“PARP inhibitor as backbone in ovarian cancer treatment”

[Interview] Dr. Kim Byoung Gie (Samsung Medical Center) and Dr. Kim Jae Won (SNU Hospital)

“Need to start prescribing from first-line maintenance, could use as a backbone for second and later-line therapy”

Dr.

 

Kim Byoung Gie (left) and Dr.

 

Kim Jae Won

Disease with limited treatment options tends to simplify the treatment pattern itself.

 

But an emergence of a new treatment mechanism can open doors to various treatment strategies.

 

A poly ADP-ribose polymerase (PARP) inhibitor is the new mechanism opening the new doors to the ovarian cancer treatment scene.

 

PARP inhibitors that target BRCA gene like Lynparza (olaparib) and Zejula (niraparib) are indicated as a monotherapy for the maintenance treatment in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to first and second -line platinum-based chemotherapy, and also as a fourth-line monotherapy in patients, who have been treated with third and later-line chemotherapy.

 

Beyond treating the BRCA mutation-positive patients, the medicine has expanded to a new biomarker like homologous repair deficiency (HRD).

 

Especially, Zejula won an all-comer indication after proving its efficacy at all lines of treatments regardless of the gene mutation.

 

Recently, a number of studies are confirming the effects of chemotherapy, Avastin (bevacizumab) and immunotherapy in combination with PARP inhibitor as a backbone.

 

Daily Pharm interviewed Dr.

 

Kim Byoung Gie, an obstetrics and gynecology professor at Samsung Medical Center and Dr.

 

Kim Jae Won, an obstetrics and gynecology professor at Seoul National University Hospital about the current status of PARP inhibitor use and their future strategies in ovarian cancer treatment.

 

-What does a PARP inhibitor mean in regards to the ovarian cancer treatment scene?

 

Dr.

 

Kim Byoung Gie

Dr.

 

Kim Byoung Gie (“KB:”): The search for a new treatment option in ovarian cancer has continued since two decades ago, but there was no noteworthy progress.

 

But finding the PARP inhibitor for treating an ovarian cancer was the biggest breakthrough in last decade.

 

While the existing standard of care Avastin for ovarian cancer is also effective in treating other types of cancer, PARP inhibitor has been actively conducting biomarker researches and entered the ovarian cancer treatment market as a result.

 

Dr.

 

Kim Jae Won (“KJ”): At a global gynecologic oncology society seminar a few years ago, we had a discussion on the “game changer” in ovarian cancer.

 

I personally think the PARP inhibitor would be the game changer for ovarian cancer patients.

 

Unlike before, the overall survival for the patients has been extended.

 

-Other than BRCA gene mutation, PARP inhibitor also targets HRD as another biomarker.

 

Please elaborate on the efficacy and value of HRD as a biomarker?

 

KB: Based on the clinical findings so far, PARP inhibitor monotherapy demonstrates the best treatment effect in BRCA mutation-positive patients.

 

The next in line is HRD group, where the medicine confirmed its effect through clinical studies.

 

However, the problem was ‘how to define HRD?’ The BRCA mutation could be dichotomously divided into positive or negative mutation, but HRD is rather scaled by the level of severity.

 

Therefore, the cut-off line for diagnosing the patients became crucial.

 

No clear standard was set to determine score the severity of HRD that categorizes the patients.

 

And as the standard could change depending on the PARP inhibitor and the line of treatment, more studies should follow in the future.

 

KJ: I agree.

 

It is great news that PARP inhibitor prescription can now cover both BRCA and HRD groups.

 

But HRD diagnosis has to be developed further as it is not a clear dichotomy, but a spectrum.

 

Then, does that mean there is no consensus on the clear cut-off line to define the HRD group at the moment?

 

KB: There is a consensus agreed upon each drug.

 

The PRIMA study on Zejula as a first-line treatment was conducted by dividing the patient group by the HRD cut-off score set at 42 points.

 

Zejula’s efficacy was confirmed in all patients, regardless of biomarker, but the study divided the HRD group, because the prognosis has to be observed in different patient groups.

 

Another PARP inhibitor candidate ‘veliparib’ by AbbVie has conducted a trial based on cut-off score of 33 points.

 

Dr.

 

Kim Jae Won

-As mentioned just now, Zejula has an all-comer indication.

 

But the South Korean government is conservative on granting the insurance benefit on BRCA or HRD-negative patients.

 

Do you think the coverage should be provided for all types of ovarian cancer patients?

 

KJ: With the launch of Zejula, a patient group who are homologous recombination proficient (HRp) can use a maintenance therapy, which can significantly raise the survival rate.

 

And a first-line maintenance therapy and a second or later-line therapy showed a vast difference.

 

Obviously, using the drug earlier boosts the survival rate.

 

Personally, the first-line maintenance therapy should be covered with insurance for all patients, if possible.” JB: But the fairness among other types of cancer is important, and it would also require concrete evidence related to efficacy and survival rate.

 

Currently listed for reimbursement in first-line therapy, Avastin’s overall survival (OS) evidence played a big role in the listing process.

 

Zejula would also be able to receive the reimbursement, when the survival rate data is accumulated enough for all-comers.

 

-In South Korea, Lynparza and Zejula can be prescribed as a first-line maintenance treatment.

 

When there is a patient group with overlapping indications, how do you choose a drug?

 

KJ: Zejula’s PRIMA study included more patients with advanced ovarian cancer.

 

So I lean towards using Zejula more, when treating a patient in an advanced stage.

 

And depending on the patients, I also take administration convenience into account.

 

-The treatment scene has changed through the emergence of PARP inhibitor, and it would continue to evolve in the future.

 

When there are more options to treat a disease, then naturally you would have to consider sequential treatment.

 

KJ: While Avastin has evidence of the efficacy in a second-line treatment when relapsing after a first-line treatment, PARP inhibitors do not have such evidence, yet.

 

It would be advisable to use PARP inhibitor in first-line maintenance treatment, and prescribing Avastin when relapsed.

 

-It seems like PARP inhibitor would become a backbone substance in treating ovarian cancer.

 

Is there a promising option with PARP inhibitor backbone in the future?

 

KB: Currently, there are about four clinical trials in process to confirm combination therapies using PARP inhibitor as a backbone.

 

Based on beyond biomarker testing, the clinical trials are seeking for mechanisms to treat patients without BRCA mutation more effectively, which would be integral studies for the prospective ovarian cancer treatment scene.