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Risk factors Weight

Fasting blood glucose

Dietary advice

(± dietary consultation)

• Physical activity (30 min walk /d)

[284]

/LSLGSURÀOHDOWHUDWLRQ Lipid assessment

(increase in HDL-Chol) Dietary advice

(± dietary consultation)

• Physical activity (30 min walk /d)

[285]

&DUGLRYDVFXODUULVN Risk factors

(personal history ++)

Dietary advice

(± dietary consultation) Physical activity (30 min walk /d) Smoking cessation

[286]

6DUFRSHQLD Risk factors Vitamin D Bone density

Dietary advice

(± dietary consultation

± 800-1,000 IU/d Vitamin D and 800-1,200 mg/d calcium supplementation)

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Smoking cessation Physical activity

Rheumatology consultation if risk factor or bone density < -1.5

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5LVNRIIDOOLQJ Risk factors Consultation with a specialist if detected (geriatrics) >@

SRI: serotonin reuptake inhibitor ICI: Intracavernosal injections VAS: visual analogue scale

mini-GDS: mini geriatric depression score mini-Cog: mini-cognitive test

MMT: Mini Mental Test

NIDDM: non-insulin dependent diabetes mellitus

and peripheral oedema. It requires fortnightly monitoring of LFTs initially because of the risk of cytolysis (1%) in the ÀUVWWZRPRQWKVDQGRIWKHEORRGHOHFWURO\WHVEHFDXVHRI the possibility of hypokalaemia.

Enzalutamide

Enzalutamide is the first agent in a new class of androgen receptor (AR) inhibitors with a novel mechanism of action.

Once attached to the AR, it prevents its translocation and attachment to DNA. It also reduces the recruitment of transcriptional co-activators. Its affinity for ARs is superior to first generation antiandrogens. It is prescribed at a dose of 160 mg per day in a single dose between meals. The main side effect is asthenia. There is a < 1%

risk of seizure.

Apalutamide

It is an antiandrogen with a structure similar to that of enzalutamide. It is prescribed at a dose of 240 mg per day.

It causes skin rashes in 23% of the cases.

Darolutamide

It is prescribed at a dose of 200 mg x 2 per day. It does not cross the blood-brain barrier, so there is no risk of seizure.

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7DEOHChemotherapies evaluated for the treatment of PCA.

Mitoxantrone 12 mg/m2 IV every

21 days Liver toxicity.

Leukaemia risk Docetaxel PJP2 every

21 days

Liver toxicity.

Alopecia.

Peripheral neuropathy.

Capillary leak Cabazitaxel 20-25 mg/m2

every 21 days Liver toxicity.

Diarrhoea.

Cisplatin PJP2 every 21 days

Haematological, renal and neurological toxicity Carboplatin AUC 5

every 21 days Haematological toxicity (especially platelet)

7DEOH ADT EVALUATION and MONITORING.

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&OLQLFDO Quality of life Yes Yes

Asthenia Yes Yes

Cardiovascular risk factors Yes Yes

Risk factors for sarcopenia Yes Yes

Risk factors for falls Yes Yes

Erection + Sexuality Yes Yes

Mood Yes Yes

Weight + Height Yes Yes

3DUDFOLQLFDO Liver assessment Optional Optional

Fasting blood glucose Yes Yes

Lipid assessment Yes Depending on the risk

Vitamin D Yes Yes

Osteodensitometry (hip + spine)

Yes No

Haemoglobin Optional Optional

Alkaline phosphatase Optional Optional

PSA Yes Yes

Serum testosterone level ,IDQGURJHQGHÀFLHQF\

warning sign

Depending on the therapeutic response (PSA)

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:KHQQRWVSHFLÀFDOO\SUHYHQWHGERQHPHWDVWDVLVFRPSOLFD-tions occur in one out of every two patients within 24 months of the diagnosis of mCRPC. These complications cause very VLJQLÀFDQWDOWHUDWLRQVLQTXDOLW\RIOLIH

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Bisphosphonates inhibit bone resorption related to osteoclast activity and have a clinical effect on skeletal complications and pain. Tolerability is usually good, apart from the risk of osteonecrosis of the jaw, which is rare.

Zoledronic acid (4 mg in a slow IV injection every 4 weeks) has been shown to be effective in preventing mCRPC bone metastases complications [288]. Zoledronic acid (slow IV LQMHFWLRQHYHU\WRZHHNVKDVGHPRQVWUDWHGHIÀFDF\RQO\

in mCRPC and not in the castration-sensitive phase [289].

There is renal toxicity related to the diathesis (diabetes), dehydration, and the duration of infusion. The dose should be adjusted according to age and creatinine clearance (to be monitored).

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to zoledronate in preventing bone problems in mCRPC [290].

It is injected subcutaneously and presents no renal toxicity.

The risk of osteonecrosis of the jaw is comparable to that of zoledronic acid. It can lead to hypocalcaemia, which requires bone and calcium monitoring.

Precautions for the use of bisphosphonates and anti-RANKL antibodies

Denosumab and zoledronic acid require an initial dental check-up because of the risk of osteonecrosis of the jaw.

Tooth extractions, corticosteroid therapy, and the length of exposure to treatment contribute to this complication.

Prevention is based on a check-up with panoramic dental x-rays, prior dental extractions and strict dental hygiene.

The risk is approximately 1% for two years of treatment (recommended duration). It increases with the duration of exposure and reaches 4% for 40 months in the study on bone metastasis prevention.

As is the case for zoledronic acid, it is recommended that denosumab be prescribed for 24 months when metastatic bone CRPC has been diagnosed. Reliable data for longer periods are not available, but this is not a maximum duration RIXVH7KHULVNEHQHÀWUDWLRVKRXOGEHDVVHVVHGIRUHDFK patient.

Denosumab and zoledronic acid require an initial dental check-up (risk of osteonecrosis of the jaw). The risk is approximately 1% for two years of treatment (recom-mended duration). It increases to 4% for 40 months in the study on bone metastasis prevention.

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Radium 223 dichloride (223RACl2RU;RÀJRŠLVDQHOHPHQW very close to calcium that binds preferentially to bone.

It is an alpha emitter with a half-life of 11.4 days. Alpha particles have a high linear energy transfer and induce VLJQLÀFDQWGDPDJHWRWXPRXU'1$2QWKHRWKHUKDQGWKH\

have a very short range in matter (50 μm). Therefore, their bone marrow toxicity is very low. A randomised study on castration-resistant prostate cancer (AlsymPCaa) compared

223RACl2ZLWKWKHEHVWVXSSRUWLYHFDUH$EHQHÀWLQRYHUDOO survival was noted (median survival: 14 vs 11.2 months) [291-293]. Side effects are very limited, especially haematological (thrombocytopenia: 4%). If the product becomes available in France, it could be offered for mCRPC before or after docetaxel.

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360$ 3URVWDWH 6SHFLÀF 0HPEUDQH$QWLJHQ OLJDQGV FDQ be combined with a β- or α-emitting isotope and have a therapeutic effect in that case, as these particles are highly energetic and have a short mean range in biological tissue.

The combined use of a therapeutic PSMA ligand and the same ligand for diagnostic purposes constitutes a theranostic approach, with PET imaging to identify and quantify the presence of the target, monitor the progression over time and adapt the dose if necessary (personalized dosimetry).

The most widely used isotope for therapeutic applications LV/XWHWLXPLu, β-emitter). The second most com-monly used isotope is Actinium-225 (225Ac, α-emitter) [294].

The treatment modalities consist of slow intravenous injection of the radiopharmaceutical agent. The number of treatment cycles is 3 or 4, at 6 to 8-week intervals [295,296].

The main side effects are grade 3-4 haematotoxicity (particularly thrombocytopenia) in 10 to 13% of the cases DQGJUDGH[HURVWRPLDLQXSWRRIWKHFDVHV>@

withLu-PSMA. With 225Ac-PSMA, haematological side effects are less frequent [299].

Most studies on the clinical impact ofLu-PSMA have involved patients with progressive metastatic castration-resistant cancer (mCRPC) who have received at least one SULRUWUHDWPHQW7KHVWXGLHVUHSRUWWKHUDSHXWLFHIÀFDF\ZLWK a biochemical response rate (PSA decrease by at least 50%) RIDQGUHVSHFWLYHO\>@

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Sipuleucel-T is an active immune therapy that consists of infusing peripheral blood mononuclear cells, activated in vitro by a fusion protein (PA2024). Three samples of circulating blood cells are harvested from the patient to recover immune cells, particularly antigen presenting cells (APCAs). These cells are cultured in vitro and activated by the protein PA2024, then reinjected 3 days after the last sampling. In a randomised, placebo-controlled study [301]

which included 512 patients with mCRPC, this resulted in a VLJQLÀFDQWLQFUHDVHLQVXUYLYDOWLPHPRQWKVLQERWKFKH-motherapy- and non-cheVLJQLÀFDQWLQFUHDVHLQVXUYLYDOWLPHPRQWKVLQERWKFKH-motherapy-treated patients. These ZHUHPRVWO\SDWLHQWVZLWKDQ,683JUDGH”DQGSUHGRPLQDQW bone disease, which are forms with a rather good prognosis.

This treatment is not currently available in Europe.

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Ipilimumab (anti-CTLA4 antibody) was evaluated in a Phase ,,,VWXG\>@LQSDWLHQWVZLWKP&53&DIWHU*\RIERQH irradiation to stimulate the immune response. There was an LQVLJQLÀFDQWLPSURYHPHQWLQRYHUDOOVXUYLYDO