Tag: Ovarian Cancer

ASCO Guideline: PARP Inhibitors in the Management of Ovarian Cancer

RR

SUMMARY: It is estimated that in the United States, approximately 21,750 women will be diagnosed with ovarian cancer in 2020 and 13,940 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Approximately 85% of all ovarian cancers are epithelial in origin, and approximately 70% of all epithelial ovarian cancers are High-Grade Serous adenocarcinomas. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5 year Overall Survival rate of about 20-30%.

Germline mutations in BRCA1 and BRCA2 genes account for about 17% of ovarian cancers (mutations present in all individual cells), whereas somatic mutations are found in an additional 7% (mutations present exclusively in tumor cells). BRCA1 and BRCA2 are tumor suppressor genes and they recognize and repair double strand DNA breaks via Homologous Recombination (HR) pathway. Homologous Recombination is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. The PARP (Poly ADP Ribose Polymerase) family of enzymes include PARP1 and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. PARP inhibitors traps PARP onto DNA at sites of single-strand breaks, thereby preventing their repair and generate double-strand breaks. These breaks cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death.

This systematic review-based guideline was developed by a multidisciplinary ASCO Expert Panel to provide clinicians and other health care practitioners, recommendations on the use of PARP inhibitors for management of Epithelial Ovarian, tubal, or Primary Peritoneal Cancer (herein referred to as EOC), based on best available evidence. The recommendations were developed following a systematic review of the literature which identified 17 randomized controlled trials published from 2011 through 2020, that included patients who have not previously received a PARP inhibitor.

ASCO Guideline Questions:
1) Should PARP inhibitor therapy for EOC be repeated over the course of treatment?
2) In which patients with newly diagnosed EOC are PARP inhibitors recommended?
a. What are the histologic types of EOC for which PARP inhibitors are recommended?
b. What are the biomarker subsets for which PARP inhibitors are recommended?
3) Is PARP inhibitor monotherapy recommended for recurrent EOC? If so,
a. In which settings (eg, second-line maintenance or treatment of recurrent disease)?
b. At what dose and duration?
4) Are there settings where PARP inhibitors in combination with chemotherapy or other targeted therapy are recommended?
5) How should clinicians manage the specific toxicities of the various PARP inhibitors?

Recommendations: The following recommendations pertain only to patients with EOC who have not previously received a PARP inhibitor.

Repeating PARP Inhibitor

Recommendation 1.0: Repeating therapy with a PARP inhibitor in the treatment of EOC is not recommended at this time. Consideration should be made as to the best time in the life cycle of an individual patient’s EOC in which to use PARP inhibitor. Clinical trial participation is encouraged.

Newly Diagnosed Ovarian Cancer

Recommendation 2.0: PARP inhibitors are not recommended for use in initial treatment of early stage (Stage I-II) EOC because there is insufficient evidence to support use in this population.

Recommendation 2.1: Women with newly diagnosed Stage III-IV EOC that is in Complete or Partial Response to first-line platinum-based chemotherapy should be offered PARP inhibitor maintenance therapy with Olaparib (for those with germline or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes) or Niraparib (all women) in High-Grade Serous or endometrioid ovarian cancer.
PARP inhibitor maintenance therapy should consist of Olaparib (300 mg orally every 12 hours for 2 years) or Niraparib (200-300 mg orally daily for 3 years). Longer duration could be considered in selected individuals.

Recommendation 2.2: The addition of Olaparib to Bevacizumab maintenance may be offered to patients who have Stage III-IV High-Grade Serous or endometrioid ovarian cancer and germline or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes and/or genomic instability, as determined by Myriad myChoice CDx, and who have had a Partial or Complete Response to chemotherapy plus Bevacizumab combination.

Recommendation 2.3: Inclusion of the PARP inhibitor Veliparib with combination chemotherapy followed by Veliparib maintenance therapy cannot be recommended at this time. There are no data that this approach is superior, equal, or less toxic than a switch maintenance.
Note: Veliparib is not commercially available at the time of these recommendations.

Recurrent Ovarian Cancer: Second-Line or Greater Maintenance and Treatment

Recommendation 3.0: PARP inhibitor monotherapy maintenance (second-line or more) may be offered to patients with EOC who have not already received a PARP inhibitor and who have responded to platinum-based therapy regardless of BRCA mutation status. Treatment is continued until disease progression or toxicity despite dose reductions and best supportive care. Options include Olaparib 300 mg every 12 hours, Rucaparib 600 mg every 12 hours or Niraparib 200-300 mg once daily.

Recommendation 3.1: Treatment with a PARP inhibitor should be offered to patients with recurrent EOC who have not already received a PARP inhibitor and have a germline or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes. Options include Olaparib 300 mg every 12 hours, Rucaparib 600 mg every 12 hours or Niraparib 200-300 mg once daily.

Recommendation 3.2: Treatment with a PARP inhibitor monotherapy should be offered to patients with recurrent EOC who have not already received a PARP inhibitor, and whose tumor demonstrates genomic instability, as determined by Myriad myChoice CDx, and has not recurred within 6 months of platinum-based therapy

Recommendation 3.3: PARP inhibitors are not recommended for treatment of BRCA wild-type or platinum-resistant recurrent EOC

PARP Inhibitors in Combination

Recommendation 4.0: PARP inhibitors are not recommended for use in combination with chemotherapy, other targeted agents, or immune-oncology agents in the recurrent setting outside the context of a clinical trial. Clinical trial participation is encouraged.

Management of Adverse Events

Recommendation 5.0 Anemia: Patients requiring a blood transfusion for symptom relief and/or hemoglobin level less than 8 g/dL should be monitored. PARP inhibitor dose should be reduced with evidence of repeated anemia to avoid multiple transfusions. Patients with progressive anemia may be offered growth factor per ASCO guidelines and physician and patient comfort.

Recommendation 5.1 Neutropenia: Growth factor is not indicated for use in patients receiving daily PARP inhibitor. Neutropenia (grade 4 lasting at least 5-7 days or associated with fever) should result in dose hold until recovery of infection and granulocyte count, followed by dose reduction. Growth factor support may be used in this setting to support patient safety during the drug hold period.

Recommendation 5.2 Platelets: Thrombocytopenia is most common with Niraparib. Niraparib dosing guidelines should be used to lower starting dose (200 mg) based on weight and platelet count. Discontinue PARP inhibitor for persistent thrombocytopenia or significant bleeding despite dose reduction.

Recommendation 5.3 Persistent cytopenia: Evaluation for treatment-related Myelodysplastic Syndrome/Acute Myeloid Leukemia should be initiated in patients with persistent cytopenia that occurs despite drug hold.

Recommendation 5.4 Nausea: Many patients will have tachyphylaxis of nausea symptoms over the first cycle of therapy. Persistent nausea requiring daily antiemetic intervention, causing a reduction in performance status, and/or resulting in more than 5% weight loss, should result in dose reduction.

PARP Inhibitors in the Management of Ovarian Cancer: ASCO Guideline. Tew WP, Lacchetti C, Ellis A, et al. J Clin Oncol 2020;38:3468-3493.

ASCO Guideline: PARP Inhibitors in the Management of Ovarian Cancer

RR

SUMMARY: It is estimated that in the United States, approximately 21,750 women will be diagnosed with ovarian cancer in 2020 and 13,940 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Approximately 85% of all ovarian cancers are epithelial in origin, and approximately 70% of all epithelial ovarian cancers are High-Grade Serous adenocarcinomas. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5 year Overall Survival rate of about 20-30%.

Germline mutations in BRCA1 and BRCA2 genes account for about 17% of ovarian cancers (mutations present in all individual cells), whereas somatic mutations are found in an additional 7% (mutations present exclusively in tumor cells). BRCA1 and BRCA2 are tumor suppressor genes and they recognize and repair double strand DNA breaks via Homologous Recombination (HR) pathway. Homologous Recombination is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. The PARP (Poly ADP Ribose Polymerase) family of enzymes include PARP1 and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. PARP inhibitors traps PARP onto DNA at sites of single-strand breaks, thereby preventing their repair and generate double-strand breaks. These breaks cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death.

This systematic review-based guideline was developed by a multidisciplinary ASCO Expert Panel to provide clinicians and other health care practitioners, recommendations on the use of PARP inhibitors for management of Epithelial Ovarian, tubal, or Primary Peritoneal Cancer (herein referred to as EOC), based on best available evidence. The recommendations were developed following a systematic review of the literature which identified 17 randomized controlled trials published from 2011 through 2020, that included patients who have not previously received a PARP inhibitor.

ASCO Guideline Questions:
1) Should PARP inhibitor therapy for EOC be repeated over the course of treatment?
2) In which patients with newly diagnosed EOC are PARP inhibitors recommended?
a. What are the histologic types of EOC for which PARP inhibitors are recommended?
b. What are the biomarker subsets for which PARP inhibitors are recommended?
3) Is PARP inhibitor monotherapy recommended for recurrent EOC? If so,
a. In which settings (eg, second-line maintenance or treatment of recurrent disease)?
b. At what dose and duration?
4) Are there settings where PARP inhibitors in combination with chemotherapy or other targeted therapy are recommended?
5) How should clinicians manage the specific toxicities of the various PARP inhibitors?

Recommendations: The following recommendations pertain only to patients with EOC who have not previously received a PARP inhibitor.

Repeating PARP Inhibitor

Recommendation 1.0: Repeating therapy with a PARP inhibitor in the treatment of EOC is not recommended at this time. Consideration should be made as to the best time in the life cycle of an individual patient’s EOC in which to use PARP inhibitor. Clinical trial participation is encouraged.

Newly Diagnosed Ovarian Cancer

Recommendation 2.0: PARP inhibitors are not recommended for use in initial treatment of early stage (Stage I-II) EOC because there is insufficient evidence to support use in this population.

Recommendation 2.1: Women with newly diagnosed Stage III-IV EOC that is in Complete or Partial Response to first-line platinum-based chemotherapy should be offered PARP inhibitor maintenance therapy with Olaparib (for those with germline or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes) or Niraparib (all women) in High-Grade Serous or endometrioid ovarian cancer.
PARP inhibitor maintenance therapy should consist of Olaparib (300 mg orally every 12 hours for 2 years) or Niraparib (200-300 mg orally daily for 3 years). Longer duration could be considered in selected individuals.

Recommendation 2.2: The addition of Olaparib to Bevacizumab maintenance may be offered to patients who have Stage III-IV High-Grade Serous or endometrioid ovarian cancer and germline or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes and/or genomic instability, as determined by Myriad myChoice CDx, and who have had a Partial or Complete Response to chemotherapy plus Bevacizumab combination.

Recommendation 2.3: Inclusion of the PARP inhibitor Veliparib with combination chemotherapy followed by Veliparib maintenance therapy cannot be recommended at this time. There are no data that this approach is superior, equal, or less toxic than a switch maintenance.
Note: Veliparib is not commercially available at the time of these recommendations.

Recurrent Ovarian Cancer: Second-Line or Greater Maintenance and Treatment

Recommendation 3.0: PARP inhibitor monotherapy maintenance (second-line or more) may be offered to patients with EOC who have not already received a PARP inhibitor and who have responded to platinum-based therapy regardless of BRCA mutation status. Treatment is continued until disease progression or toxicity despite dose reductions and best supportive care. Options include Olaparib 300 mg every 12 hours, Rucaparib 600 mg every 12 hours or Niraparib 200-300 mg once daily.

Recommendation 3.1: Treatment with a PARP inhibitor should be offered to patients with recurrent EOC who have not already received a PARP inhibitor and have a germline or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes. Options include Olaparib 300 mg every 12 hours, Rucaparib 600 mg every 12 hours or Niraparib 200-300 mg once daily.

Recommendation 3.2: Treatment with a PARP inhibitor monotherapy should be offered to patients with recurrent EOC who have not already received a PARP inhibitor, and whose tumor demonstrates genomic instability, as determined by Myriad myChoice CDx, and has not recurred within 6 months of platinum-based therapy

Recommendation 3.3: PARP inhibitors are not recommended for treatment of BRCA wild-type or platinum-resistant recurrent EOC

PARP Inhibitors in Combination

Recommendation 4.0: PARP inhibitors are not recommended for use in combination with chemotherapy, other targeted agents, or immune-oncology agents in the recurrent setting outside the context of a clinical trial. Clinical trial participation is encouraged.

Management of Adverse Events

Recommendation 5.0 Anemia: Patients requiring a blood transfusion for symptom relief and/or hemoglobin level less than 8 g/dL should be monitored. PARP inhibitor dose should be reduced with evidence of repeated anemia to avoid multiple transfusions. Patients with progressive anemia may be offered growth factor per ASCO guidelines and physician and patient comfort.

Recommendation 5.1 Neutropenia: Growth factor is not indicated for use in patients receiving daily PARP inhibitor. Neutropenia (grade 4 lasting at least 5-7 days or associated with fever) should result in dose hold until recovery of infection and granulocyte count, followed by dose reduction. Growth factor support may be used in this setting to support patient safety during the drug hold period.

Recommendation 5.2 Platelets: Thrombocytopenia is most common with Niraparib. Niraparib dosing guidelines should be used to lower starting dose (200 mg) based on weight and platelet count. Discontinue PARP inhibitor for persistent thrombocytopenia or significant bleeding despite dose reduction.

Recommendation 5.3 Persistent cytopenia: Evaluation for treatment-related Myelodysplastic Syndrome/Acute Myeloid Leukemia should be initiated in patients with persistent cytopenia that occurs despite drug hold.

Recommendation 5.4 Nausea: Many patients will have tachyphylaxis of nausea symptoms over the first cycle of therapy. Persistent nausea requiring daily antiemetic intervention, causing a reduction in performance status, and/or resulting in more than 5% weight loss, should result in dose reduction.

PARP Inhibitors in the Management of Ovarian Cancer: ASCO Guideline. Tew WP, Lacchetti C, Ellis A, et al. J Clin Oncol 2020;38:3468-3493.

LYNPARZA® Superior to Chemotherapy in BRCA Mutated Platinum Sensitive Advanced Ovarian Cancer

RR

SUMMARY: It is estimated that in the United States, approximately 21,750 women will be diagnosed with ovarian cancer in 2020 and 13,940 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5 year Overall Survival rate of about 20-30%.

DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 are tumor suppressor genes and they recognize and repair double strand DNA breaks via Homologous Recombination (HR) pathway. Homologous Recombination is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity.

Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway. At least 15 genes are involved in the Homologous Recombination Repair (HRR) pathway including BRCA1 and BRCA2 genes. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13, and they regulate cell growth and prevent abnormal cell division and development of malignancy. Mutations in BRCA1 and BRCA2 account for about 20-25% of hereditary breast cancers 15% of ovarian cancers, in addition to other cancers such as Colon and Prostate. BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic).MOA-of-LYNPARZA

The PARP (Poly ADP Ribose Polymerase) family of enzymes include PARP1 and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. LYNPARZA® is a PARP inhibitor that traps PARP onto DNA at sites of single-strand breaks, preventing their repair and generating double-strand breaks that cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, leading to cumulative DNA damage and tumor cell death.

Previously published studies demonstrated a durable response to LYNPARZA® administered as treatment (rather than maintenance), in women with heavily pretreated relapsed ovarian cancer and a germline BRCA mutation, with an Objective Response Rate (ORR) of 42% in the subgroup of patients with platinum-sensitive disease, who had received at least 3 prior chemotherapy regimens. Single-agent nonplatinum chemotherapy is often used in heavily pretreated women with relapsed ovarian cancer. The authors conducted this study to evaluate whether LYNPARZA® monotherapy improves outcomes, compared with physician’s choice single-agent nonplatinum chemotherapy, in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA mutation, who have received at least 2 prior lines of platinum-based chemotherapy.

SOLO3 is an International, randomized, controlled, open label Phase III trial, that compared LYNPARZA® with non-platinum chemotherapy, in patients with platinum sensitive, relapsed ovarian cancer, and a germline BRCA1/2 mutation. This study included 266 patients who were randomly assigned 2:1 to LYNPARZA® 300 mg orally given twice a day (N=178) or physician’s choice of single-agent chemotherapy (N=88), which could be either Pegylated Liposomal Doxorubicin (PLD) 50 mg/m2 IV on day 1 every 4 weeks, Paclitaxel 80 mg/m2 IV on days 1, 8, 15, and 22 every 4 weeks, Gemcitabine 1000 mg/m2 IV on days 1, 8, and 15 every 4 weeks or Topotecan 4 mg/m2 IV on days 1, 8, and 15 every 4 weeks. Eligible patients had relapsed high-grade serous or high-grade endometrioid ovarian cancer, primary peritoneal cancer, and/or fallopian tube cancer, with at least 1 measurable and/or nonmeasurable lesion, that could be accurately assessed at baseline, by CT or MRI, and was suitable for repeated evaluation. Patients had received at least 2 prior lines of platinum-based chemotherapy for ovarian cancer and were platinum sensitive (progression more than 6 months after the end of the last platinum-based regimen). Treatment groups were well balanced and the median patient age was 59 years. The Primary end point was Objective Response Rate (ORR) in those with measurable disease, as assessed by Blinded Independent Central Review (BICR). The key Secondary end point was Progression Free Survival (PFS) assessed by BICR in the intent-to-treat population.

It was noted that ORR was significantly higher in the LYNPARZA® group than in the chemotherapy group (72.2% versus 51.4%; Odds Ratio=2.53; P=0.002), suggesting a 2.53 times higher likelihood of responding to LYNPARZA®, than to chemotherapy. In the subgroup who had received 2 prior lines of treatment, the ORR with LYNPARZA® was 84.6% and 61.5% with chemotherapy (Odds Ratio= 3.44), suggesting a 3.44 times higher likelihood of responding to LYNPARZA®, than to chemotherapy. The median time to onset of response was 2 months with LYNPARZA®, versus 3.5 months with chemotherapy, and the median Duration of Response was 9.4 months and 10.2 months respectively. The PFS also significantly favored LYNPARZA® versus chemotherapy (13.4 versus 9.2 months; HR=0.62; P=0.013). Adverse events were consistent with the established safety profiles of LYNPARZA® and chemotherapy. The most common Grade 3 or more adverse events were anemia in the LYNPARZA® group and PPE (Palmar-Plantar Erythrodysesthesia) and neutropenia in the chemotherapy group.

It was concluded that treatment with LYNPARZA® resulted in statistically significant and clinically relevant improvements in Objective Response Rate and Progression Free Survival, compared with nonplatinum chemotherapy, in patients with germline BRCA-mutated, platinum-sensitive, relapsed ovarian cancer, who had received at least 2 prior lines of platinum-based chemotherapy. This chemotherapy-free treatment option will be welcome news for patients with germline BRCA-mutated advanced ovarian cancer.

Olaparib Versus Nonplatinum Chemotherapy in Patients With Platinum-Sensitive Relapsed Ovarian Cancer and a Germline BRCA1/2 Mutation (SOLO3): A Randomized Phase III Trial. Penson RT, Valencia RV, Cibula D, et al. J Clin Oncol. 2020;38:1164-1174.

LYNPARZA® (Olaparib)

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The FDA on May 8, 2020, expanded the indication of LYNPARZA® to include its combination with Bevacizumab for first-line maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in Complete or Partial Response to first-line Platinum-based chemotherapy, and whose cancer is associated with Homologous Recombination Deficiency (HRD) positive status, defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability. LYNPARZA® is a product of AstraZeneca Pharmaceuticals, LP.

FDA Approves ZEJULA® for Newly Diagnosed Patients with Advanced Ovarian Cancer

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SUMMARY: The FDA on April 29, 2020 approved ZEJULA® (Niraparib) for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to first-line platinum-based chemotherapy. It is estimated that in the United States, approximately 21,750 women will be diagnosed with ovarian cancer in 2020 and 13,940 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5 year Overall Survival rate of about 20-30%.MOA-of-PARP-Inhibitors

DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. The PARP (Poly ADP Ribose Polymerase) family of enzymes, include PARP1 and PARP2. In the context of DNA repair, BRCA1 and BRCA2 genes recognize and repair double strand DNA breaks via Homologous Recombination (HR) pathway. Homologous Recombination is a type of genetic recombination, and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway. At least 15 genes are involved in the Homologous Recombination Repair (HRR) pathway including BRCA1 and BRCA2 genes. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. BRCA1 and BRCA2 are tumor suppressor genes and functional BRCA proteins repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. Mutations in BRCA1 and BRCA2 account for about 20-25% of hereditary breast cancers and about 5-10% of all breast cancers. They also account for 15% of ovarian cancers, in addition to other cancers such as Colon and Prostate. BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic). Somatic mutations account for a significant portion of overall BRCA1 and BRCA2 aberrations. Loss of BRCA function due to frequent somatic aberrations likely deregulates HR pathway, and other pathways then come in to play, which are less precise and error prone, resulting in the accumulation of additional mutations and chromosomal instability in the cell, with subsequent malignant transformation. HRD therefore indicates an important loss of DNA repair function. Hereditary Epithelial Ovarian Cancer was thought to be caused almost exclusively by mutations in BRCA1 and BRCA2. It however is now well known that about 50% of the high grade serous ovarian cancers have aberrations in HR repair pathway. Deregulated HR pathway increases sensitivity to platinum drugs. Majority of the women with germline BRCA mutations (gBRCA) are positive for HR deficiency.

PARP is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair. In the presence of a PARP inhibitor, there is synthetic lethality because loss of both genes, leading to cell death. Thus PARP inhibitors are only harmful to cancer cells. ZEJULA® is a highly selective PARP 1/2 inhibitor, that causes cumulative DNA damage and cell death by inhibiting PARP. Previously published phase III study among patients with platinum-sensitive, recurrent ovarian cancer (NEJM 2016;375:2154-2164) concluded that Niraparib significantly prolonged Progression Free Survival (PFS) compared to placebo, and this benefit was achieved regardless of the presence or absence of germline BRCA mutations or HRD status.

PRIMA trial is a randomized, double-blind, placebo-controlled, international Phase III trial conducted to test the efficacy and safety of ZEJULA® maintenance therapy after a response to platinum-based chemotherapy, in patients with newly diagnosed advanced ovarian cancer at high risk for relapse. It should be noted that at the time PRIMA trial was designed, AVASTIN® (Bevacizumab) was not approved for first-line treatment in all participating countries. A total of 733 patients with newly diagnosed, high risk, advanced ovarian cancer were randomly assigned in a 2:1 ratio to receive ZEJULA® (N=487) or placebo (N=246) once daily in 28-day cycles for 36 months or until disease progression, after a response to platinum-based chemotherapy regimen. Patients received a dose of 200-300mg once daily, based on body weight and platelet count. Enrolled patients were at high risk for progressive disease with 23.1% having Stage III ovarian cancer with residual disease after primary debulking surgery, 66.7% had received neoadjuvant chemotherapy, 35% had Stage IV ovarian cancer, and 30.5% had a Partial Response to first-line platinum-based chemotherapy. Tumor samples were tested for HRD status and HRD was defined by either presence of tumor BRCA mutation or Genomic Instability Score (GIS) of 42 or more. Of the randomized patients, 50.9% had tumors with HRD, 30.4% had BRCA mutations and 20.5% were BRCA wild type. The treatment groups were well balanced. The Primary endpoint was Progression Free Survival (PFS) in patients who had tumors with HRD, and then in the overall population, as determined on hierarchical testing. Secondary end points included Overall Survival, time until the first subsequent therapy, PFS 2, defined as time from randomization to progression while the patient was receiving a subsequent anticancer therapy and Patient-Reported Outcomes. The median duration of follow-up at the time of the data cutoff was 13.8 months.

There was a statistically significant improvement in PFS for patients randomized to ZEJULA® compared with placebo in the HRD group, as well as the overall population. The median PFS in the HRD group was 21.9 months for patients receiving ZEJULA® compared with 10.4 months for those receiving placebo (HR=0.43; P<0.001). The median PFS in the overall population was 13.8 months for patients receiving ZEJULA® compared with 8.2 months for those receiving placebo (HR=0.62; P<0.001). At the 24-month interim analysis, the rate of Overall Survival was 84% in the ZEJULA® group and 77% in the placebo group (HR=0.70). The most common adverse reactions in patients receiving ZEJULA® were cytopenias, fatigue, AST/ALT elevation, hypertension, low grade nausea and decreased appetite.

It was concluded that among patients with newly diagnosed advanced ovarian cancer who had responded to platinum-based chemotherapy, ZEJULA® significantly prolonged Progression Free Survival, compared to those who received placebo, regardless of the presence or absence of Homologous Recombination Deficiency.
Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. González-Martín A, Pothuri B, Vergote I, et al. for the PRIMA/ENGOT-OV26/GOG-3012 Investigators. N Engl J Med 2019; 381:2391-2402

ZEJULA® (Niraparib)

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The FDA on April 29, 2020 approved ZEJULA® for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a Complete or Partial Response to first-line platinum-based chemotherapy. ZEJULA® is a product of GlaxoSmithKline.

ZEJULA® (Niraparib)

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The FDA on October 23, 2019 approved ZEJULA® for patients with advanced Ovarian, Fallopian tube, or Primary Peritoneal cancer treated with three or more prior chemotherapy regimens and whose cancer is associated with Homologous Recombination Deficiency (HRD)-positive status. HDR is defined by either a deleterious or suspected deleterious BRCA mutation, or genomic instability in patients with disease progression greater than six months after response to the last Platinum-based chemotherapy. ZEJULA® is a product of Tesaro, Inc.

Substantial Benefit with Maintenance LYNPARZA® in Patients with Newly Diagnosed Advanced Ovarian Cancer

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SUMMARY: It is estimated that in the United States, approximately 22,530 women will be diagnosed with ovarian cancer in 2019 and 13,980 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5 year Overall Survival rate of about 20-30%.

BRCA1 and BRCA2 are tumor suppressor genes and functional BRCA proteins that repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. Mutations in BRCA1 and BRCA2 account for about 20-25% of hereditary breast cancers and about 5-10% of all breast cancers. They also account for 15% of ovarian cancers, in addition to other cancers such as colon and prostate. BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic). Somatic mutations account for a significant portion of overall BRCA1 and BRCA2 aberrations. Loss of BRCA function due to frequent somatic aberrations in ovarian cancers likely deregulates Homologous Recombination (HR) pathway and increases sensitivity to platinum drugs. Majority of the women with Germline BRCA mutations (gBRCA) are positive for HR deficiency. The PARP (Poly ADP Ribose Polymerase) family of enzymes which include PARP1 and PARP2, repair damaged DNA. PARP inhibitors kill tumors defective in the BRCA1 or BRCA2 genes through the concept of synthetic lethality. Epithelial ovarian cancers with Homologous Recombination Deficiency have demonstrated sensitivity to PARP inhibitors.MOA-of-LYNPARZA

SOLO1 is an international, randomized, double-blind, Phase III trial, conducted to evaluate the efficacy of maintenance therapy with a PARP inhibitor LYNPARZA® (Olaparib), in patients with newly diagnosed advanced ovarian cancer with a Germline or Somatic mutation in BRCA1, BRCA2, or both (BRCA1/2), who had a complete or partial clinical response after platinum-based chemotherapy. Patients (N=391) were randomly assigned in a 2:1 ratio, to receive LYNPARZA® tablets 300 mg PO twice daily (N=260) or placebo (N=131). Enrolled patients had international FIGO Stage III or IV high-grade Serous or Endometrioid ovarian cancer, Primary Peritoneal cancer, or Fallopian tube cancer (or a combination thereof), and majority of the enrolled patients (N=388) had a centrally confirmed Germline BRCA1/2 mutation, and 2 patients had a centrally confirmed Somatic BRCA1/2 mutation. Patients with Stage III disease had cytoreductive surgery attempted upfront before the start chemotherapy, or had interval cytoreductive surgery after the start but before the end of chemotherapy. Patients with Stage IV disease either had a biopsy for tissue diagnosis or underwent upfront or interval cytoreductive surgery. The Primary end point was Progression Free Survival (PFS) and Secondary end points included second PFS which was the time from randomization to second disease progression or death, and Overall Survival.

After a median follow up of 41 months, the risk of disease progression or death was 70% lower with LYNPARZA® when compared to placebo, with an estimated rate of freedom from disease progression and death at 3 years of 60% versus 27% (HR for disease progression or death= 0.30; P<0.001). The estimated rate of freedom from second disease progression and death at 3 years was 75% in the LYNPARZA® group, as compared with 60% in the placebo group (HR for second disease progression or death=0.50; P<0.001). Adverse events were consistent with the known toxic effects of LYNPARZA®, with anemia being the most common serious side effect. Adverse events were usually managed by dose interruption or dose reduction, rather than discontinuation of the study drug.

It was concluded that maintenance therapy with LYNPARZA® after platinum-based chemotherapy provided a substantial Progression Free Survival benefit, with a 70% lower risk of disease progression or death, when compared to placebo, among women with newly diagnosed advanced ovarian cancer and a BRCA1/2mutation. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. Moore K, Colombo N, Scambia G, et al. N Engl J Med 2018; 379:2495-2505

Aspirin Lowers Risk for Ovarian and Hepatocellular Carcinoma

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SUMMARY: Aspirin (AcetylSalicylic Acid) has been studied as a chemopreventive agent for several decades and the temporal relationship between systemic inflammation and cancer has been a topic of ongoing investigation. The US Preventive Services Task Force (USPSTF) found adequate evidence that Aspirin use reduces the incidence of ColoRectal Cancer (CRC) in adults after 5-10 years of use, and recommends initiating low-dose Aspirin use for the primary prevention of CardioVascular Disease (CVD) and ColoRectal Cancer (CRC) in adults aged 50-69 years, who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose Aspirin daily for at least 10 years.MOA-of-ASPIRIN

The molecular mechanisms underlying Aspirin’s chemoprevention effects as well as the dose, duration, and timing of Aspirin chemoprevention have remained unclear. More recent data suggests that platelets may play a role in tumorigenesis as well, through the release of angiogenic and growth factors due to overexpression of COX-2. Daily low dose Aspirin inhibits COX-1 and COX-2. It is postulated that Aspirin also works by COX-independent mechanisms such as, the inhibition of NF-kB and Wnt/ β-catenin signaling, which may play a role in its chemopreventive properties.

Two recently published studies examining different doses of Aspirin in different cancers, highlight the beneficial role of Aspirin in reducing cancer risk.

The first report is a large prospective study which attempted to reproduce findings from case-control studies that reported lower Ovarian cancer risk among low-dose Aspirin users. This prospective study evaluated whether regular Aspirin or nonaspirin NonSteroidal Anti-Inflammatory Drug (NSAID) use and patterns of use was associated with lower risk of Ovarian cancer. This cohort study analyzed NSAID use and Ovarian cancer diagnosis data on 205,498 women from 2 prospective cohorts; 93 664 women in the Nurses’ Health Study (NHS), who were 93% non-Hispanic white, with a mean age at baseline of 46 years, followed up from 1980 to 2014, and 111834 women in the Nurses’ Health Study II (NHSII), who were 92% non-Hispanic white, with a mean age at baseline of 34.2 years, followed up from 1989 to 2015. For each analgesic type (Aspirin, low-dose Aspirin, nonaspirin NSAIDs, and Acetaminophen), timing, duration, frequency, and number of tablets used were evaluated, and information was updated every 2-4 years.

It was noted that among both cohorts, there were 1054 women who developed epithelial Ovarian cancer. Recent use of low-dose Aspirin (100 mg or less) was associated with a lower risk of Ovarian cancer (HR=0.77), whereas there was no such association noted with standard-dose of 325 mg Aspirin (HR=1.17). The associations between Aspirin use and risk of Ovarian cancer did not differ among premenopausal versus postmenopausal women. This study also suggested that use of non-aspirin NSAIDs, such as Ibuprofen and Naproxen, when taken in quantities of at least 10 tablets per week for multiple years was positively associated with an increased risk of Ovarian cancer. There was however no clear associations for the use of Acetaminophen.

The authors concluded that consistent with case-control studies, this prospective analysis showed a reduced risk of Ovarian cancer among regular users of low-dose Aspirin and an increased risk of Ovarian cancer with the use of nonaspirin NSAIDs. These findings suggest that low-dose Aspirin recommended for cardiovascular prophylaxis and ColoRectal Cancer risk reduction can also reduce the risk of Ovarian cancer.

The second report is another large prospective study which analyzed the data on the risk of HepatoCellular Carcinoma (HCC) within 2 populations of a total of 133 371 health care professionals who self reported use of Aspirin. In this pooled analysis, 87 507 were women, with a mean age was 62 years, and 45 864 were men, with a mean age of 64 years. Women reported data biennially since 1980 and men since 1986, on frequency, dosage, and duration of Aspirin use, and data were accessed from November 2017 through March 2018. Individuals with a cancer diagnosis at baseline (except nonmelanoma skin cancer) were excluded.

The researchers noted that regular Aspirin use of 2 or more standard dose 325 mg tablets per week was associated with a 49% reduction in risk of HCC (adjusted HR=0.51) compared to non regular use. This benefit was dose-dependent with the greatest benefit among those taking more than 5 tablets per week (P for trend =0 .006). Further, significantly lower risk for HCC was observed with increasing duration of Aspirin intake (P for trend =0.03), with this decreasing risk noted with the use of 1.5 or more standard-dose Aspirin tablets per week for 5 or more years (adjusted HR=0.41). The use of nonaspirin NSAIDs however was not significantly associated with HCC risk.

The authors from this study concluded that regular and long-term use of standard dose (325 mg) Aspirin, taken at least 2 or more times per week is associated with a dose-dependent reduction in HCC risk, which is apparent after 5 or more years of use.

Taken together, these 2 studies provide the evidence supporting the ability of regular use of Aspirin to prevent Ovarian cancer and HepatoCellular Cancer (HCC). Aspirin is rapidly emerging as a valuable chemoprevention agent for various malignancies.

Association of Analgesic Use With Risk of Ovarian Cancer in the Nurses’ Health Studies. Barnard ME, Poole EM, Curhan GC, et al. JAMA Oncol. 2018;4:1675-1682.

Association Between Aspirin Use and Risk of Hepatocellular Carcinoma. Simon TG, Ma Y, Ludvigsson JF, et al. JAMA Oncol. 2018;4:1683-1690

LYNPARZA® (Olaparib)

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The FDA on December 19, 2018 approved LYNPARZA® for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in Complete or Partial Response to first-line platinum-based chemotherapy. LYNPARZA® is a product of AstraZeneca Pharmaceuticals LP.