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Globally, prostate cancer is the second most common malignant tumor in men, second only to lung cancer
.
Almost all patients with advanced prostate cancer will eventually progress to castration-resistant prostate cancer (CRPC) after receiving endocrine therapy (Figure 1), and metastatic castration-resistant prostate cancer (mCRPC) is the main cause of death
.
Despite the increase in existing treatments, the 5-year survival rate of mCRPC patients is still very low, and new treatments are urgently needed
.
This article summarizes the relevant research progress in the field of mCRPC targeted therapy and immunotherapy in recent years
.
Figure 1 Different stages of prostate cancer and possible treatment options Androgen receptor (AR) targeted therapy At present, new AR targeted therapy is the accepted therapy for mCRPC patients
.
Phase III COU-AA-301 study and COU-AA-302 study showed that abiraterone + prednisone compared with placebo can prolong the overall survival (OS) of patients by more than 4 months
.
The AFFIRM and PREVALIL studies have shown that, compared with placebo, enzalutamide can prolong the median OS of patients by 4-5 months (Table 1, Figure 1)
.
Table 1 Key research on CRPC system therapy PARP inhibitor therapy Approximately 23% of mCRPCs have somatic or germline mutations in DNA damage repair (DDR) genes, including BRCA2, BRCA1, ATM and CHEK2
.
DDR defects can cause genome instability and tumor-specific damage.
PARP inhibitors are using this feature to induce cell synthesis and lethality during treatment
.
TOPARP-A study The TOPARP-A study showed that 32% of mCRPC patients treated with multi-line therapy responded to olaparib, and 88% of the responders had mutations in the DDR gene, including BRCA1, BRCA2, ATM and FANC
.
The TOPARP-B validation cohort showed that the overall response rate of olaparib was 47%, of which 83% of patients had BRCA1 and BRCA2 mutations, 57% of patients had PALB2 mutations, 37% of patients had ATM mutations, and 25% of patients had CDK12 mutations.
.
PROfound study In the phase III PROfound study, mCRPC patients who had progressed on AR inhibitor treatment and had DDR defects were randomly assigned to receive olaparib or AR inhibitors selected by the investigator at a 2:1 ratio
.
Cohort A (n=245) included patients with BRCA1/2 mutations and ATM mutations, and cohort B (n=142) included patients with other designated DDR gene mutations
.
The results showed that compared with the control group, the olaparib group could significantly improve the median radiological progression-free survival (rPFS) of cohort A patients.
The rPFS of the two groups were 7.
39 months and 3.
55 months (HR=0.
34).
, P<0.
0001), and improved the rPFS of the total population (HR=0.
69, P<0.
0175)
.
In cohort A, the median OS of the olaparib group and the control group were 17.
3 months and 14.
0 months, respectively (HR=0.
69, P<0.
0175)
.
The overall population also showed an improvement trend (HR=0.
79, P=0.
0515)
.
The PROfound study established the role of PARP inhibitors in patients with mCRPC lacking DDR and opened up a new era of molecular stratification therapy for mCRPC
.
Other PARP inhibitors, such as rucaprib, niraparib, and talazopanib have shown similar effects
.
Overall, the frequency of DDR gene mutations and the response to PARP inhibitors support the detection of germline mutations and tumor gene sequencing for routine clinical practice
.
Prostate Cancer Specific Membrane Antigen (PMSA) Therapy PMSA is expressed in most prostate cancers, and its expression increases in mCRPC patients, making PSMA a potential effective target
.
Anti-tumor therapy using PSMA mainly focuses on PSMA-targeted radioligands, antibody-drug conjugates, antibodies or α/β radioisotopes.
Among them, there are many clinical studies on [¹⁷⁷Lu]Lu-PSMA-617 linked to β-radiation particles
.
[¹⁷⁷Lu]Lu-PSMA-617 is a PSMA targeted radioligand therapy
.
In an early prospective study, [¹⁷⁷Lu]Lu-PSMA-617 can reduce the PSA of 64% of patients with mCRPC without treatment available by more than 50%
.
Based on this, the researchers conducted two clinical studies: Phase II TheraP study and Phase III VISION study
.
The TheraP Phase II TheraP study included patients with mCRPC who had progressed in docetaxel and AR inhibitor treatment, and were randomly assigned to receive [¹⁷⁷Lu]Lu-PSMA-617 or cabazitaxel treatment
.
The results show that compared with cabazitaxel (37%), [¹⁷⁷Lu]Lu-PSMA-617 can significantly improve the PSA response rate (66%) (P＜0.
0001) and delay the progress of PSA (HR=0.
63, P=0.
0028)
.
VISION Study VISION is an international, open-label, multi-center phase III clinical study designed to evaluate the efficacy and safety of [¹⁷⁷Lu]Lu-PSMA-617 combined with the best standard treatment selected by the investigator versus standard treatment for mCRPC sex
.
The study included 831 patients with PSMA-positive treated mCRPC
.
At a median follow-up of 20.
9 months, compared with the standard treatment group, the risk of imaging progression or death in the [¹⁷⁷Lu]Lu-PSMA-617 group was reduced by 60%.
The rPFS was 8.
7 months and 3.
4 months, respectively (HR=0.
40, P<0.
001)
.
[¹⁷⁷Lu]Lu-PSMA-617 will become the new standard for mCRPC treatment
.
At present, clinical research is evaluating the efficacy of this therapy in early disease and the best treatment sequence
.
The heterogeneity of PSMA expression in metastases in the same patient and in different patients is the key issue, and the selection of the best beneficiary patients, primary and secondary drug resistance are issues that need to be resolved
.
Immunotherapy autoimmune therapy and vaccine autoimmune cell therapy sipuleucel-T became the first vaccine therapy against solid malignant tumors approved by the U.
S.
Food and Drug Administration (FDA) in 2010.
Studies have shown that sipuleucel-T can bring 4.
1 Month survival advantage
.
However, this complex and expensive cellular immunotherapy has not been recognized by doctors
.
The results of the Phase III PROSTVAC-VF study of PSA-based targeted vaccines are not satisfactory
.
PD-1/PD-L1 inhibitors Immune checkpoint inhibitors, including PD-1/PD-L1 inhibitors and CTLA4 inhibitors, have changed the treatment pattern of many tumor types
.
Early studies have shown that the effective rate of PD-1/PD-L1 inhibitors is about 15%
.
Two phase III studies showed that the CTLA4 inhibitor ipilimumab compared with placebo showed a response in mCRPC patients treated with docetaxel, but did not show a survival advantage
.
Immune combination therapy shows high anti-tumor activity in unselected mCRPC patients
.
In a phase II study, pembrolizumab + enzalutamide can reduce the PSA of 18% (5/28) enzalutamide patients with advanced mCRPC patients by more than 50%
.
The CheckMate650 study showed that compared with patients with advanced chemotherapy (10%), ipilimumab + nivolumab had an objective response rate (ORR) of 25% in mCRPC patients without chemotherapy, while in patients with DDR gene defects In the ORR reached 50%
.
Research suggests that when the tumor burden and tumor heterogeneity are small, immunotherapy may be more effective in patients with DDR gene mutations and early-stage patients
.
Similarly, CDK12 mutations and mismatch repair defects can lead to greater genomic instability and more tumor neoantigens, which may improve the response to immunotherapy
.
In the next few years, there will be more problems and challenges regarding the immunotherapy of prostate cancer
.
Reference: Prostate cance.
https://doi.
org/10.
1016/ S0140-6736(21)00950-8 Contribution email: tougao@medlive.
cn
.
Almost all patients with advanced prostate cancer will eventually progress to castration-resistant prostate cancer (CRPC) after receiving endocrine therapy (Figure 1), and metastatic castration-resistant prostate cancer (mCRPC) is the main cause of death
.
Despite the increase in existing treatments, the 5-year survival rate of mCRPC patients is still very low, and new treatments are urgently needed
.
This article summarizes the relevant research progress in the field of mCRPC targeted therapy and immunotherapy in recent years
.
Figure 1 Different stages of prostate cancer and possible treatment options Androgen receptor (AR) targeted therapy At present, new AR targeted therapy is the accepted therapy for mCRPC patients
.
Phase III COU-AA-301 study and COU-AA-302 study showed that abiraterone + prednisone compared with placebo can prolong the overall survival (OS) of patients by more than 4 months
.
The AFFIRM and PREVALIL studies have shown that, compared with placebo, enzalutamide can prolong the median OS of patients by 4-5 months (Table 1, Figure 1)
.
Table 1 Key research on CRPC system therapy PARP inhibitor therapy Approximately 23% of mCRPCs have somatic or germline mutations in DNA damage repair (DDR) genes, including BRCA2, BRCA1, ATM and CHEK2
.
DDR defects can cause genome instability and tumor-specific damage.
PARP inhibitors are using this feature to induce cell synthesis and lethality during treatment
.
TOPARP-A study The TOPARP-A study showed that 32% of mCRPC patients treated with multi-line therapy responded to olaparib, and 88% of the responders had mutations in the DDR gene, including BRCA1, BRCA2, ATM and FANC
.
The TOPARP-B validation cohort showed that the overall response rate of olaparib was 47%, of which 83% of patients had BRCA1 and BRCA2 mutations, 57% of patients had PALB2 mutations, 37% of patients had ATM mutations, and 25% of patients had CDK12 mutations.
.
PROfound study In the phase III PROfound study, mCRPC patients who had progressed on AR inhibitor treatment and had DDR defects were randomly assigned to receive olaparib or AR inhibitors selected by the investigator at a 2:1 ratio
.
Cohort A (n=245) included patients with BRCA1/2 mutations and ATM mutations, and cohort B (n=142) included patients with other designated DDR gene mutations
.
The results showed that compared with the control group, the olaparib group could significantly improve the median radiological progression-free survival (rPFS) of cohort A patients.
The rPFS of the two groups were 7.
39 months and 3.
55 months (HR=0.
34).
, P<0.
0001), and improved the rPFS of the total population (HR=0.
69, P<0.
0175)
.
In cohort A, the median OS of the olaparib group and the control group were 17.
3 months and 14.
0 months, respectively (HR=0.
69, P<0.
0175)
.
The overall population also showed an improvement trend (HR=0.
79, P=0.
0515)
.
The PROfound study established the role of PARP inhibitors in patients with mCRPC lacking DDR and opened up a new era of molecular stratification therapy for mCRPC
.
Other PARP inhibitors, such as rucaprib, niraparib, and talazopanib have shown similar effects
.
Overall, the frequency of DDR gene mutations and the response to PARP inhibitors support the detection of germline mutations and tumor gene sequencing for routine clinical practice
.
Prostate Cancer Specific Membrane Antigen (PMSA) Therapy PMSA is expressed in most prostate cancers, and its expression increases in mCRPC patients, making PSMA a potential effective target
.
Anti-tumor therapy using PSMA mainly focuses on PSMA-targeted radioligands, antibody-drug conjugates, antibodies or α/β radioisotopes.
Among them, there are many clinical studies on [¹⁷⁷Lu]Lu-PSMA-617 linked to β-radiation particles
.
[¹⁷⁷Lu]Lu-PSMA-617 is a PSMA targeted radioligand therapy
.
In an early prospective study, [¹⁷⁷Lu]Lu-PSMA-617 can reduce the PSA of 64% of patients with mCRPC without treatment available by more than 50%
.
Based on this, the researchers conducted two clinical studies: Phase II TheraP study and Phase III VISION study
.
The TheraP Phase II TheraP study included patients with mCRPC who had progressed in docetaxel and AR inhibitor treatment, and were randomly assigned to receive [¹⁷⁷Lu]Lu-PSMA-617 or cabazitaxel treatment
.
The results show that compared with cabazitaxel (37%), [¹⁷⁷Lu]Lu-PSMA-617 can significantly improve the PSA response rate (66%) (P＜0.
0001) and delay the progress of PSA (HR=0.
63, P=0.
0028)
.
VISION Study VISION is an international, open-label, multi-center phase III clinical study designed to evaluate the efficacy and safety of [¹⁷⁷Lu]Lu-PSMA-617 combined with the best standard treatment selected by the investigator versus standard treatment for mCRPC sex
.
The study included 831 patients with PSMA-positive treated mCRPC
.
At a median follow-up of 20.
9 months, compared with the standard treatment group, the risk of imaging progression or death in the [¹⁷⁷Lu]Lu-PSMA-617 group was reduced by 60%.
The rPFS was 8.
7 months and 3.
4 months, respectively (HR=0.
40, P<0.
001)
.
[¹⁷⁷Lu]Lu-PSMA-617 will become the new standard for mCRPC treatment
.
At present, clinical research is evaluating the efficacy of this therapy in early disease and the best treatment sequence
.
The heterogeneity of PSMA expression in metastases in the same patient and in different patients is the key issue, and the selection of the best beneficiary patients, primary and secondary drug resistance are issues that need to be resolved
.
Immunotherapy autoimmune therapy and vaccine autoimmune cell therapy sipuleucel-T became the first vaccine therapy against solid malignant tumors approved by the U.
S.
Food and Drug Administration (FDA) in 2010.
Studies have shown that sipuleucel-T can bring 4.
1 Month survival advantage
.
However, this complex and expensive cellular immunotherapy has not been recognized by doctors
.
The results of the Phase III PROSTVAC-VF study of PSA-based targeted vaccines are not satisfactory
.
PD-1/PD-L1 inhibitors Immune checkpoint inhibitors, including PD-1/PD-L1 inhibitors and CTLA4 inhibitors, have changed the treatment pattern of many tumor types
.
Early studies have shown that the effective rate of PD-1/PD-L1 inhibitors is about 15%
.
Two phase III studies showed that the CTLA4 inhibitor ipilimumab compared with placebo showed a response in mCRPC patients treated with docetaxel, but did not show a survival advantage
.
Immune combination therapy shows high anti-tumor activity in unselected mCRPC patients
.
In a phase II study, pembrolizumab + enzalutamide can reduce the PSA of 18% (5/28) enzalutamide patients with advanced mCRPC patients by more than 50%
.
The CheckMate650 study showed that compared with patients with advanced chemotherapy (10%), ipilimumab + nivolumab had an objective response rate (ORR) of 25% in mCRPC patients without chemotherapy, while in patients with DDR gene defects In the ORR reached 50%
.
Research suggests that when the tumor burden and tumor heterogeneity are small, immunotherapy may be more effective in patients with DDR gene mutations and early-stage patients
.
Similarly, CDK12 mutations and mismatch repair defects can lead to greater genomic instability and more tumor neoantigens, which may improve the response to immunotherapy
.
In the next few years, there will be more problems and challenges regarding the immunotherapy of prostate cancer
.
Reference: Prostate cance.
https://doi.
org/10.
1016/ S0140-6736(21)00950-8 Contribution email: tougao@medlive.
cn
