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In 2022, the most significant advances in the treatment of gynecologic cancers were achieved for patients with ovarian cancer. While ovarian cancer continues to carry the worst prognosis of all gynecologic cancers, 5-year relative survival has gradually increased, from 34.4% in 1975 to 52.4% in 2014.1
In this Update, we highlight the recent advances in our understanding of targeted therapy in ovarian cancer. We review SORAYA, a trial that demonstrated that mirvetuximab soravtansine, an antibody-drug conjugate, has promising efficacy in platinum-resistant ovarian cancers that overexpress folate receptor α. We also spotlight progress in the treatment of low-grade serous ovarian cancer, another notoriously chemotherapy-resistant disease, in GOG 281/LOGS, a phase 2 study of the MEK inhibitor trametinib. Finally, we discuss emerging long-term follow-up data on poly(ADP-ribose) polymerase (PARP) inhibitors, which are helping to refine the role of these groundbreaking drugs.
New drug approved for platinum-resistant epithelial ovarian cancer—the first since 2014
Matulonis UA, Lorusso D, Oaknin A, et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: results from the SORAYA study. J Clin Oncol. 2023;41:2436-2445. doi:10.1200/JCO.22.01900.
While most patients diagnosed with advanced ovarian cancer will respond to platinum-based chemotherapy, those whose disease recurs eventually develop resistance to platinum agents. Treatment options for platinum-resistant ovarian cancer are limited and prognosis is poor. Most regimens have a response rate of only 10%. Since the approval of bevacizumab combined with chemotherapy in 2014, no new agents have been approved by the US Food and Drug Administration (FDA) for use in platinum-resistant ovarian cancer.
Efficacy shown with mirvetuximab
Recently, Matulonis and colleagues published results of the SORAYA study, a single-arm,phase 2 trial, that examined the efficacy and safety of mirvetuximab soravtansine-gynx among women with platinum-resistant ovarian cancer.2 Mirvetuximab is an antibody-drug conjugate composed of an antibody directed at the folate receptor α attached to a cytotoxic microtubule inhibitor.
The study included 106 patients with platinum-resistant ovarian cancer whose tumors expressed folate receptor α at a high level—a feature of approximately 50% of patients screened for the study. Twenty-nine patients experienced a partial response and 5 had a complete response, corresponding to a remarkable objective response rate of 32.4%. The median progression-free survival was 4.3 months.
Like other antibody-drug conjugates, ocular toxicities, including blurred vision (41%) and keratopathy (29%), were common. However, toxicity was manageable and rarely led to drug discontinuation.
The FDA has granted accelerated approval to mirvetuximab soravtansine-gynx for women with platinum-resistant ovarian cancer with high folate receptor α expression who have received 1 to 3 prior systemic treatment regimens.
Continue to: A novel agent for recurrent low-grade serous ovarian carcinoma...
A novel agent for recurrent low-grade serous ovarian carcinoma
Low-grade serous carcinoma is a histologic subtype that makes up approximately 5% of all epithelial ovarian cancers.3 Patients with low-grade serous carcinoma are often younger and, because of the indolent nature of the histology, generally have a longer overall survival compared with patients with high-grade serous carcinoma. Unlike high-grade disease, however, low-grade serous carcinoma usually is resistant to chemotherapy, making treatment options limited for patients with advanced and recurrent disease.
Trametinib: A potential option
In an international, randomized, open-label trial (GOG 281/LOGS), Gershenson and colleagues investigated the efficacy of trametinib compared with standard-of-care chemotherapy in patients with recurrent low-grade serous ovarian cancer.4 Trametinib, a mitogen-activated protein kinase MEK inhibitor, is a targeted agent that is FDA approved for treatment in BRAF-mutated melanoma, lung, and thyroid cancers.
Patients with recurrent low-grade serous ovarian cancer were randomly assigned to trametinib (n = 130) or 1 of 5 standard-of-care treatment options (n = 130), including both chemotherapy and hormonal treatments. Those assigned to trametinib were significantly less likely to have disease progression (78% vs 89%), with a median progression-free survival of 13 months, compared with7.2 months in controls (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.36–0.64). Additionally, patients who had a radiographic response to trametinib experienced a longer duration of response compared with those who responded to standard-of-care treatment (13.6 months vs 5.9 months).
While there was no statistically significant difference in overall survival (HR, 0.76; 95% CI, 0.51–1.12), crossover to trametinib from the standard-of-care group was allowed and occurred among 68% of patients, which limits the study’s ability to measure differences in overall survival.
Trametinib was well tolerated by patients, but skin rash and anemia followed by hypertension were the most common adverse effects. In the standard-of-care group, the most common toxicities were abdominal pain, nausea, and anemia. A slightly higher proportion of patients in the trametinib group discontinued the drug due to toxicity compared with the standard-of-care group (36% vs 30%), but the there was no difference between the 2 groups in scores on quality-of-life assessments.
Although trametinib is not yet FDA approved for the treatment of ovarian cancer, the National Comprehensive Cancer Network has added trametinib as a treatment option for recurrent low-grade serous ovarian carcinoma, given the significant improvement in progression-free survival compared with standard-of-care treatment.
Continue to: PARP inhibitors benefit many women with ovarian cancer, but they may hurt others...
PARP inhibitors benefit many women with ovarian cancer, but they may hurt others
Monk BJ, Parkinson C, Lim MC, et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). J Clin Oncol. 2022;40:3952-3964. doi:10.1200/JCO.22.01003.
Poly(ADP-ribose) polymerase (PARP) inhibitors are a class of oral anticancer agents that target DNA repair. Since the initial FDA approval in 2014 of olaparib for the treatment of patients with recurrent BRCA-mutated ovarian cancer, PARP inhibitors have been approved for maintenance in both the frontline setting and after platinum-sensitive recurrence, and as single-agenttreatment for ovarian cancer with BRCA mutations or evidence of homologous repair deficiency (HRD), a BRCA-like molecular phenotype.5 The expanding role for PARP inhibitors in ovarian cancer seemed inexorable.
Restricted prescribing advised
In 2022, we learned that in certain settings, PARP inhibitors may be the wrong choice. Several “Dear Health Care Provider” letters were issued by AstraZeneca, Clovis, and GSK to advise physicians to restrict the prescribing of olaparib, rucaparib, and niraparib.6,7
AstraZeneca and Clovis issued letters spurred by the final analysis of ARIEL4 and SOLO3 studies, 2 randomized trials that investigated, respectively, rucaparib and olaparib monotherapy compared with chemotherapy in recurrent ovarian cancer.8,9 In both cases patients randomized to PARP inhibitors may have experienced an overall survival decrement compared with those who received chemotherapy.
At the FDA’s request, Clovis has withdrawn rucaparib as a treatment for patients with recurrent BRCA-mutant ovarian cancer who had received 2 or more lines of chemotherapy, and AstraZeneca withdrew olaparib monotherapy in germline BRCA-mutant patients with recurrent ovarian cancer. Shortly after these withdrawals, GSK also withdrew its indication for niraparib as a treatment for women with HRD, platinum-sensitive ovarian cancer who have received 3 or more prior chemotherapies. Furthermore, based on the final overall survival analysis of the NOVA study, GSK also restricted its indication for niraparib maintenance for recurrent ovarian cancer to patients with germline BRCA mutations, due to evidence of an overall survival detriment in this setting.10
Positive study results
Fortunately, 2022 was not all bad news for PARP inhibitors in ovarian cancer. In June 2022, the ATHENA-MONO trial, a phase 3 double-blind randomized controlled trial, demonstrated that rucaparib maintenance in patients with newly diagnosed epithelial ovarian cancer was associated with a significantly longer progression-free survival compared with placebo.11 The effect was most pronounced in the BRCA-mutant/HRD population, with a median progression-free survival of 28.7 months in the rucaparib group compared with 11.3 months in the placebo group (HR, 0.47; 95% CI, 0.31–0.72). Thus, rucaparib was added to the list of PARP inhibitors approved for upfront maintenance therapy in epithelial ovarian cancer.
Similarly, the long-term overall survival analysis from the upfront trials SOLO-1 and PAOLA-1 showed an overall survival advantage of PARP inhibitor, compared with placebo, maintenance in patients with BRCA mutations or HRD tumors.12,13 ●
PARP inhibitor maintenance therapy after upfront chemotherapy in women with BRCA-mutant and HRD epithelial ovarian cancer has been game changing in ovarian cancer. However, PARP inhibitors have a more limited role than previously thought for patients with recurrent ovarian cancer.
- Cancer stat facts: ovarian cancer. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed March 11, 2023. https://seer.cancer.gov/statfacts /html/ovary.html
- Matulonis UA, Lorusso D, Oaknin A, et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinumresistant ovarian cancer with high folate receptor alpha expression: results from the SORAYA study. J Clin Oncol. 2023;41:2436-2445. doi:10.1200/JCO.22.01900
- Prat J, D’Angelo E, Espinosa I. Ovarian carcinomas: at least five different diseases with distinct histological features and molecular genetics. Hum Pathol. 2018;80:11-27. doi:10.1016 /j.humpath.2018.06.018
- Gershenson DM, Miller A, Brady WE, et al. Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial. Lancet. 2022;399:541-553. doi:10.1016/S0140-6736(21)02175-9
- Tew WP, Lacchetti C, Ellis A, et al. PARP inhibitors in the management of ovarian cancer: ASCO guideline. J Clin Oncol. 2020;38:3468-3493. doi:10.1200/JCO.20.01924
- Rubraca (rucaparib) for treatment of BRCA-mutated ovarian cancer after 2 or more chemotherapies is voluntarily withdrawn in the US. Clovis Oncology. June 2022. Accessed May 11, 2022. chrome-extension://efaidnbmnnnibpcajpcglcle findmkaj/https://clovisoncology.com/pdfs/US_DHCPL _final_signed.pdf
- Lynparza (olaparib) for treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy is voluntarily withdrawn in the US. AstraZeneca. August 26, 2022. Accessed May 11, 2023. https://www.lynparzahcp.com/content/dam /physician-services/us/590-lynparza-hcp-branded/hcp -global/pdf/solo3-dhcp-final-signed.pdf
- Penson RT, Valencia RV, Cibula D, et al. Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 mutation (SOLO3): a randomized phase III trial. J Clin Oncol. 2020;38:1164-1174. doi:10.1200/JCO.19.02745
- Kristeleit R, Lisyanskaya A, Fedenko A, et al. Rucaparib versus standard-of-care chemotherapy in patients with relapsed ovarian cancer and a deleterious BRCA1 or BRCA2 mutation (ARIEL4): an international, open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23:465-478. doi:10.1016 /S1470-2045(22)00122-X
- Dear Health Care Provider Letter (Niraparib). GSK. November 2022. Accessed May 11, 2023. https://www.zejulahcp .com/content/dam/cf-pharma/hcp-zejulahcp-v2/en_US /pdf/ZEJULA%20(niraparib)%20Dear%20HCP%20Letter%20 November%202022.pdf
- Monk BJ, Parkinson C, Lim MC, et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). J Clin Oncol. 2022;40:3952-3964. doi:10.1200/JCO.22.01003
- Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379:2495-2505. doi:10.1056 /NEJMoa1810858
- Ray-Coquard I, Pautier P, Pignata S, et al; PAOLA-1 Investigators. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381:2416-2428. doi:10.1056/NEJMoa1911361
Alexandra S. Bercow, MD
Dr. Bercow is a Clinical and Research
Fellow in the Meigs Division of
Gynecologic Oncology, Vincent
Department of Obstetrics and Gynecology,
at Massachusetts General Hospital,
a Harvard Medical School
affiliated hospital.
Alexander Melamed, MD, MPH
Dr. Melamed is an Assistant Professor
in the Meigs Division of Gynecologic
Oncology, Vincent Department
of Obstetrics and Gynecology, at
Massachusetts General Hospital, a Harvard
Medical School affiliated hospital.
He is also the Norman F. Gant American
Board of Obstetrics and Gynecology Fellow
at the National Academy of Medicine.
Dr. Melamed serves on the advisory board of AstraZeneca and is a consultant for Kaya17. Dr. Bercow reports no financial relationships relevant to this article.
Alexandra S. Bercow, MD
Dr. Bercow is a Clinical and Research
Fellow in the Meigs Division of
Gynecologic Oncology, Vincent
Department of Obstetrics and Gynecology,
at Massachusetts General Hospital,
a Harvard Medical School
affiliated hospital.
Alexander Melamed, MD, MPH
Dr. Melamed is an Assistant Professor
in the Meigs Division of Gynecologic
Oncology, Vincent Department
of Obstetrics and Gynecology, at
Massachusetts General Hospital, a Harvard
Medical School affiliated hospital.
He is also the Norman F. Gant American
Board of Obstetrics and Gynecology Fellow
at the National Academy of Medicine.
Dr. Melamed serves on the advisory board of AstraZeneca and is a consultant for Kaya17. Dr. Bercow reports no financial relationships relevant to this article.
Alexandra S. Bercow, MD
Dr. Bercow is a Clinical and Research
Fellow in the Meigs Division of
Gynecologic Oncology, Vincent
Department of Obstetrics and Gynecology,
at Massachusetts General Hospital,
a Harvard Medical School
affiliated hospital.
Alexander Melamed, MD, MPH
Dr. Melamed is an Assistant Professor
in the Meigs Division of Gynecologic
Oncology, Vincent Department
of Obstetrics and Gynecology, at
Massachusetts General Hospital, a Harvard
Medical School affiliated hospital.
He is also the Norman F. Gant American
Board of Obstetrics and Gynecology Fellow
at the National Academy of Medicine.
Dr. Melamed serves on the advisory board of AstraZeneca and is a consultant for Kaya17. Dr. Bercow reports no financial relationships relevant to this article.
In 2022, the most significant advances in the treatment of gynecologic cancers were achieved for patients with ovarian cancer. While ovarian cancer continues to carry the worst prognosis of all gynecologic cancers, 5-year relative survival has gradually increased, from 34.4% in 1975 to 52.4% in 2014.1
In this Update, we highlight the recent advances in our understanding of targeted therapy in ovarian cancer. We review SORAYA, a trial that demonstrated that mirvetuximab soravtansine, an antibody-drug conjugate, has promising efficacy in platinum-resistant ovarian cancers that overexpress folate receptor α. We also spotlight progress in the treatment of low-grade serous ovarian cancer, another notoriously chemotherapy-resistant disease, in GOG 281/LOGS, a phase 2 study of the MEK inhibitor trametinib. Finally, we discuss emerging long-term follow-up data on poly(ADP-ribose) polymerase (PARP) inhibitors, which are helping to refine the role of these groundbreaking drugs.
New drug approved for platinum-resistant epithelial ovarian cancer—the first since 2014
Matulonis UA, Lorusso D, Oaknin A, et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: results from the SORAYA study. J Clin Oncol. 2023;41:2436-2445. doi:10.1200/JCO.22.01900.
While most patients diagnosed with advanced ovarian cancer will respond to platinum-based chemotherapy, those whose disease recurs eventually develop resistance to platinum agents. Treatment options for platinum-resistant ovarian cancer are limited and prognosis is poor. Most regimens have a response rate of only 10%. Since the approval of bevacizumab combined with chemotherapy in 2014, no new agents have been approved by the US Food and Drug Administration (FDA) for use in platinum-resistant ovarian cancer.
Efficacy shown with mirvetuximab
Recently, Matulonis and colleagues published results of the SORAYA study, a single-arm,phase 2 trial, that examined the efficacy and safety of mirvetuximab soravtansine-gynx among women with platinum-resistant ovarian cancer.2 Mirvetuximab is an antibody-drug conjugate composed of an antibody directed at the folate receptor α attached to a cytotoxic microtubule inhibitor.
The study included 106 patients with platinum-resistant ovarian cancer whose tumors expressed folate receptor α at a high level—a feature of approximately 50% of patients screened for the study. Twenty-nine patients experienced a partial response and 5 had a complete response, corresponding to a remarkable objective response rate of 32.4%. The median progression-free survival was 4.3 months.
Like other antibody-drug conjugates, ocular toxicities, including blurred vision (41%) and keratopathy (29%), were common. However, toxicity was manageable and rarely led to drug discontinuation.
The FDA has granted accelerated approval to mirvetuximab soravtansine-gynx for women with platinum-resistant ovarian cancer with high folate receptor α expression who have received 1 to 3 prior systemic treatment regimens.
Continue to: A novel agent for recurrent low-grade serous ovarian carcinoma...
A novel agent for recurrent low-grade serous ovarian carcinoma
Low-grade serous carcinoma is a histologic subtype that makes up approximately 5% of all epithelial ovarian cancers.3 Patients with low-grade serous carcinoma are often younger and, because of the indolent nature of the histology, generally have a longer overall survival compared with patients with high-grade serous carcinoma. Unlike high-grade disease, however, low-grade serous carcinoma usually is resistant to chemotherapy, making treatment options limited for patients with advanced and recurrent disease.
Trametinib: A potential option
In an international, randomized, open-label trial (GOG 281/LOGS), Gershenson and colleagues investigated the efficacy of trametinib compared with standard-of-care chemotherapy in patients with recurrent low-grade serous ovarian cancer.4 Trametinib, a mitogen-activated protein kinase MEK inhibitor, is a targeted agent that is FDA approved for treatment in BRAF-mutated melanoma, lung, and thyroid cancers.
Patients with recurrent low-grade serous ovarian cancer were randomly assigned to trametinib (n = 130) or 1 of 5 standard-of-care treatment options (n = 130), including both chemotherapy and hormonal treatments. Those assigned to trametinib were significantly less likely to have disease progression (78% vs 89%), with a median progression-free survival of 13 months, compared with7.2 months in controls (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.36–0.64). Additionally, patients who had a radiographic response to trametinib experienced a longer duration of response compared with those who responded to standard-of-care treatment (13.6 months vs 5.9 months).
While there was no statistically significant difference in overall survival (HR, 0.76; 95% CI, 0.51–1.12), crossover to trametinib from the standard-of-care group was allowed and occurred among 68% of patients, which limits the study’s ability to measure differences in overall survival.
Trametinib was well tolerated by patients, but skin rash and anemia followed by hypertension were the most common adverse effects. In the standard-of-care group, the most common toxicities were abdominal pain, nausea, and anemia. A slightly higher proportion of patients in the trametinib group discontinued the drug due to toxicity compared with the standard-of-care group (36% vs 30%), but the there was no difference between the 2 groups in scores on quality-of-life assessments.
Although trametinib is not yet FDA approved for the treatment of ovarian cancer, the National Comprehensive Cancer Network has added trametinib as a treatment option for recurrent low-grade serous ovarian carcinoma, given the significant improvement in progression-free survival compared with standard-of-care treatment.
Continue to: PARP inhibitors benefit many women with ovarian cancer, but they may hurt others...
PARP inhibitors benefit many women with ovarian cancer, but they may hurt others
Monk BJ, Parkinson C, Lim MC, et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). J Clin Oncol. 2022;40:3952-3964. doi:10.1200/JCO.22.01003.
Poly(ADP-ribose) polymerase (PARP) inhibitors are a class of oral anticancer agents that target DNA repair. Since the initial FDA approval in 2014 of olaparib for the treatment of patients with recurrent BRCA-mutated ovarian cancer, PARP inhibitors have been approved for maintenance in both the frontline setting and after platinum-sensitive recurrence, and as single-agenttreatment for ovarian cancer with BRCA mutations or evidence of homologous repair deficiency (HRD), a BRCA-like molecular phenotype.5 The expanding role for PARP inhibitors in ovarian cancer seemed inexorable.
Restricted prescribing advised
In 2022, we learned that in certain settings, PARP inhibitors may be the wrong choice. Several “Dear Health Care Provider” letters were issued by AstraZeneca, Clovis, and GSK to advise physicians to restrict the prescribing of olaparib, rucaparib, and niraparib.6,7
AstraZeneca and Clovis issued letters spurred by the final analysis of ARIEL4 and SOLO3 studies, 2 randomized trials that investigated, respectively, rucaparib and olaparib monotherapy compared with chemotherapy in recurrent ovarian cancer.8,9 In both cases patients randomized to PARP inhibitors may have experienced an overall survival decrement compared with those who received chemotherapy.
At the FDA’s request, Clovis has withdrawn rucaparib as a treatment for patients with recurrent BRCA-mutant ovarian cancer who had received 2 or more lines of chemotherapy, and AstraZeneca withdrew olaparib monotherapy in germline BRCA-mutant patients with recurrent ovarian cancer. Shortly after these withdrawals, GSK also withdrew its indication for niraparib as a treatment for women with HRD, platinum-sensitive ovarian cancer who have received 3 or more prior chemotherapies. Furthermore, based on the final overall survival analysis of the NOVA study, GSK also restricted its indication for niraparib maintenance for recurrent ovarian cancer to patients with germline BRCA mutations, due to evidence of an overall survival detriment in this setting.10
Positive study results
Fortunately, 2022 was not all bad news for PARP inhibitors in ovarian cancer. In June 2022, the ATHENA-MONO trial, a phase 3 double-blind randomized controlled trial, demonstrated that rucaparib maintenance in patients with newly diagnosed epithelial ovarian cancer was associated with a significantly longer progression-free survival compared with placebo.11 The effect was most pronounced in the BRCA-mutant/HRD population, with a median progression-free survival of 28.7 months in the rucaparib group compared with 11.3 months in the placebo group (HR, 0.47; 95% CI, 0.31–0.72). Thus, rucaparib was added to the list of PARP inhibitors approved for upfront maintenance therapy in epithelial ovarian cancer.
Similarly, the long-term overall survival analysis from the upfront trials SOLO-1 and PAOLA-1 showed an overall survival advantage of PARP inhibitor, compared with placebo, maintenance in patients with BRCA mutations or HRD tumors.12,13 ●
PARP inhibitor maintenance therapy after upfront chemotherapy in women with BRCA-mutant and HRD epithelial ovarian cancer has been game changing in ovarian cancer. However, PARP inhibitors have a more limited role than previously thought for patients with recurrent ovarian cancer.
In 2022, the most significant advances in the treatment of gynecologic cancers were achieved for patients with ovarian cancer. While ovarian cancer continues to carry the worst prognosis of all gynecologic cancers, 5-year relative survival has gradually increased, from 34.4% in 1975 to 52.4% in 2014.1
In this Update, we highlight the recent advances in our understanding of targeted therapy in ovarian cancer. We review SORAYA, a trial that demonstrated that mirvetuximab soravtansine, an antibody-drug conjugate, has promising efficacy in platinum-resistant ovarian cancers that overexpress folate receptor α. We also spotlight progress in the treatment of low-grade serous ovarian cancer, another notoriously chemotherapy-resistant disease, in GOG 281/LOGS, a phase 2 study of the MEK inhibitor trametinib. Finally, we discuss emerging long-term follow-up data on poly(ADP-ribose) polymerase (PARP) inhibitors, which are helping to refine the role of these groundbreaking drugs.
New drug approved for platinum-resistant epithelial ovarian cancer—the first since 2014
Matulonis UA, Lorusso D, Oaknin A, et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: results from the SORAYA study. J Clin Oncol. 2023;41:2436-2445. doi:10.1200/JCO.22.01900.
While most patients diagnosed with advanced ovarian cancer will respond to platinum-based chemotherapy, those whose disease recurs eventually develop resistance to platinum agents. Treatment options for platinum-resistant ovarian cancer are limited and prognosis is poor. Most regimens have a response rate of only 10%. Since the approval of bevacizumab combined with chemotherapy in 2014, no new agents have been approved by the US Food and Drug Administration (FDA) for use in platinum-resistant ovarian cancer.
Efficacy shown with mirvetuximab
Recently, Matulonis and colleagues published results of the SORAYA study, a single-arm,phase 2 trial, that examined the efficacy and safety of mirvetuximab soravtansine-gynx among women with platinum-resistant ovarian cancer.2 Mirvetuximab is an antibody-drug conjugate composed of an antibody directed at the folate receptor α attached to a cytotoxic microtubule inhibitor.
The study included 106 patients with platinum-resistant ovarian cancer whose tumors expressed folate receptor α at a high level—a feature of approximately 50% of patients screened for the study. Twenty-nine patients experienced a partial response and 5 had a complete response, corresponding to a remarkable objective response rate of 32.4%. The median progression-free survival was 4.3 months.
Like other antibody-drug conjugates, ocular toxicities, including blurred vision (41%) and keratopathy (29%), were common. However, toxicity was manageable and rarely led to drug discontinuation.
The FDA has granted accelerated approval to mirvetuximab soravtansine-gynx for women with platinum-resistant ovarian cancer with high folate receptor α expression who have received 1 to 3 prior systemic treatment regimens.
Continue to: A novel agent for recurrent low-grade serous ovarian carcinoma...
A novel agent for recurrent low-grade serous ovarian carcinoma
Low-grade serous carcinoma is a histologic subtype that makes up approximately 5% of all epithelial ovarian cancers.3 Patients with low-grade serous carcinoma are often younger and, because of the indolent nature of the histology, generally have a longer overall survival compared with patients with high-grade serous carcinoma. Unlike high-grade disease, however, low-grade serous carcinoma usually is resistant to chemotherapy, making treatment options limited for patients with advanced and recurrent disease.
Trametinib: A potential option
In an international, randomized, open-label trial (GOG 281/LOGS), Gershenson and colleagues investigated the efficacy of trametinib compared with standard-of-care chemotherapy in patients with recurrent low-grade serous ovarian cancer.4 Trametinib, a mitogen-activated protein kinase MEK inhibitor, is a targeted agent that is FDA approved for treatment in BRAF-mutated melanoma, lung, and thyroid cancers.
Patients with recurrent low-grade serous ovarian cancer were randomly assigned to trametinib (n = 130) or 1 of 5 standard-of-care treatment options (n = 130), including both chemotherapy and hormonal treatments. Those assigned to trametinib were significantly less likely to have disease progression (78% vs 89%), with a median progression-free survival of 13 months, compared with7.2 months in controls (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.36–0.64). Additionally, patients who had a radiographic response to trametinib experienced a longer duration of response compared with those who responded to standard-of-care treatment (13.6 months vs 5.9 months).
While there was no statistically significant difference in overall survival (HR, 0.76; 95% CI, 0.51–1.12), crossover to trametinib from the standard-of-care group was allowed and occurred among 68% of patients, which limits the study’s ability to measure differences in overall survival.
Trametinib was well tolerated by patients, but skin rash and anemia followed by hypertension were the most common adverse effects. In the standard-of-care group, the most common toxicities were abdominal pain, nausea, and anemia. A slightly higher proportion of patients in the trametinib group discontinued the drug due to toxicity compared with the standard-of-care group (36% vs 30%), but the there was no difference between the 2 groups in scores on quality-of-life assessments.
Although trametinib is not yet FDA approved for the treatment of ovarian cancer, the National Comprehensive Cancer Network has added trametinib as a treatment option for recurrent low-grade serous ovarian carcinoma, given the significant improvement in progression-free survival compared with standard-of-care treatment.
Continue to: PARP inhibitors benefit many women with ovarian cancer, but they may hurt others...
PARP inhibitors benefit many women with ovarian cancer, but they may hurt others
Monk BJ, Parkinson C, Lim MC, et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). J Clin Oncol. 2022;40:3952-3964. doi:10.1200/JCO.22.01003.
Poly(ADP-ribose) polymerase (PARP) inhibitors are a class of oral anticancer agents that target DNA repair. Since the initial FDA approval in 2014 of olaparib for the treatment of patients with recurrent BRCA-mutated ovarian cancer, PARP inhibitors have been approved for maintenance in both the frontline setting and after platinum-sensitive recurrence, and as single-agenttreatment for ovarian cancer with BRCA mutations or evidence of homologous repair deficiency (HRD), a BRCA-like molecular phenotype.5 The expanding role for PARP inhibitors in ovarian cancer seemed inexorable.
Restricted prescribing advised
In 2022, we learned that in certain settings, PARP inhibitors may be the wrong choice. Several “Dear Health Care Provider” letters were issued by AstraZeneca, Clovis, and GSK to advise physicians to restrict the prescribing of olaparib, rucaparib, and niraparib.6,7
AstraZeneca and Clovis issued letters spurred by the final analysis of ARIEL4 and SOLO3 studies, 2 randomized trials that investigated, respectively, rucaparib and olaparib monotherapy compared with chemotherapy in recurrent ovarian cancer.8,9 In both cases patients randomized to PARP inhibitors may have experienced an overall survival decrement compared with those who received chemotherapy.
At the FDA’s request, Clovis has withdrawn rucaparib as a treatment for patients with recurrent BRCA-mutant ovarian cancer who had received 2 or more lines of chemotherapy, and AstraZeneca withdrew olaparib monotherapy in germline BRCA-mutant patients with recurrent ovarian cancer. Shortly after these withdrawals, GSK also withdrew its indication for niraparib as a treatment for women with HRD, platinum-sensitive ovarian cancer who have received 3 or more prior chemotherapies. Furthermore, based on the final overall survival analysis of the NOVA study, GSK also restricted its indication for niraparib maintenance for recurrent ovarian cancer to patients with germline BRCA mutations, due to evidence of an overall survival detriment in this setting.10
Positive study results
Fortunately, 2022 was not all bad news for PARP inhibitors in ovarian cancer. In June 2022, the ATHENA-MONO trial, a phase 3 double-blind randomized controlled trial, demonstrated that rucaparib maintenance in patients with newly diagnosed epithelial ovarian cancer was associated with a significantly longer progression-free survival compared with placebo.11 The effect was most pronounced in the BRCA-mutant/HRD population, with a median progression-free survival of 28.7 months in the rucaparib group compared with 11.3 months in the placebo group (HR, 0.47; 95% CI, 0.31–0.72). Thus, rucaparib was added to the list of PARP inhibitors approved for upfront maintenance therapy in epithelial ovarian cancer.
Similarly, the long-term overall survival analysis from the upfront trials SOLO-1 and PAOLA-1 showed an overall survival advantage of PARP inhibitor, compared with placebo, maintenance in patients with BRCA mutations or HRD tumors.12,13 ●
PARP inhibitor maintenance therapy after upfront chemotherapy in women with BRCA-mutant and HRD epithelial ovarian cancer has been game changing in ovarian cancer. However, PARP inhibitors have a more limited role than previously thought for patients with recurrent ovarian cancer.
- Cancer stat facts: ovarian cancer. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed March 11, 2023. https://seer.cancer.gov/statfacts /html/ovary.html
- Matulonis UA, Lorusso D, Oaknin A, et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinumresistant ovarian cancer with high folate receptor alpha expression: results from the SORAYA study. J Clin Oncol. 2023;41:2436-2445. doi:10.1200/JCO.22.01900
- Prat J, D’Angelo E, Espinosa I. Ovarian carcinomas: at least five different diseases with distinct histological features and molecular genetics. Hum Pathol. 2018;80:11-27. doi:10.1016 /j.humpath.2018.06.018
- Gershenson DM, Miller A, Brady WE, et al. Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial. Lancet. 2022;399:541-553. doi:10.1016/S0140-6736(21)02175-9
- Tew WP, Lacchetti C, Ellis A, et al. PARP inhibitors in the management of ovarian cancer: ASCO guideline. J Clin Oncol. 2020;38:3468-3493. doi:10.1200/JCO.20.01924
- Rubraca (rucaparib) for treatment of BRCA-mutated ovarian cancer after 2 or more chemotherapies is voluntarily withdrawn in the US. Clovis Oncology. June 2022. Accessed May 11, 2022. chrome-extension://efaidnbmnnnibpcajpcglcle findmkaj/https://clovisoncology.com/pdfs/US_DHCPL _final_signed.pdf
- Lynparza (olaparib) for treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy is voluntarily withdrawn in the US. AstraZeneca. August 26, 2022. Accessed May 11, 2023. https://www.lynparzahcp.com/content/dam /physician-services/us/590-lynparza-hcp-branded/hcp -global/pdf/solo3-dhcp-final-signed.pdf
- Penson RT, Valencia RV, Cibula D, et al. Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 mutation (SOLO3): a randomized phase III trial. J Clin Oncol. 2020;38:1164-1174. doi:10.1200/JCO.19.02745
- Kristeleit R, Lisyanskaya A, Fedenko A, et al. Rucaparib versus standard-of-care chemotherapy in patients with relapsed ovarian cancer and a deleterious BRCA1 or BRCA2 mutation (ARIEL4): an international, open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23:465-478. doi:10.1016 /S1470-2045(22)00122-X
- Dear Health Care Provider Letter (Niraparib). GSK. November 2022. Accessed May 11, 2023. https://www.zejulahcp .com/content/dam/cf-pharma/hcp-zejulahcp-v2/en_US /pdf/ZEJULA%20(niraparib)%20Dear%20HCP%20Letter%20 November%202022.pdf
- Monk BJ, Parkinson C, Lim MC, et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). J Clin Oncol. 2022;40:3952-3964. doi:10.1200/JCO.22.01003
- Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379:2495-2505. doi:10.1056 /NEJMoa1810858
- Ray-Coquard I, Pautier P, Pignata S, et al; PAOLA-1 Investigators. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381:2416-2428. doi:10.1056/NEJMoa1911361
- Cancer stat facts: ovarian cancer. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed March 11, 2023. https://seer.cancer.gov/statfacts /html/ovary.html
- Matulonis UA, Lorusso D, Oaknin A, et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinumresistant ovarian cancer with high folate receptor alpha expression: results from the SORAYA study. J Clin Oncol. 2023;41:2436-2445. doi:10.1200/JCO.22.01900
- Prat J, D’Angelo E, Espinosa I. Ovarian carcinomas: at least five different diseases with distinct histological features and molecular genetics. Hum Pathol. 2018;80:11-27. doi:10.1016 /j.humpath.2018.06.018
- Gershenson DM, Miller A, Brady WE, et al. Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial. Lancet. 2022;399:541-553. doi:10.1016/S0140-6736(21)02175-9
- Tew WP, Lacchetti C, Ellis A, et al. PARP inhibitors in the management of ovarian cancer: ASCO guideline. J Clin Oncol. 2020;38:3468-3493. doi:10.1200/JCO.20.01924
- Rubraca (rucaparib) for treatment of BRCA-mutated ovarian cancer after 2 or more chemotherapies is voluntarily withdrawn in the US. Clovis Oncology. June 2022. Accessed May 11, 2022. chrome-extension://efaidnbmnnnibpcajpcglcle findmkaj/https://clovisoncology.com/pdfs/US_DHCPL _final_signed.pdf
- Lynparza (olaparib) for treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy is voluntarily withdrawn in the US. AstraZeneca. August 26, 2022. Accessed May 11, 2023. https://www.lynparzahcp.com/content/dam /physician-services/us/590-lynparza-hcp-branded/hcp -global/pdf/solo3-dhcp-final-signed.pdf
- Penson RT, Valencia RV, Cibula D, et al. Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 mutation (SOLO3): a randomized phase III trial. J Clin Oncol. 2020;38:1164-1174. doi:10.1200/JCO.19.02745
- Kristeleit R, Lisyanskaya A, Fedenko A, et al. Rucaparib versus standard-of-care chemotherapy in patients with relapsed ovarian cancer and a deleterious BRCA1 or BRCA2 mutation (ARIEL4): an international, open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23:465-478. doi:10.1016 /S1470-2045(22)00122-X
- Dear Health Care Provider Letter (Niraparib). GSK. November 2022. Accessed May 11, 2023. https://www.zejulahcp .com/content/dam/cf-pharma/hcp-zejulahcp-v2/en_US /pdf/ZEJULA%20(niraparib)%20Dear%20HCP%20Letter%20 November%202022.pdf
- Monk BJ, Parkinson C, Lim MC, et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). J Clin Oncol. 2022;40:3952-3964. doi:10.1200/JCO.22.01003
- Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379:2495-2505. doi:10.1056 /NEJMoa1810858
- Ray-Coquard I, Pautier P, Pignata S, et al; PAOLA-1 Investigators. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381:2416-2428. doi:10.1056/NEJMoa1911361
