Terapie

Abiraterone

• Yonsa
• Zytiga

Bisphosphonates

• Ke snížení bolestí při meta do kostí

Cabazitaxel

• Jevtana

Docetaxel

Enzalutamide

• Xtandi

MULTIPLE POLY (ADP-ribose) polymerase (PARP) inhibitors

• Damage to a single strand of DNA
• The Poly (ADP-ribose) polymerase (PARP) complex binds to the broken strand to initiate repair
• PARP inhibitors are administered
• Trap the PARP complex and DNA replication stalls
• Causing double strand breaks
• Synthetic lethality hypothesis
• PARP inhibitors are given to normal cells with wild type BRCA 1 / 2
• Cell manages to survive
• Tumor cells, with mutated BRCA 1 / 2 genes
• Administration of PARP inhibitors, there is loss of heterozygosity (LOH)
• Causing synthetic lethality
• Disintegration of the tumor cell [5]

• Study in metastatic prostate cancer
• Some studies suggest that the best use of PARP inhibitors may be in
• Patients whose cancers harbor DNA-repair defects
• BRCA1/2 mutations
• Other data suggest broader application
• Promise for the use of PARP inhibitors in previously treated metastatic castration-resistant prostate cancer
• Phase Ib/II KEYNOTE-365 study
• Patients with metastatic castration-resistant prostate cancer (unselected for DNA-repair defects)
• Combination of the checkpoint inhibitor pembrolizumab plus the PARP inhibitor olaparib [2]

Eg

Rucaparib

Veliparib

Talozaparib

Niraparib

Open-label phase II GALAHAD study

• Patients with metastatic castration-resistant prostate cancer and DNA-repair defects, mainly BRCA1/2 defects
• Whose disease progressed after docetaxel and enzalutamide and/or abiraterone acetate
• Single-agent niraparib at 300 mg/d [2]

• Median follow-up of 5.7 months
• In the 23 patients with BRCA1/2 mutations
• Niraparib achieved an objective response rate of 38%
• Composite response rate of 65%
• 16 patients who had another DNA-repair alteration
• Objective response rate was 11%
• Composite response rate was 31% [2]

• Response Evaluation Criteria in Solid Tumors for response
• At least a 50% decline in prostate-specific antigen (PSA)
• And/or conversion of circulating tumor cells to < 5 per 7.5 mL of blood [2]

• May play important role in the treatment of men with metastatic castration-resistant prostate cancer
• Who have mutations in DNA-repair genes

• Most common grades 3 and 4 adverse events:
• Hematologic:
• Anemia (26%),
• Thrombocytopenia (15%);
• Neutropenia (8%),
• Leukopenia (6%)
• Most common grades 3 and 4 nonhematologic adverse events:
• Asthenia (6%)
• Back pain (5%).

Phase III trial called MAGNITUDE

• Niraparib in combination with abiraterone acetate and prednisone
• As front-line treatment of castration-resistant prostate cancer

Olaparib - PARP inhibitor

• PARP inhibitor olaparib (Lynparza) in metastatic prostate cancer
• Antitumor activity associating with BRCA2/ATM defects [5]

KEYNOTE-365 - THE PHASE IB /II KEYNOTE-365 trial

• Pembrolizumab in combination with several different treatment options
• PARP inhibitor in cohort A - 41 men
• Pembrolizumab at 200 mg every 3 weeks
• Olaparib at 400 mg twice daily
• Disease progression within 6 months after 1 to 2 previous lines of chemotherapy (docetaxel or cabazitaxel) for
• Metastatic castration-resistant prostate cancer and
• Up to 2 second-generation hormonal therapies (enzalutamide and/ or abiraterone acetate).
• Median age of patients was 69 years

• IMMUNE-MEDIATED adverse events
• In about 15% of patients
• Hypothyroidism in 2 patients
• No grade 3 or 4 immune-mediated adverse events were reported.

• 50% of patients experienced some decline in PSA level
• 39% had tumor reduction
• 29% had tumor reduction of more than 30%
• Median follow-up of 11 months
• Composite response rate in these patients was 12%
• Confirmed overall response rate was 7%.
• Median radiographic progression-free survival was 4.7 months
• Median overall survival was 13.5 months.

TOPARP-A trial

• PARP inhibitor monotherapy can lead to response in a subset of patients deficient in DNA repair
• Similar homologous repair deficient phenotype
• Can be induced by ADT
• Loss of the androgen receptor
• Led to downregulation of homologous repair gene expression
• PARP-mediated repair pathways
• Were upregulated in PCa cells following ADT
• DNA repair mutation
• In these patients the median rPFS in the olaparib group was 17.8 months compared with 6.5 months in the placebo group [4]

Platinum

Radium-223

• Xofigo

Rucaparib (Rubraca)

• Poly (ADP-ribose) polymerase (PARP) inhibitor
• May be active in men with BRCA1/2-positive metastatic castration-resistant prostate cancer

TRITON2 trial

• Objective response rate was 44% (95% confidence interval, 24%–65%) in 25 patients
• Evaluable by RECIST (Response Evaluation Criteria in Solid Tumors) (ESMO) 2018 Congress [3]

Sipuleucel-T

• Provenge

Androgen deprivation therapy (ADT)

• Many patients initially respond to androgen deprivation therapy
• Nearly all the patients relapse
• Eventually develop castration-resistant prostate cancer (CRPC)
• Androgen receptor (AR) plays a pivotal role in the development of resistance to hormone therapies in both primary and recurrent prostate cancer
• Antiandrogens in advanced prostate cancer

• Second-generation antiandrogens [7]

• Enzalutamide (Enza)

• Androgen synthesis inhibitors

• Abiraterone acetate (Abi)

• Newly developed therapies also suffer a short therapeutic durability due to acquired resistance [7]
• Improved quality of life and survival of patients with metastatic castration-resistant prostate cancer (mCRPC)
• Most patients eventually progress to develop treatment-refractory metastatic disease
• Persistent activation of the androgen receptor (AR) axis still drives mCRPC

Radiation therapy

Surgery