All patients will receive nCPAP at 5-6 cm H2O pressure with an oxygen concentration of 21% or more to maintain preductal saturation between 90% and 95%. Patients assigned to the active group will be treated with 0.15 mg/kg body weight (diluted in 3 mL 0.9% NaCl) nebulised salbutamol (Ventolin®, GlaxoSmithKline, Dublin, Ireland) for 30 min.

Patients assigned to the active group will be treated with 0.15 mg/kg body weight (diluted in 3 mL 0.9% NaCl) nebulized salbutamol (Ventolin®, GlaxoSmithKline, Dublin, Ireland) for 30 min.

Salbutamol

Patients in the placebo group will also receive nCPAP at 5-6 cm H2O pressure with an oxygen concentration of 21% or more to maintain preductal saturation between 90% and 95%. In addition, patients will receive 3 mL nebulised 0.9% NaCl administered for 30 min. as a placebo

3 mL nebulized 0.9% NaCl administered for 30 min.

0,9% Chloride Sodium

Patients receive radium Ra 223 dichloride IV over 1 minute on day 1. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.

Biopsy Procedure

Biospecimen Collection

Computed Tomography

Laboratory Biomarker Analysis

Magnetic Resonance Imaging

Olaparib

Quality-of-Life Assessment

Radium Ra 223 Dichloride

Patients receive radium Ra 223 dichloride as in Arm I. Patients with radiographic progression may crossover to Arm I. If patients have already completed all 6 infusions of radium, they will receive monotherapy with olaparib. If they have not yet completed all 6 radium-223 infusion, they will continue radium-223 infusion until completion and receive concurrent treatment with olaparib. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.

Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 and radium Ra 223 dichloride IV over 1 minute on day 1 of each cycle. Treatment with radium Ra 223 dichloride repeats every 28 days for 6 cycles and treatment with paclitaxel repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan, bone scan and/or MRI, as well as collection of blood samples throughout trial. Patients may optionally undergo SPECT on trial.

Bone Scan

Electronic Health Record Review

Paclitaxel

Single Photon Emission Computed Tomography

Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan, bone scan, and/or MRI, as well as collection of blood samples throughout trial. Patients may optionally undergo SPECT on trial.

Patients receive radium Ra 223 dichloride IV over 1 minute on day 1 of cycles 1-6 and cabozantinib S-malate PO QD on days 1-28 of every cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood and urine sample collection, bone scan, CT, or MRI, and may undergo FDG-PET or NaF-PET throughout the study.

Undergo blood and urine sample collection

Cabozantinib S-malate

Positron Emission Tomography

Questionnaire Administration

Patients receive cabozantinib S-malate PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood and urine sample collection, bone scan, CT, or MRI, and may undergo FDG-PET or NaF-PET throughout the study.

Adult men with bone mCRPC having \< 6 bone metastases

Drug will be administered as aqueous solution intravenously at a dose of 55 kBq/kg body weight every 4 weeks for 6 cycles (cycle length = 4 weeks).

Radium-223 dichloride (Xofigo, BAY88-8223)

Adult men with bone mCRPC having ≥ 6 bone metastases

Patients receive radium-223 dichloride IV over 1 minute on day 1. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone scan, and CT or MRI throughout the study.

Patients receive radium-223 dichloride as in Arm A and peposertib PO or BID on days 3-26. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone scan, and CT or MRI throughout the study.

Peposertib

Patients receive radium-223 dichloride IV as in Arm A and peposertib PO QD or BID as in Arm B. Patients also receive avelumab IV over 60 minutes on days 1 and 15 of cycles 2-6. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone scan, and CT or MRI throughout the study.

살부타몰, 0.9% 염화물 나트륨

생검 절차, 생체 시료 채취, 컴퓨터 단층 촬영, 실험실 생체 표지자 분석, 자기 공명 영상, 올라파립, 삶의 질 평가, 라듐 Ra 223 이염화물

생체 시료 채취, 골 스캔, 컴퓨터 단층 촬영, 전자 건강 기록 검토, 자기 공명 영상, 파클리탁셀, 라듐 Ra 223 이염화물, 단일 광자 방출 컴퓨터 단층 촬영

생체 시료 채취, 골 스캔, 카보잔티닙 S-말레이트, 컴퓨터 단층 촬영, 자기 공명 영상, 양전자 방출 단층 촬영, 설문 조사, 라듐 Ra 223 이염화물

라듐-223 이염화물(Xofigo, BAY88-8223)

아벨루맙, 생체 시료 채취, 골 스캔, 컴퓨터 단층 촬영, 자기 공명 영상, 페포서팁, 설문 조사, 라듐 Ra 223 이염화물