complications
18. Legal incapacity