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In the past ten years, the treatment of recurrent ovarian cancer has gradually developed into a personalized selection of treatment strategies for patients under the guidance of biomarkers.
All patients with recurrent ovarian cancer who respond to platinum-containing treatments can be given platinum-containing chemotherapy regimens.
Bevacizumab can increase the efficacy of cytotoxic chemotherapy regimens.
For patients with recurrent high-grade ovarian cancer, regardless of the BRCA mutation status, maintenance therapy with PARP inhibitors can bring survival benefits.
This article briefly summarizes the treatment options and related research progress for patients with recurrent ovarian cancer.
Chemotherapy drugs containing platinum and non-platinum chemotherapy can be used for recurrent ovarian cancer.
The choice of chemotherapy regimen should be based on the toxicity profile of the specific regimen and the patient's wishes.
Platinum is one of the most effective chemotherapy drugs for the treatment of epithelial ovarian cancer.
If the patient relapses more than 6 months after the end of the previous platinum-containing treatment, it is considered to be a “platinum-sensitive” population and may be considered for further platinum-containing chemotherapy.
Patients who relapse within 6 months are considered to be "platinum-resistant" people and are generally suitable for non-platinum-containing treatments.
The concept of re-introducing platinum-containing chemotherapy was put forward in the late 1980s, when there were few drugs for patients with recurrent ovarian cancer.
Blackledge et al.
discovered for the first time that a platinum-based combination treatment program is used for recurrent ovarian cancer with a high remission rate.
For the late-line treatment of recurrent ovarian cancer, there is currently no high-level evidence showing that combination therapy is superior to carboplatin monotherapy, but a meta-analysis shows that platinum-containing combination therapy can bring patients with progression-free survival (PFS) and overall Survival (OS) is a significant benefit.
Patients who are not suitable for further platinum-containing chemotherapy usually choose paclitaxel, polyethylene glycol liposomal doxorubicin (PLD) and topotecan.
An exploratory subgroup analysis of the OVA-301 study showed that compared with PLD alone (19.
5 months), PLD+trabectedin (22.
4 months) can improve the OS of patients with recurrent ovarian cancer at an interval of 6-12 months without platinum treatment.
The new drug lurbinectedin has not shown better efficacy.
A phase III clinical study showed that compared with standard chemotherapy, lurbinectedin did not improve PFS in patients with platinum-free treatment intervals of less than 6 months.
The median PFS of lurbinectedin and standard chemotherapy groups were 3.
5 months and 3.
6 months, respectively.
Anti-angiogenesis drugs, chemotherapeutics, when used in combination with bevacizumab, can enhance the response of patients with recurrent ovarian cancer to treatment.
A number of studies have shown that anti-angiogenic drugs + chemotherapy sequential chemotherapy maintenance treatment can improve the patient's objective response rate (ORR) and PFS.
Currently, bevacizumab is the only anti-angiogenic drug approved for the treatment of ovarian cancer.
The recent AGO-OVAR 2.
21 study showed that carboplatin (AUG5) + PLD (30 mg/m2 q4w) + bevacizumab (10 mg/kg q2w) (CD-bev) treatment for the first relapse after platinum treatment Recurrent ovarian cancer (without platinum treatment interval> 6 months) is better than carboplatin (AUG4) + gemcitabine (1000mg/m2, d1, d8, q3w) + bevacizumab (15 mg/kg q3w) (CG- bev), the median PFS of the CD-bev group and CG-bev were 13.
3 months and 11.
7 months, respectively (HR=0.
807, P=0.
01).
The CD-bev regimen can also bring OS benefits to patients (HR= 0.
81, P=0.
03).
The MITO168 study explored whether patients who relapsed during or after treatment with first-line bevacizumab (a platinum-free treatment interval> 6 months), and then receive bevacizumab combined with platinum-containing treatment can have more survival benefits.
The results showed that in patients who had previously received bevacizumab treatment, receiving bevacizumab plus chemotherapy could prolong PFS by 3 months (HR=0.
51, P<0.
01). PARP inhibitor PARP is a key enzyme involved in DNA single-strand break repair.
Blocking PARP can lead to the accumulation of DNA double-strand breaks (repaired by homologous recombination).
In the case of homologous recombination repair defects (HRD), by producing unrepaired double-stranded DNA, PARP inhibitors can cause synthetic lethality.
Tumor cells die.
Homologous recombination repair defects are common in ovarian cancer, especially in patients with high-grade serous ovarian cancer (HGSOC).
Therefore, PARP inhibitors can benefit most patients with ovarian cancer.
PARP inhibitor maintenance therapy Currently, the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have approved three PARP inhibitors that can be used for ovarian cancer: olaparib, niraparib and rucaparib.
PARP inhibitors are mainly used for maintenance treatment of patients with ovarian cancer after responding to platinum-containing chemotherapy.
Regardless of BRCA mutations, these three PARP inhibitors are effective when used for maintenance treatment of high-grade ovarian cancer.
Based on the SOLO-1 study, olaparib has been used clinically for the first-line maintenance treatment of patients with BRCA mutations.
Based on the PRIMA study, niraparib was approved by the FDA for the first-line maintenance treatment of advanced epithelial ovarian cancer without progression after platinum-containing treatment.
Based on the ARIEL3 study, rucaparib has also been approved by the FDA for the maintenance treatment of patients with recurrent epithelial ovarian cancer, fallopian tube cancer and primary peritoneal cancer (regardless of BRCA mutation).
PARP inhibitor maintenance therapy can bring the greatest PFS benefit to patients with BRCA mutations, followed by patients with HRD-positive tumors.
The SOLO-2 study showed that maintenance treatment with olaparib can prolong the OS of platinum-sensitive patients with recurrent ovarian cancer by 12.
9 months.
Importantly, 22% of patients continue to use olaparib and continue to benefit more than 5 years.
At present, it is not clear whether olaparib re-challenge can bring more benefits to patients.
The OReO study is an ongoing study to explore the effectiveness of olaparib re-challenge. PARP inhibitors used in the back-line treatment Rucaparib single agent has been approved by the EMA for the treatment of patients with recurrent ovarian cancer with BRCA mutations who have received at least two lines of platinum-containing therapy and cannot receive platinum-containing therapy.
The ARIEL2 study showed that rucaparib used in patients with BRCA1/2 mutations who had received at least two lines of chemotherapy had an ORR of 54% and a duration of remission (DOR) of 9.
2 months.
Based on related phase II studies, olaparib and niraparib as a single agent have also been approved by the FDA for the treatment of recurrent ovarian cancer.
In the SOLO-3 study, patients with BRCA-mutated recurrent ovarian cancer who had progressed at least two lines of chemotherapy and had no platinum treatment interval> 6 months were randomized to receive olaparib or non-platinum chemotherapy.
The overall response rate (ORR) of the olaparib group and the chemotherapy group were 72.
2% and 51.
4%, respectively (OR=2.
53, P=0.
002).
The combination of PARP inhibitors and anti-angiogenic drugs olaparib + bevacizumab has been approved by the FDA for the treatment of advanced epithelial ovarian cancer with HRD positive or BRCA mutation.
By down-regulating the homologous recombination repair signaling pathway, hypoxia may increase the sensitivity of tumor cells to PARP inhibitors.
Therefore, anti-angiogenic drugs may increase the anti-tumor activity of PARP inhibitors.
Cediranib disrupts homologous recombination repair by inducing hypoxia, thereby inhibiting the expression of homologous recombination repair genes, and plays a direct role in DNA repair by inhibiting platelet-derived growth factor receptors.
In a phase II study, olaparib+cediranib has shown certain anti-tumor activity.
A retrospective study showed that olaparib+cediranib has the most significant effect in patients with ovarian cancer without BRCA mutations.
In the AVANOVA2 study, the efficacy advantage of niraparib + bevacizumab compared to niraparib alone was also observed.
Currently, the Phase III ICON9 study is exploring the efficacy of olaparib+cediranib for maintenance treatment of platinum-responsive recurrent ovarian cancer.
Immunotherapy Current research shows that immune checkpoint inhibitors are not effective in recurrent ovarian cancer.
The JAVELIN Ovarian 200 study showed that PLD+avelumab did not show any benefit compared with PLD alone.
Similarly, the JAVELIN OVARIAN 100 study showed that avelumab + carboplatin + paclitaxel sequential avelumab maintenance treatment compared with chemotherapy alone did not show a survival benefit.
The anti-tumor activity of PD-1 inhibitor + CTLA4 inhibitor is stronger, but the toxicity is also increased.
Another treatment strategy is PARP inhibitor + immune checkpoint inhibitor, PARP inhibitor can activate the STING signaling pathway and increase T cell infiltration.
The TOPACIO and MEDIOLA research shows that the joint scheme is feasible and the response rate is high.
TOPACIO subgroup analysis showed that niraparib + pembrolizumab is particularly effective in patients without BRCA mutations or HRD negative.
Researchers are also exploring the efficacy of immune checkpoint inhibitors + anti-angiogenic drugs.
A phase I study showed that duvalizumab + cediranib can achieve partial remission (PR) in patients with recurrent ovarian cancer after multi-line treatment.
However, no immunotherapy drugs have been approved for recurrent ovarian cancer.
Figure: Treatment strategies for recurrent ovarian cancer References: Baert T, Ferrero A, Sehouli J, O´Donnell DM, González-Martín A, Joly F, van der Velden J, Blecharz P, Tan DSP, Querleu D, Colombo N, du Bois A, Ledermann JA, The Systemic Treatment of Recurrent Ovarian Cancer revisited, Annals of Oncology (2021), doi: https:// doi.
org/10.
1016/j.
annonc.
2021.
02.
015.
All patients with recurrent ovarian cancer who respond to platinum-containing treatments can be given platinum-containing chemotherapy regimens.
Bevacizumab can increase the efficacy of cytotoxic chemotherapy regimens.
For patients with recurrent high-grade ovarian cancer, regardless of the BRCA mutation status, maintenance therapy with PARP inhibitors can bring survival benefits.
This article briefly summarizes the treatment options and related research progress for patients with recurrent ovarian cancer.
Chemotherapy drugs containing platinum and non-platinum chemotherapy can be used for recurrent ovarian cancer.
The choice of chemotherapy regimen should be based on the toxicity profile of the specific regimen and the patient's wishes.
Platinum is one of the most effective chemotherapy drugs for the treatment of epithelial ovarian cancer.
If the patient relapses more than 6 months after the end of the previous platinum-containing treatment, it is considered to be a “platinum-sensitive” population and may be considered for further platinum-containing chemotherapy.
Patients who relapse within 6 months are considered to be "platinum-resistant" people and are generally suitable for non-platinum-containing treatments.
The concept of re-introducing platinum-containing chemotherapy was put forward in the late 1980s, when there were few drugs for patients with recurrent ovarian cancer.
Blackledge et al.
discovered for the first time that a platinum-based combination treatment program is used for recurrent ovarian cancer with a high remission rate.
For the late-line treatment of recurrent ovarian cancer, there is currently no high-level evidence showing that combination therapy is superior to carboplatin monotherapy, but a meta-analysis shows that platinum-containing combination therapy can bring patients with progression-free survival (PFS) and overall Survival (OS) is a significant benefit.
Patients who are not suitable for further platinum-containing chemotherapy usually choose paclitaxel, polyethylene glycol liposomal doxorubicin (PLD) and topotecan.
An exploratory subgroup analysis of the OVA-301 study showed that compared with PLD alone (19.
5 months), PLD+trabectedin (22.
4 months) can improve the OS of patients with recurrent ovarian cancer at an interval of 6-12 months without platinum treatment.
The new drug lurbinectedin has not shown better efficacy.
A phase III clinical study showed that compared with standard chemotherapy, lurbinectedin did not improve PFS in patients with platinum-free treatment intervals of less than 6 months.
The median PFS of lurbinectedin and standard chemotherapy groups were 3.
5 months and 3.
6 months, respectively.
Anti-angiogenesis drugs, chemotherapeutics, when used in combination with bevacizumab, can enhance the response of patients with recurrent ovarian cancer to treatment.
A number of studies have shown that anti-angiogenic drugs + chemotherapy sequential chemotherapy maintenance treatment can improve the patient's objective response rate (ORR) and PFS.
Currently, bevacizumab is the only anti-angiogenic drug approved for the treatment of ovarian cancer.
The recent AGO-OVAR 2.
21 study showed that carboplatin (AUG5) + PLD (30 mg/m2 q4w) + bevacizumab (10 mg/kg q2w) (CD-bev) treatment for the first relapse after platinum treatment Recurrent ovarian cancer (without platinum treatment interval> 6 months) is better than carboplatin (AUG4) + gemcitabine (1000mg/m2, d1, d8, q3w) + bevacizumab (15 mg/kg q3w) (CG- bev), the median PFS of the CD-bev group and CG-bev were 13.
3 months and 11.
7 months, respectively (HR=0.
807, P=0.
01).
The CD-bev regimen can also bring OS benefits to patients (HR= 0.
81, P=0.
03).
The MITO168 study explored whether patients who relapsed during or after treatment with first-line bevacizumab (a platinum-free treatment interval> 6 months), and then receive bevacizumab combined with platinum-containing treatment can have more survival benefits.
The results showed that in patients who had previously received bevacizumab treatment, receiving bevacizumab plus chemotherapy could prolong PFS by 3 months (HR=0.
51, P<0.
01). PARP inhibitor PARP is a key enzyme involved in DNA single-strand break repair.
Blocking PARP can lead to the accumulation of DNA double-strand breaks (repaired by homologous recombination).
In the case of homologous recombination repair defects (HRD), by producing unrepaired double-stranded DNA, PARP inhibitors can cause synthetic lethality.
Tumor cells die.
Homologous recombination repair defects are common in ovarian cancer, especially in patients with high-grade serous ovarian cancer (HGSOC).
Therefore, PARP inhibitors can benefit most patients with ovarian cancer.
PARP inhibitor maintenance therapy Currently, the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have approved three PARP inhibitors that can be used for ovarian cancer: olaparib, niraparib and rucaparib.
PARP inhibitors are mainly used for maintenance treatment of patients with ovarian cancer after responding to platinum-containing chemotherapy.
Regardless of BRCA mutations, these three PARP inhibitors are effective when used for maintenance treatment of high-grade ovarian cancer.
Based on the SOLO-1 study, olaparib has been used clinically for the first-line maintenance treatment of patients with BRCA mutations.
Based on the PRIMA study, niraparib was approved by the FDA for the first-line maintenance treatment of advanced epithelial ovarian cancer without progression after platinum-containing treatment.
Based on the ARIEL3 study, rucaparib has also been approved by the FDA for the maintenance treatment of patients with recurrent epithelial ovarian cancer, fallopian tube cancer and primary peritoneal cancer (regardless of BRCA mutation).
PARP inhibitor maintenance therapy can bring the greatest PFS benefit to patients with BRCA mutations, followed by patients with HRD-positive tumors.
The SOLO-2 study showed that maintenance treatment with olaparib can prolong the OS of platinum-sensitive patients with recurrent ovarian cancer by 12.
9 months.
Importantly, 22% of patients continue to use olaparib and continue to benefit more than 5 years.
At present, it is not clear whether olaparib re-challenge can bring more benefits to patients.
The OReO study is an ongoing study to explore the effectiveness of olaparib re-challenge. PARP inhibitors used in the back-line treatment Rucaparib single agent has been approved by the EMA for the treatment of patients with recurrent ovarian cancer with BRCA mutations who have received at least two lines of platinum-containing therapy and cannot receive platinum-containing therapy.
The ARIEL2 study showed that rucaparib used in patients with BRCA1/2 mutations who had received at least two lines of chemotherapy had an ORR of 54% and a duration of remission (DOR) of 9.
2 months.
Based on related phase II studies, olaparib and niraparib as a single agent have also been approved by the FDA for the treatment of recurrent ovarian cancer.
In the SOLO-3 study, patients with BRCA-mutated recurrent ovarian cancer who had progressed at least two lines of chemotherapy and had no platinum treatment interval> 6 months were randomized to receive olaparib or non-platinum chemotherapy.
The overall response rate (ORR) of the olaparib group and the chemotherapy group were 72.
2% and 51.
4%, respectively (OR=2.
53, P=0.
002).
The combination of PARP inhibitors and anti-angiogenic drugs olaparib + bevacizumab has been approved by the FDA for the treatment of advanced epithelial ovarian cancer with HRD positive or BRCA mutation.
By down-regulating the homologous recombination repair signaling pathway, hypoxia may increase the sensitivity of tumor cells to PARP inhibitors.
Therefore, anti-angiogenic drugs may increase the anti-tumor activity of PARP inhibitors.
Cediranib disrupts homologous recombination repair by inducing hypoxia, thereby inhibiting the expression of homologous recombination repair genes, and plays a direct role in DNA repair by inhibiting platelet-derived growth factor receptors.
In a phase II study, olaparib+cediranib has shown certain anti-tumor activity.
A retrospective study showed that olaparib+cediranib has the most significant effect in patients with ovarian cancer without BRCA mutations.
In the AVANOVA2 study, the efficacy advantage of niraparib + bevacizumab compared to niraparib alone was also observed.
Currently, the Phase III ICON9 study is exploring the efficacy of olaparib+cediranib for maintenance treatment of platinum-responsive recurrent ovarian cancer.
Immunotherapy Current research shows that immune checkpoint inhibitors are not effective in recurrent ovarian cancer.
The JAVELIN Ovarian 200 study showed that PLD+avelumab did not show any benefit compared with PLD alone.
Similarly, the JAVELIN OVARIAN 100 study showed that avelumab + carboplatin + paclitaxel sequential avelumab maintenance treatment compared with chemotherapy alone did not show a survival benefit.
The anti-tumor activity of PD-1 inhibitor + CTLA4 inhibitor is stronger, but the toxicity is also increased.
Another treatment strategy is PARP inhibitor + immune checkpoint inhibitor, PARP inhibitor can activate the STING signaling pathway and increase T cell infiltration.
The TOPACIO and MEDIOLA research shows that the joint scheme is feasible and the response rate is high.
TOPACIO subgroup analysis showed that niraparib + pembrolizumab is particularly effective in patients without BRCA mutations or HRD negative.
Researchers are also exploring the efficacy of immune checkpoint inhibitors + anti-angiogenic drugs.
A phase I study showed that duvalizumab + cediranib can achieve partial remission (PR) in patients with recurrent ovarian cancer after multi-line treatment.
However, no immunotherapy drugs have been approved for recurrent ovarian cancer.
Figure: Treatment strategies for recurrent ovarian cancer References: Baert T, Ferrero A, Sehouli J, O´Donnell DM, González-Martín A, Joly F, van der Velden J, Blecharz P, Tan DSP, Querleu D, Colombo N, du Bois A, Ledermann JA, The Systemic Treatment of Recurrent Ovarian Cancer revisited, Annals of Oncology (2021), doi: https:// doi.
org/10.
1016/j.
annonc.
2021.
02.
015.
