The Latest Developments in Ovarian Cancer Treatment

Cancers arising from the epithelium of the female ovary are medically termed ovarian cancer . In 2018, 3729 new ovarian cancers were diagnosed in our country, accounting for 1.8% of all new annual cancer cases. The average age at occurrence is 63. Because it often produces no early symptoms and there is no sensitive cancer screening test, 75% of patients are diagnosed at an advanced stage —that is, when the cancer has spread beyond the ovaries and fluid accumulation in the abdomen (ascites) has begun.

The standard treatment for ovarian cancer has remained almost unchanged for the past 15 years: cytoreductive surgery (removal of all tumors visible in the abdomen during surgery), followed by platinum+taxane chemotherapy. However, 70-80% of these patients experience recurrence within the first 2 years. Each time the disease recurs, the response rate to the next line of treatment progressively declines. Thus, while the time until recurrence after initial treatment is approximately 18 months, this interval decreases to as little as 4 months with subsequent recurrences.

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Because ovarian cancers recur frequently, there is a need for maintenance treatments that prolong the time until recurrence. Until now, no effective treatment had been found in this regard. However, over the past 2 years, maintenance treatment with PARP inhibitors has produced much better results than expected. PARP inhibitors have also achieved successful results not only in maintenance treatment, but in treating patients with ovarian cancer who have received multiple treatments.

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Among PARP inhibitors, the first FDA approvals were not for maintenance treatment but for 4th-line treatment (olaparib – 2014) and 3rd-line treatment (rucaparib – 2016). At these stages, when treatment options have diminished, it is very encouraging that these drugs produce response rates of 30-50% and extend the time until disease progression to 9 months. After olaparib and rucaparib, niraparib was also approved in October 2019 for patients with homologous recombination deficiency (with or without a BRCA mutation) whose disease had progressed after 3 or more treatment lines. FDA approval in these lines applies to patients with BRCA mutations. Studies combining PARP inhibitors with immunotherapy or other targeted treatments are currently ongoing, particularly in patients receiving multiple treatments.

Poly (ADP-ribose) polymerase, DNA mutationsare repaired by this cellular system, known for short as PARP . Small-molecule drugs have been developed to inhibit the functioning of the PARP system; among these, olaparib (Lynparza) is the first and most widely used PARP inhibitor. Olaparib has previously received approval for use in ovarian and breast cancer from the FDA... The BRCA gene family is another DNA repair system.

Explanation of the figure: The BRCA and PARP genes on which olaparib acts are involved in repairing DNA damage. If only one of these genes is defective, the cancer cell survives. But if both are defective, the cancer cell cannot repair DNA effectively. Therefore, in patients with germline (inherited ) BRCA gene mutations, PARP inhibitors targeting the PARP gene exert a stronger anticancer effect.

For patients with advanced ovarian cancer, the first FDA approvals in maintenance treatment were in patients who had received two or more lines of treatment. Niraparib was the first drug approved for maintenance treatment (March 2017), followed in turn by olaparib and rucaparib. When given as maintenance treatment after successful chemotherapy, these drugs have been shown to increase the time until progression 4-fold and reduce the risk of recurrence or death by more than 70%. This success is more pronounced in patients with BRCA mutations, but risk reduction was also around 60% in those without BRCA mutations. Consequently, FDA approvals for maintenance treatment after 2 or more lines were independent of BRCA mutation status.

After first-line treatment, the first PARP inhibitor approved for maintenance treatment was olaparib (December 2018). In patients receiving olaparib as maintenance treatment after the first line, recurrence risk was found to decrease by 70%. FDA approval in this setting applies to patients with BRCA mutations. The niraparib study of maintenance after first-line treatment (PRIMA) was published in September 2019; it reduced progression risk by 57% and extended the time to progression 2-fold, in patients with homologous recombination deficiency. FDA approval followed on 29 April 2020.

Although these drugs benefit maintenance treatment regardless of BRCA mutation status, the benefit is 2-3 times greater in those with BRCA mutations. Looking at the groundbreaking success of these PARP inhibitors approved by the FDA in the past 5 years leads to this conclusion: every patient with ovarian carcinoma now needs to be tested for BRCA mutations. However, because these drugs have not yet been approved in our country, they cannot be used under reimbursement coverage.

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