Rucaparib (Rubraca^®)

The US Food and Drug Administration (FDA) approval of the poly (ADP-ribose) polymerase (PARP) inhibitor class of drugs for the treatment of select patients with recurrent ovarian cancer¹ has been welcomed by both treatment providers and patients, for whom few effective options existed. Although surgery and platinum-based cytotoxic regimens remain the cornerstones of front-line therapy for patients with ovarian cancer,² the availability of a new class of oral agents, which has demonstrated efficacy³ for those with a poor prognosis [namely, patients who harbor either a germline or somatic homologous recombination deficiency (HRD), such as BRCA1], is considered by many in the field to be a major advance.⁴ Currently, the use of these oral drugs as maintenance therapy^5-7 has been shown to significantly prolong progression free survival.⁸

Rucaparib, the second PARP inhibitor to be approved for select patients with recurrent ovarian cancer, is an FDA-approved treatment for women who have received at least two lines of chemotherapy and whose tumors are associated with deleterious BRCA mutation–associated (germline and/or somatic) advanced ovarian cancer.¹⁰ It may also be used for maintenance in patients considered to have had a complete or partial response to platinum-based therapy.^5,8

Maintenance Versus Treatment: Very Different Decisions

According to Elizabeth Swisher, MD, Professor in Gynecologic Oncology and Adjunct Professor in Medical Genetics at the University of Washington Medicine, “the decisions patients need to make in the two settings (ie, maintenance vs monotherapy) are radically different. Despite the excellent data that were reported [with PARP inhibitors in the maintenance setting],⁸ not all patients want to be on prolonged maintenance therapy. Patients really like being off therapy. It gives them a period of time to ‘feel normal,’” she explained.

Dr. Swisher, who is also Director of the Breast and Ovarian Cancer Prevention Program with the Seattle Cancer Care Alliance, told JNCCN 360 she would encourage a patient with an inherited or somatic BRCA mutation to consider maintenance treatment, because that population clearly derives the greatest benefit. Nevertheless, “making a decision about maintenance is a big deal because the choice is between a somewhat toxic drug and nothing,” she pointed out. “You are always going to feel better on nothing.”

In contrast, for treatment of recurrence (after multiple lines of chemotherapy), the choice is often between chemotherapy and a PARP inhibitor. “Rucaparib or another PARP inhibitor is better tolerated than chemotherapy.”

“We order germline and tumor testing for BRCA mutations at the time of diagnosis,” Dr. Swisher said [Editor’s Note: Testing is recommended in the NCCN Guidelines for persistent/recurrent disease.²] That’s useful information to have upfront, she noted, “particularly now that we can offer PARP inhibitor clinical trials in earlier settings. I have a patient, for instance, with a somatic BRCA mutation, who is currently receiving front-line chemotherapy. Because I know about the mutation in her cancer, we can discuss maintenance as something she is very likely to derive benefit from.”

Surprisingly Broad Drug Approval

In the maintenance setting, rucaparib was approved for any patient who is in a complete or partial response to platinum-based chemotherapy for recurrent ovarian cancer, “which is unusual,” Dr. Swisher remarked, “because it is broader than the criteria used in the clinical trial.” For instance, she pointed out, patients with clear cell ovarian cancer were not eligible for the study,^11,12 but the FDA did not make that histologic distinction in the labeling. “Without data, we don’t know whether these drugs, which are expensive and toxic, will offer benefit for patients with clear cell histology.” Likewise, Dr. Swisher continued, according to the current labeling, a patient with a partial response to platinum, even a partial response that did not persist after completion of chemotherapy, can receive rucaparib. However, to be eligible for the clinical trial, she said, “the patient’s response to platinum had to be very good.” The encompassing nature of the FDA approval was surprising in that it did not precisely reflect entry criteria from the trial.

Dr. Swisher noted that HRD testing is not done routinely at her institution because it is not part of the FDA labeling, and in the studies, “all patients derived benefit when rucaparib was used in the maintenance setting, regardless of HRD status. I don’t think we know how to use that test and in which patient population the results really add clinical information.”

Obtaining Payer Approval for Newer Drugs

Although the indications for the three available PARP inhibitors are somewhat different, “now that they’ve all been studied and approved [for maintenance therapy], those differences will tend to blur,” Dr. Swisher shared with JNCCN 360. “The hazard ratios in all the studies were highly similar, so these drugs may be considered basically interchangeable,” she said. [Editor’s Note: The NCCN Guidelines do not recommend these agents interchangeably.]

So far, Dr. Swisher reported, subtle differences in the labeling have not affected insurance coverage. If demand increases substantially, payers may become stricter, but for now, Dr. Swisher said, treatment with any of the PARP inhibitors is approved without much difficulty. “We haven’t needed to document how many previous lines of therapy a patient has had, for instance. And I know of colleagues in other cities who ordered olaparib for patients with somatic mutations and didn’t receive any pushback from the insurance company.” [Editor’s Note: Olaparib is indicated for monotherapy after three lines of therapy, whereas rucaparib is indicated for use after two lines. Likewise, olaparib is indicated for patients whose tumors harbor germline (ie, inherited) BRCA mutations, whereas rucaparib is indicated for patients with germline or somatic BRCA mutations.]

Ease of access in terms of actually obtaining the drug sometimes differs. In the Seattle area, for instance, “we can obtain rucaparib through multiple pharmacies, but only one distributes olaparib,” Dr. Swisher observed. “So we may select rucaparib because it is more convenient.”

Are Differences Between PARP Inhibitors Clinically Meaningful?

“It’s natural for providers to wonder whether a patient who benefited from one agent would derive additional or continued benefit from a different PARP inhibitor,” Dr. Swisher said. There’s no evidence that switching drugs is useful, “but it’s something we think about.” Or, if a patient has substantial nausea with one agent, “would a different agent be better? We don’t have enough clinical experience to know those answers,” she admitted.

For patients who might be starting treatment with low platelets at baseline, “olaparib or rucaparib would be better tolerated than niraparib, which is generally harder on platelets,” Dr. Swisher said. In the recurrent treatment setting, we use rucaparib or olaparib, but for maintenance, we could use any of the three available agents. Toxicities are roughly similar for all these agents, Dr. Swisher explained, although niraparib is associated with more hematologic effects. In contrast, niraparib is administered once a day, so it may be considered somewhat more convenient.

Effect on Liver and Kidneys

There have been reports of elevated liver enzymes with rucaparib, but Dr. Swisher explained that they are primarily related to cellular transport. “Those elevated laboratory values do not actually represent damage to the liver,” she said. “Rucaparib is not toxic to the liver. Rather, it creates a temporary bump in laboratory findings. I would not be worried about liver damage, but in terms of monitoring and the inconvenience of having to evaluate that elevation, I might choose another agent for a patient with elevated alanine transaminase or aspartate transaminase at baseline.”

Likewise, rucaparib can create a bump in creatinine laboratory values. Again, Dr. Swisher said, “although I am not worried about kidney damage, evaluating those results makes management a bit more complex in a patient with baseline elevated creatinine numbers.”

Initiating Therapy

Patient selection is important for success with PARP inhibitor therapy, according to Tyra S. Gatewood, PharmD, of the Moffitt Cancer Center, Tampa, Florida. In an interview with JNCCN 360, she explained that most patients who receive rucaparib have had at least two lines of platinum-based treatment. These patients may be fragile because of previous treatment and progression of disease, so it is important to “conduct a thorough history,” she said. “Ask about how previous treatment was tolerated. Did she experience nausea/vomiting? Did she develop thrombocytopenia? Did she need colony-stimulating factor?”

When rucaparib is started, I ask patients to come see me weekly for the first month.

Once the decision is made to start rucaparib, “we don’t just send patients home with their new oral prescription and say ‘see you in a month,’” Dr. Gatewood said. Because these patients have had previous treatment, they need to be monitored carefully and frequently. “When rucaparib is started,” Dr. Gatewood said, “I ask patients to come see me weekly for the first month. And, we ask them to call right away if they notice signs of anemia (eg, shortness of breath, unusual fatigue) or thrombocytopenia (eg, bruising easily, bleeding gums, nosebleeds). Likewise, I also want to know if any of their other medications are changed, and, of course, if they are experiencing significant nausea or vomiting.” 

Helping Patients Stay on Therapy

The primary adverse effects associated with rucaparib are nausea and fatigue, which both tend to improve after about 4 weeks, according to Dr. Swisher. Patients who receive rucaparib for maintenance may become discouraged, she said, unless they are reassured that they will likely feel better after the first month. “We really try not to dose reduce for the first 4 weeks but help patients push through by repeated counseling and encouragement. We also prescribe a prophylactic antinausea regimen to be taken 30 minutes before taking rucaparib,” Dr. Swisher added. Together with a recommendation to take rucaparib with food or soon after a meal, nausea may abate after the first month, and “many patients can stop taking the antiemetic.”

We really try not to dose reduce for the first 4 weeks but help patients push through by repeated counseling and encouragement.

Dr. Gatewood noted that severe nausea is difficult to control, “so I tend to play it safe by sending the patient home with a 5-HT3 antagonist to be used prior to each rucaparib dose and phenothiazine every 6 hours as needed. If the instructions to take rucaparib with food and the antinausea medication seem insufficient, we will recommend using [the antinausea medication] more frequently to gain better control. Finally, we will consider dose reduction if the nausea continues to be intolerable after a few weeks.”

One of Dr. Gatewood’s tips is to be consistent about the timing and circumstances of taking the medication. Patients should take their antinausea medication and then take rucaparib with a meal or after a meal, she advised. “Results will not be optimal if they sometimes take the antinausea drug and sometimes don’t or sometimes take rucaparib with a meal and other times on an empty stomach.”

I’ve probably done more dose reduction for fatigue than for any other adverse effect in those who receive rucaparib long term.

Clinically, fatigue appears to have a bimodal pattern, Dr. Swisher observed. After the first month on the new medication (ie, rucaparib), energy returns to normal or near-normal levels. But, when patients have been on treatment for a long time, “maybe a year or longer,” Dr. Swisher said, the fatigue seems to set in again. “It’s difficult, though, to tease out whether that’s drug-related or due to disease progression. I’ve probably done more dose reduction for fatigue than for any other adverse effect in those who receive rucaparib long term,” she told JNCCN 360. “We are trying to maintain quality of life, and if fatigue becomes severe, that’s not acceptable.” Dose reductions of rucaparib are generally from 600 mg to 500 mg, still twice a day.  

With regard to fatigue, Dr. Gatewood noted, “we encourage patients to stay as active as they can and to try moderate exercise as a way of maintaining energy. If the fatigue is drug-related, we may consider dose reduction or even transfusion.” 

Next Steps and Closing Thoughts

One of the next logical steps in drug development is to determine whether there is any role for rucaparib in the first-line treatment of patients with ovarian cancer. Additionally, Dr. Swisher noted, “there is a good deal of interest in combining rucaparib with an immune checkpoint inhibitor, both in the front-line and recurrent disease settings.” Other researchers are considering whether there is value in combining PARP inhibitors with bevacizumab or other antiangiogenic agents, such as cediranib,¹³ she said.

Rucaparib and the other agents in the PARP inhibitor class are really exciting, Dr. Swisher pointed out, “but we still are not curing most patients with recurrent disease.” Those who receive monotherapy for progressive disease usually achieve partial responses, which last for less than 1 year.¹⁴ Therefore, “although we have reason to be optimistic and to view these results as representative of an important advance,” she concluded, “they are still not good enough for our patients. We are working hard to figure out how best to utilize these drugs, perhaps in combination with other drugs, so we can turn some of these responses into cures. We need to remember that goal and keep striving toward it.”

DISCLOSURES 

Elizabeth Swisher, MD, disclosed no relevant relationships.

Tyra S. Gatewood, PharmD, disclosed no relevant relationships.

References

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