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Clinical Challenges: PARP Inhibitors in Ovarian Cancer

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Clinical Challenges: PARP Inhibitors in Ovarian Cancer

Four choices for maintenance therapy — including none

MedpageToday

  • by Senior Associate Editor, MedPage Today

In a short period of time, maintenance therapy for recurrent, platinum-sensitive ovarian cancer has evolved from a promising but unproven clinical concept to a widely accepted and used therapeutic strategy.

Since the beginning of 2017, the FDA has approved three poly ADP-ribose polymerase (PARP) inhibitors for maintenance treatment after chemotherapy for recurrent, platinum-sensitive disease: olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca). The sudden availability of multiple options where a void existed not that long ago has raised some fairly obvious questions:

  • Whether every patient who is a candidate for PARP inhibitor maintenance therapy should receive it
  • How to choose among the PARP inhibitors
  • The role of bevacizumab (Avastin), also approved for maintenance therapy

“I think it is too simplistic to state that all patients who are potential candidates for PARP inhibitor maintenance therapy should receive it,” said Charles A. Leath III, MD, of the University of Alabama at Birmingham. “Patients who are potentially eligible certainly should be considered for PARP inhibitor maintenance therapy and should have a discussion of both the pros and cons of this therapy — based on the presence or absence of a germline BRCA mutation, a somatic or tumor mutation, as well as the absence of these changes — with their oncology provider.

“While all patients, regardless of germline line and tumor testing results might be eligible for PARP inhibitor maintenance therapy, they need to understand the expected and potential magnitude of benefit based on their specific clinical situation, including not only their germline status but also potential residual toxicity(ies) from previous therapy. Moreover, these therapies may be associated with side effects, albeit predictable, to include gastrointestinal as well as hematologic toxicities in general, among others, and may be expensive from an insurance standpoint.”

Clinical Ground Rules

The FDA set different ground rules for use of a PARP inhibitor as treatment for ovarian cancer versus maintenance therapy, said Don Dizon, MD, of Brown University and Rhode Island Hospital in Providence. Use as primary treatment requires the presence of a BRCA mutation, whereas maintenance therapy can be given to any patients with recurrent, platinum-sensitive disease, irrespective of mutation status.

The less restrictive rules for the maintenance therapy “has opened up PARP inhibitors to quite a large group of women,” Dizon told MedPage Today. “Whether everybody should get these PARP inhibitors is debatable.

“On the one hand, there are no restrictions by histology in the treatment of recurrent ovarian cancer. But if you look at the clinical trials, the PARP inhibitors were studied in women with high-grade serous carcinomas of the ovaries. Is there going to be a better fit in low-grade, mucinous, or even clear-cell carcinomas? We don’t know.”

The harder, more germane question is not whether a patient should receive PARP inhibitor maintenance therapy, but instead, who is a candidate, said David R. Spriggs, MD, of Massachusetts General Hospital Cancer Center. Investigators in clinical trials developed the data for PARP inhibitor maintenance from nested analyses of fixed-size populations of patients with BRCA-positive, homologous recombination deficiency (HRD)-abnormal, and wild type tumors.

“What that means is that the clinical trials are not sized for the population; they’re sized for the treatment effect they’re looking for,” said Spriggs, who has an extensive background in therapeutic development. ‘They have far more germline BRCA-mutated patients in those trials. The effect on BRCA-mutated patients is profound for all of the drugs. It is less profound for either the somatic BRCA-mutated patient or the HRD-abnormal patient. The effect is there for patients who have none of those, but it’s very modest.”

Sorting Through Options

For patients with germline BRCA mutations, “there is no doubt that a PARP inhibitor is the best maintenance therapy,” better than bevacizumab, he continued. Patients with somatic BRCA mutations and HRD abnormalities “probably” do better with a PARP inhibitor than with another option, such as bevacizumab. Patients without any of the abnormalities “probably aren’t going to be big winners with any of the PARP inhibitors.”

A caveat to such a nuanced approach to using PARP inhibitors as maintenance therapy is that mutation status should be documented by an appropriate laboratory test, and most insurers will pay for only one test, said Spriggs.

“The niraparib people were the first ones to design their studies so you couldn’t pull out the wild-type BRCA population and managed to come out with a win across the board,” he added. “You can put those patients on niraparib, whether that’s the best maintenance or whether those patients ought to get bevacizumab.”

With regard to his own decision tree, Spriggs said olaparib has the most clinical experienced and data and probably is his choice for BRCA-mutated patients, assuming they can tolerate the nausea, fatigue, and anemia associated with prolonged maintenance. For the HRD-mutated and wild-type subgroups, he leans toward niraparib because of greater potency.

“If I go with niraparib second, I’m really going to have to watch the patients closely because you can really trash someone’s platelet count with an immunosuppressive drug,” he said. “The real issue with niraparib is whether the patient will tolerate it.”

Rucaparib is a good drug, Spriggs added, but its approval for maintenance therapy came later, leaving it in a position of having to play catch-up with olaparib and niraparib. Using the drug poses “a little bit of a hassle,” because it causes transient elevations of creatinine and liver enzymes, “which can be a little scary, but the effects go away.”

Approved as maintenance therapy in 2016, ahead of all the PARP inhibitors, bevacizumab remains an option for maintenance therapy, particularly for patients whose disease is not associated with specific genetic/molecular abnormalities. Some clinicians may favor it over a PARP inhibitor because of greater familiarity with the drug and its activity across mutational subtypes. Another consideration with bevacizumab is mode of administration: intravenous infusion versus oral treatment with all of the PARP inhibitors.

Leath disclosed relationships with Mateon Therapeutics, Celsion, AstraZeneca, Tesaro, Roche/Genetech, AbbVie, and TapImmune.

Dizon reported relationships with InfiniteMD, NeuHope, Fuji Pharma, Pfizer, UpToDate, Aeterna Zentaris, Bristol-Myers Squibb, Hologic, and Teva.

Spriggs reported having no relevant relationships with industry.

2018-06-13T14:45:00-0400
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Medpage Today

Clinical Challenges: PARP Inhibitors in Ovarian Cancer

Four choices for maintenance therapy -- including none

MedpageToday

  • by Senior Associate Editor, MedPage Today

In a short period of time, maintenance therapy for recurrent, platinum-sensitive ovarian cancer has evolved from a promising but unproven clinical concept to a widely accepted and used therapeutic strategy.

Since the beginning of 2017, the FDA has approved three poly ADP-ribose polymerase (PARP) inhibitors for maintenance treatment after chemotherapy for recurrent, platinum-sensitive disease: olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca). The sudden availability of multiple options where a void existed not that long ago has raised some fairly obvious questions:

  • Whether every patient who is a candidate for PARP inhibitor maintenance therapy should receive it
  • How to choose among the PARP inhibitors
  • The role of bevacizumab (Avastin), also approved for maintenance therapy

"I think it is too simplistic to state that all patients who are potential candidates for PARP inhibitor maintenance therapy should receive it," said Charles A. Leath III, MD, of the University of Alabama at Birmingham. "Patients who are potentially eligible certainly should be considered for PARP inhibitor maintenance therapy and should have a discussion of both the pros and cons of this therapy -- based on the presence or absence of a germline BRCA mutation, a somatic or tumor mutation, as well as the absence of these changes -- with their oncology provider.

"While all patients, regardless of germline line and tumor testing results might be eligible for PARP inhibitor maintenance therapy, they need to understand the expected and potential magnitude of benefit based on their specific clinical situation, including not only their germline status but also potential residual toxicity(ies) from previous therapy. Moreover, these therapies may be associated with side effects, albeit predictable, to include gastrointestinal as well as hematologic toxicities in general, among others, and may be expensive from an insurance standpoint."

Clinical Ground Rules

The FDA set different ground rules for use of a PARP inhibitor as treatment for ovarian cancer versus maintenance therapy, said Don Dizon, MD, of Brown University and Rhode Island Hospital in Providence. Use as primary treatment requires the presence of a BRCA mutation, whereas maintenance therapy can be given to any patients with recurrent, platinum-sensitive disease, irrespective of mutation status.

The less restrictive rules for the maintenance therapy "has opened up PARP inhibitors to quite a large group of women," Dizon told MedPage Today. "Whether everybody should get these PARP inhibitors is debatable.

"On the one hand, there are no restrictions by histology in the treatment of recurrent ovarian cancer. But if you look at the clinical trials, the PARP inhibitors were studied in women with high-grade serous carcinomas of the ovaries. Is there going to be a better fit in low-grade, mucinous, or even clear-cell carcinomas? We don't know."

The harder, more germane question is not whether a patient should receive PARP inhibitor maintenance therapy, but instead, who is a candidate, said David R. Spriggs, MD, of Massachusetts General Hospital Cancer Center. Investigators in clinical trials developed the data for PARP inhibitor maintenance from nested analyses of fixed-size populations of patients with BRCA-positive, homologous recombination deficiency (HRD)-abnormal, and wild type tumors.

"What that means is that the clinical trials are not sized for the population; they're sized for the treatment effect they're looking for," said Spriggs, who has an extensive background in therapeutic development. 'They have far more germline BRCA-mutated patients in those trials. The effect on BRCA-mutated patients is profound for all of the drugs. It is less profound for either the somatic BRCA-mutated patient or the HRD-abnormal patient. The effect is there for patients who have none of those, but it's very modest."

Sorting Through Options

For patients with germline BRCA mutations, "there is no doubt that a PARP inhibitor is the best maintenance therapy," better than bevacizumab, he continued. Patients with somatic BRCA mutations and HRD abnormalities "probably" do better with a PARP inhibitor than with another option, such as bevacizumab. Patients without any of the abnormalities "probably aren't going to be big winners with any of the PARP inhibitors."

A caveat to such a nuanced approach to using PARP inhibitors as maintenance therapy is that mutation status should be documented by an appropriate laboratory test, and most insurers will pay for only one test, said Spriggs.

"The niraparib people were the first ones to design their studies so you couldn't pull out the wild-type BRCA population and managed to come out with a win across the board," he added. "You can put those patients on niraparib, whether that's the best maintenance or whether those patients ought to get bevacizumab."

With regard to his own decision tree, Spriggs said olaparib has the most clinical experienced and data and probably is his choice for BRCA-mutated patients, assuming they can tolerate the nausea, fatigue, and anemia associated with prolonged maintenance. For the HRD-mutated and wild-type subgroups, he leans toward niraparib because of greater potency.

"If I go with niraparib second, I'm really going to have to watch the patients closely because you can really trash someone's platelet count with an immunosuppressive drug," he said. "The real issue with niraparib is whether the patient will tolerate it."

Rucaparib is a good drug, Spriggs added, but its approval for maintenance therapy came later, leaving it in a position of having to play catch-up with olaparib and niraparib. Using the drug poses "a little bit of a hassle," because it causes transient elevations of creatinine and liver enzymes, "which can be a little scary, but the effects go away."

Approved as maintenance therapy in 2016, ahead of all the PARP inhibitors, bevacizumab remains an option for maintenance therapy, particularly for patients whose disease is not associated with specific genetic/molecular abnormalities. Some clinicians may favor it over a PARP inhibitor because of greater familiarity with the drug and its activity across mutational subtypes. Another consideration with bevacizumab is mode of administration: intravenous infusion versus oral treatment with all of the PARP inhibitors.

Leath disclosed relationships with Mateon Therapeutics, Celsion, AstraZeneca, Tesaro, Roche/Genetech, AbbVie, and TapImmune.

Dizon reported relationships with InfiniteMD, NeuHope, Fuji Pharma, Pfizer, UpToDate, Aeterna Zentaris, Bristol-Myers Squibb, Hologic, and Teva.

Spriggs reported having no relevant relationships with industry.

2018-06-13T14:45:00-0400
Comments

Accessibility Statement

At MedPage Today, we are committed to ensuring that individuals with disabilities can access all of the content offered by MedPage Today through our website and other properties. If you are having trouble accessing www.medpagetoday.com, MedPageToday's mobile apps, please email legal@ziffdavis.com for assistance. Please put "ADA Inquiry" in the subject line of your email.



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