Feature

Rucaparib induces response in BRCA-mutated pancreatic cancer

Susan M. Domchek

Some patients with advanced pancreatic cancer who harbor BRCA1 or BRCA2 mutations derived clinical benefit from rucaparib, according to study results.

Rucaparib (Rubraca, Clovis Oncology) — a PARP inhibitor approved by FDA for maintenance treatment of certain women with ovarian, fallopian tube or primary peritoneal cancers — also exhibited a tolerable safety profile.

Susan M. Domchek, MD, executive director of Basser Center for BRCA at University of Pennsylvania’s Abramson Cancer Center, and colleagues studied 19 patients with measurable locally advanced or metastatic pancreatic cancer who underwent one or two prior chemotherapy regimens. Sixteen patients had germline BRCA1 or BRCA2 mutations, and the other three had somatic mutations.

All patients received 600 mg rucaparib twice daily until disease progression. Objective response rate served as the primary outcome measure.

Four patients responded to treatment. These included two partial responses, one confirmed complete response and one unconfirmed complete response (confirmed ORR = 15.8%).

Researchers also assessed disease control rate, defined as complete response, partial response, or stable disease for 12 weeks or longer. Results showed disease control rates of 31.6% overall and 44.4% among those who received one prior chemotherapy regimen.

Investigators discontinued the study after an insufficient response rate among the first 15 patients enrolled, as the confirmed responses were observed in the last patients to enroll.

More than 60% of patients experienced nausea, and nearly half developed anemia.

Researchers also observed secondary resistance mutations in circulating free tumor DNA of two patients with germline BRCA2 mutations.

HemOnc Today spoke with Domchek about the challenges of treating pancreatic cancer, the role of BRCA mutations in malignancies other than breast or ovarian cancers, and the broader role of PARP inhibitors for this patient population.

 

Question: How did this study come about?

Answer: We have learned a lot over the last 8 or 9 years about using PARP inhibitors for individuals who have germline BRCA mutations in breast and ovarian cancer. The first FDA approval of a PARP inhibitor came in 2014 when the agency approved olaparib (Lynparza, AstraZeneca) for BRCA1/BRCA2-related ovarian cancer. There now are three PARP inhibitors approved for ovarian cancer, the others being rucaparib and niraparib (Zejula, Tesaro). Olaparib also is FDA approved for metastatic BRCA1/BRCA2-related breast cancer. In this context, there has been a great deal of interest in whether these drugs could be used in other tumors associated with BRCA1/BRCA2 mutations We have known for some time that mutations in BRCA1/BRCA2 increase one’s risk for pancreatic cancer. A prior study a few years ago looking at olaparib for BRCA1/BRCA2 mutation-associated pancreatic cancer gave us the hint that this medication could be useful for this population. The study we are discussing now used rucaparib in either germline or somatic BRCA-related pancreatic cancers. We had tumors respond that were associated with both kinds of mutations. Given how difficult advanced pancreatic cancer is to deal with, we find these results encouraging.

 

Q: Can you describe the need for new, effective therapies for pancreatic cancer?

A: Pancreatic cancer is quite challenging to treat and has a very high mortality rate, but it is also of concern that the incidence of pancreatic cancer is rising in the United States. For those reasons, there has been a great deal of interest in coming up with new treatment approaches. To date, we have just had chemotherapy. The idea that we could identify a group of individuals with pancreatic cancer who could potentially benefit from a more targeted therapy is encouraging. PARP inhibitors are oral medications that can be taken twice daily. Patients don’t lose their hair and the treatment doesn’t cause neuropathy like so many of the other drugs for pancreatic cancer do. There has been a dire need for new options for these patients.

Q: Can you describe the mechanism of this drug class and elaborate on whether it really represents a viable treatment option for pancreatic cancer ?

A: PARP inhibitors work by a number of different mechanisms. The simplest way to explain it is by using the concept of synthetic lethality. These drugs seem to work in tumors that already have compromised DNA damage repair pathways. One of the major ways a tumor can end up with a compromised DNA damage repair pathway is with a BRCA mutation. PARP inhibitors target a second DNA damage repair pathway, in addition to getting trapped and causing more DNA damage. The cumulative effect of having an already damaged DNA repair pathway in the tumor and adding these drugs can be catastrophic with death of the tumor. This was shown in cell lines and then taken into patient populations, with the largest studies to date in breast and ovarian cancer. Now we are rolling it out in pancreatic cancer. BRCA1/BRCA2-related pancreatic cancer accounts for approximately 7% of pancreatic cancer cases. This may seem like small portion of individuals, but it is still a sizable number of patients with a deadly disease who potentially could benefit from this drug. We are hopeful that these drugs may benefit individuals beyond that, including patients with tumors in other related genes, or those with compromised DNA damage repair pathways by other mechanisms.

 

Q: Could you talk more broadly about how your findings could establish the clinical significance of BRCA mutations in malignancies other than ovarian cancer and breast cancer?

A : When we think more broadly about different malignancies, this gets a little complicated. If you think about how PARP inhibitors work, even if you have a mutation in a gene, these drugs — based on what we understand now — really should only work if both copies of that gene are lost. It is possible that someone could have a mutation from BRCA1 and have a brain tumor, and that tumor has nothing to do with that mutation and didn’t have loss of that second copy. In that case, the tumor may not be responsive to PARP inhibitors. We do have to sort out how important that is. When we talk about tumors in general, we really have to think about how having a BRCA mutation may be a good signal that these drugs might work. But that may not be enough, so we have to understand more deeply what is going on there. When we talk about other genes, the picture gets even more complicated, because we know less about these other genes than we do about BRCA1/BRCA2. But the same issues apply. There are also data that PARP inhibitors may work for certain types of prostate cancer. Two studies underway at Penn are looking at PARP inhibitors in pancreatic cancer. The first is studying BRCA1/BRCA2 and PALB2 mutation-associated pancreatic cancer. In the second study, we’re looking at patients whose tumors respond to platinum-based therapy who then go on to a PARP inhibitor. In that study, we’re not looking at BRCA mutations specifically. We’re looking at whether platinum predicts response to a PARP inhibitor. We have to keep investigating because we want to identify the cancers most likely to respond to these drugs.

 

Q: What further knowledge do you hope to gain from subsequent research?

A : The lowest hanging fruit is to determine how useful these drugs are and whether we can get FDA approval for BRCA1/BRCA2-related pancreatic cancer. The next step is to determine whether these drugs can this be used for individuals who have tumors in other genes. We are also asking the question of whether we can we determine, by looking at the tumor’s mutational signature, whether these tumors have this homologous recombination repair deficiency, and whether that would make them susceptible to PARP inhibitors. That could potentially expand number of patients for whom this drug might be useful. – by Rob Volansky

 

Reference:

Shroff RT, et al. JCO Precis Oncol. 2018;doi:10.1200/PO.17.00316.

 

For more information:

Susan M. Domchek, MD, can be reached at Abramson Cancer Center, Perelman Center for Advanced Medicine, West Pavilion, 3rd Floor, 3400 Civic Center Blvd., Philadelphia, PA 19104; email: susan.domchek@uphs.upenn.edu.

Disclosure: Domchek reports honoraria from AstraZeneca, Bristol-Myers Squibb and Clovis Oncology.

Susan M. Domchek

Some patients with advanced pancreatic cancer who harbor BRCA1 or BRCA2 mutations derived clinical benefit from rucaparib, according to study results.

Rucaparib (Rubraca, Clovis Oncology) — a PARP inhibitor approved by FDA for maintenance treatment of certain women with ovarian, fallopian tube or primary peritoneal cancers — also exhibited a tolerable safety profile.

Susan M. Domchek, MD, executive director of Basser Center for BRCA at University of Pennsylvania’s Abramson Cancer Center, and colleagues studied 19 patients with measurable locally advanced or metastatic pancreatic cancer who underwent one or two prior chemotherapy regimens. Sixteen patients had germline BRCA1 or BRCA2 mutations, and the other three had somatic mutations.

All patients received 600 mg rucaparib twice daily until disease progression. Objective response rate served as the primary outcome measure.

Four patients responded to treatment. These included two partial responses, one confirmed complete response and one unconfirmed complete response (confirmed ORR = 15.8%).

Researchers also assessed disease control rate, defined as complete response, partial response, or stable disease for 12 weeks or longer. Results showed disease control rates of 31.6% overall and 44.4% among those who received one prior chemotherapy regimen.

Investigators discontinued the study after an insufficient response rate among the first 15 patients enrolled, as the confirmed responses were observed in the last patients to enroll.

More than 60% of patients experienced nausea, and nearly half developed anemia.

Researchers also observed secondary resistance mutations in circulating free tumor DNA of two patients with germline BRCA2 mutations.

HemOnc Today spoke with Domchek about the challenges of treating pancreatic cancer, the role of BRCA mutations in malignancies other than breast or ovarian cancers, and the broader role of PARP inhibitors for this patient population.

 

Question: How did this study come about?

Answer: We have learned a lot over the last 8 or 9 years about using PARP inhibitors for individuals who have germline BRCA mutations in breast and ovarian cancer. The first FDA approval of a PARP inhibitor came in 2014 when the agency approved olaparib (Lynparza, AstraZeneca) for BRCA1/BRCA2-related ovarian cancer. There now are three PARP inhibitors approved for ovarian cancer, the others being rucaparib and niraparib (Zejula, Tesaro). Olaparib also is FDA approved for metastatic BRCA1/BRCA2-related breast cancer. In this context, there has been a great deal of interest in whether these drugs could be used in other tumors associated with BRCA1/BRCA2 mutations We have known for some time that mutations in BRCA1/BRCA2 increase one’s risk for pancreatic cancer. A prior study a few years ago looking at olaparib for BRCA1/BRCA2 mutation-associated pancreatic cancer gave us the hint that this medication could be useful for this population. The study we are discussing now used rucaparib in either germline or somatic BRCA-related pancreatic cancers. We had tumors respond that were associated with both kinds of mutations. Given how difficult advanced pancreatic cancer is to deal with, we find these results encouraging.

 

Q: Can you describe the need for new, effective therapies for pancreatic cancer?

A: Pancreatic cancer is quite challenging to treat and has a very high mortality rate, but it is also of concern that the incidence of pancreatic cancer is rising in the United States. For those reasons, there has been a great deal of interest in coming up with new treatment approaches. To date, we have just had chemotherapy. The idea that we could identify a group of individuals with pancreatic cancer who could potentially benefit from a more targeted therapy is encouraging. PARP inhibitors are oral medications that can be taken twice daily. Patients don’t lose their hair and the treatment doesn’t cause neuropathy like so many of the other drugs for pancreatic cancer do. There has been a dire need for new options for these patients.

 

PAGE BREAK

Q: Can you describe the mechanism of this drug class and elaborate on whether it really represents a viable treatment option for pancreatic cancer ?

A: PARP inhibitors work by a number of different mechanisms. The simplest way to explain it is by using the concept of synthetic lethality. These drugs seem to work in tumors that already have compromised DNA damage repair pathways. One of the major ways a tumor can end up with a compromised DNA damage repair pathway is with a BRCA mutation. PARP inhibitors target a second DNA damage repair pathway, in addition to getting trapped and causing more DNA damage. The cumulative effect of having an already damaged DNA repair pathway in the tumor and adding these drugs can be catastrophic with death of the tumor. This was shown in cell lines and then taken into patient populations, with the largest studies to date in breast and ovarian cancer. Now we are rolling it out in pancreatic cancer. BRCA1/BRCA2-related pancreatic cancer accounts for approximately 7% of pancreatic cancer cases. This may seem like small portion of individuals, but it is still a sizable number of patients with a deadly disease who potentially could benefit from this drug. We are hopeful that these drugs may benefit individuals beyond that, including patients with tumors in other related genes, or those with compromised DNA damage repair pathways by other mechanisms.

 

Q: Could you talk more broadly about how your findings could establish the clinical significance of BRCA mutations in malignancies other than ovarian cancer and breast cancer?

A : When we think more broadly about different malignancies, this gets a little complicated. If you think about how PARP inhibitors work, even if you have a mutation in a gene, these drugs — based on what we understand now — really should only work if both copies of that gene are lost. It is possible that someone could have a mutation from BRCA1 and have a brain tumor, and that tumor has nothing to do with that mutation and didn’t have loss of that second copy. In that case, the tumor may not be responsive to PARP inhibitors. We do have to sort out how important that is. When we talk about tumors in general, we really have to think about how having a BRCA mutation may be a good signal that these drugs might work. But that may not be enough, so we have to understand more deeply what is going on there. When we talk about other genes, the picture gets even more complicated, because we know less about these other genes than we do about BRCA1/BRCA2. But the same issues apply. There are also data that PARP inhibitors may work for certain types of prostate cancer. Two studies underway at Penn are looking at PARP inhibitors in pancreatic cancer. The first is studying BRCA1/BRCA2 and PALB2 mutation-associated pancreatic cancer. In the second study, we’re looking at patients whose tumors respond to platinum-based therapy who then go on to a PARP inhibitor. In that study, we’re not looking at BRCA mutations specifically. We’re looking at whether platinum predicts response to a PARP inhibitor. We have to keep investigating because we want to identify the cancers most likely to respond to these drugs.

 

Q: What further knowledge do you hope to gain from subsequent research?

A : The lowest hanging fruit is to determine how useful these drugs are and whether we can get FDA approval for BRCA1/BRCA2-related pancreatic cancer. The next step is to determine whether these drugs can this be used for individuals who have tumors in other genes. We are also asking the question of whether we can we determine, by looking at the tumor’s mutational signature, whether these tumors have this homologous recombination repair deficiency, and whether that would make them susceptible to PARP inhibitors. That could potentially expand number of patients for whom this drug might be useful. – by Rob Volansky

 

Reference:

Shroff RT, et al. JCO Precis Oncol. 2018;doi:10.1200/PO.17.00316.

 

For more information:

Susan M. Domchek, MD, can be reached at Abramson Cancer Center, Perelman Center for Advanced Medicine, West Pavilion, 3rd Floor, 3400 Civic Center Blvd., Philadelphia, PA 19104; email: susan.domchek@uphs.upenn.edu.

Disclosure: Domchek reports honoraria from AstraZeneca, Bristol-Myers Squibb and Clovis Oncology.

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