Ramez N. Eskander, MD

 This is an incredibly exciting time for us in the ovarian cancer space. Just in a 2-month span, we’ve had 2 frontline drug approvals. The PRIMA results resulted in the approval of maintenance niraparib for an all-comer population in the frontline setting for patients with advanced stage III or IV high-grade ovarian carcinoma. The PAOLA-1 trial resulted in the approval of the combination of bevacizumab and olaparib in the homologous recombination deficient population inclusive of patients with 

 mutations, again in stage III or IV disease. We also have several PARP approvals in the platinum-sensitive recurrent environment. So we have several options that we didn’t have just a short while ago.

We do still have some important questions to answer. We know that immunotherapy as a single agent when combined with chemotherapy has been disappointing in patients with advanced-stage ovarian cancer. Our hope is to design combination approaches that may augment response. There are several frontline studies looking at combinations of PARP inhibitors plus immunotherapy or immunotherapy plus antiangiogenic therapy, and some triplet studies are looking at antiangiogenic therapy, PARP inhibition, and immunotherapy to try to see whether we can expand the efficacy of these agents. Again, the goal is to get a meaningful response and provide opportunity for as many of our patients who are diagnosed in the front line as possible.

If we look at just homologous recombination deficiency and 

mutation, we capture about half of those patients who have high-grade advanced-stage disease. Well, we want to try to benefit the remaining 50%, and that may lie in these combination approaches that are actively being studied in frontline clinical trials. We’re awaiting the results of these studies. Hopefully they will inform future treatment opportunities for a patient population that continues to have a significant unmet need.

Case: A 71-Year Old Woman With High-Risk Ovarian Cancer

A 71-year old woman presented to her PCP for a routine annual checkup, she complains of increasing fatigue

2017 diagnosed with stage IV ovarian cancer; 

wt; underwent TAH/BSO, lymph node dissection, with suboptimal debulking; treated with paclitaxel/carboplatin/bevacizumab followed by maintenance bevacizumab; achieved CR

Chest/abdomen/pelvis CT with contrast shows a suspicious lung lesion

Lung biopsy confirmed recurrent epithelial ovarian cancer

She was started referred to an oncologist and started on carboplatin/doxorubicin, treatment was well tolerated for 4 cycles; CA-125 35 U/mL;

Rucaparib 300 mg BID maintenance was initiated

Chest/abdomen/pelvis CT showed no gross masses or nodes

Videos

Future Directions in High-Risk Ovarian Cancer

 Regarding the use of maintenance treatment with rucaparib in the platinum-sensitive recurrent setting, we focus on data from ARIEL3. As we discussed, ARIEL3 enrolled 564 patients. It was a randomized, double-blind, placebo-controlled trial that looked at evaluating the efficacy of rucaparib as a maintenance strategy in patients who had at least 2 prior lines of platinum-based therapy and who had a complete or partial response to the penultimate platinum-based regimen. What we saw with incorporation of rucaparib as a maintenance strategy was a significant improvement in the median progression-free survival [PFS]. And in the cohorts of patients enrolled on the study, the median PFS in the rucaparib arm was 16.6 months versus 5.4 months in the 

-mutated population. And it was 13.6 months versus 5.4 months in the LOH [loss of heterozygosity]-high group, again with a cutoff of 16%. Both of these were significantly better in the treatment arm versus the placebo. Even in the intent-to-treat patient population that lumped in all patients enrolled, including LOH-low patients, it was 10.8 months versus 5.4 months.

What we see from ARIEL3 is that we have a meaningful improvement in the median progression-free survival with a maintenance strategy with no significant decrement in the quality of life, speaking to the safety of rucaparib and the tolerability. The treatment-related adverse effects are a reality for our patients on maintenance treatment, and it’s our obligation, again, to be honest, to educate them about what treatment-related adverse effects they may experience, and to be proactive about mitigation strategies. Ultimately, our goal is to keep patients on treatment, because we believe that this treatment is beneficial to preserving a remission.

In treating patients with PARP inhibitors, many of the trials that were designed to evaluate efficacy of rucaparib had end points that were essentially placed for the duration of PARP therapy and were fairly subjective or arbitrary. We want to balance efficacy versus potential toxicity, or adverse events, from the drug regimens. In clinical practice, when we treat with a PARP inhibitor like rucaparib in the recurrent setting, we treat patients until they have unacceptable toxicity or adverse effects from treatment, or conversely, if they have disease progression. As long as patients are tolerating treatment, if they remain on therapy and are in remission, they could be continued on their PARP inhibitor. A couple of the clinical trials that were performed would end treatment at 2 years if the patient remained in complete response. But again, these are fairly subjective designs. In clinical practice, patients can stay on maintenance PARP inhibitors for as long as they derive benefit.

Rucaparib Maintenance Therapy for High-Risk Ovarian Cancer

 Maintenance therapy is an important component of the treatment of patients with advanced ovarian cancer. This has transformed our management of advanced-stage ovarian cancer in the last 3 years. What we’ve discovered is that we have several opportunities for maintenance treatment during therapy. I’ll start in the frontline setting.

Again, based on the results of both PRIMA as well as the PAOLA-1 trial, we now have opportunities for maintenance PARP inhibition in the frontline setting for an all-comer population, and that’s niraparib. That’s based on an improvement in the median progression-free survival, with the goal being to extend the interval of time in which the patient is in remission, which will potentially facilitate alternate treatment options down the line.

In the PAOLA-1 study, the combination of bevacizumab plus olaparib was compared against bevacizumab plus placebo. And in that patient population, the approval was in those with a homologous recombination deficiency [HRD] who, again, appeared to have a significant benefit over bevacizumab plus placebo with the addition of a maintenance olaparib regimen. Both of these studies followed the approval of maintenance single-agent olaparib in 2018, and that was based on the SOLO-1 trial specifically in the 

-mutated germline or somatic patient population. So we went from having a maintenance strategy with olaparib, specifically in the 

-mutated population, to now having maintenance opportunities with niraparib in the all-comer population, or olaparib plus bevacizumab in patients who are homologous recombination deficient, including those with a 

And briefly we touch on the fact that bevacizumab was the initial maintenance strategy that was approved for us quite a while back as an antiangiogenic agent. Some patients may have been on bevacizumab with chemotherapy and continued on maintenance bevacizumab. Now you get into the discussion of, how can we layer these maintenance approaches, and is there relevance to sequentially applying these medications versus using them in combination? Those data have yet to be developed.

In the platinum-sensitive recurrent setting, meaning patients who have responded to their most recent penultimate platinum regimen, maintenance strategies again include single-agent bevacizumab, as an antiangiogenic agent, or maintenance PARP inhibition, again with 3 options: niraparib, olaparib, and rucaparib. Both options are based on a meaningful improvement in the median progression-free survival with incorporation of maintenance treatment.

I like to think that maintenance has become incorporated into the management of our patients. We now have maintenance opportunities in the frontline setting, and we have maintenance opportunities in the platinum-sensitive recurrent setting. It’s our obligation to try to sit with our patients and figure out which strategy and which drug regimen may be the most appropriate for them based on their disease status and their tumor testing. Because, again, all of this hinges on the information that we get from genetic testing, germline assessments of 

, genomic assessments of the tumor looking at this genomic signature of homologous recombination deficiency, of which one component is loss of heterozygosity, or LOH, and other aberrations that we can identify in gene sequencing, such as 

 mutations, not all of which always equate to a high LOH score.

I do anticipate that maintenance therapy is going to become ubiquitous in the ovarian cancer space. I think there was, very early, an aggressive adoption of olaparib in the patients with 

 mutations. Many of us are excited that now has expanded beyond 

 to include HRD and all-comers as potential options with the combination regimens or with single-agent niraparib. And certainly in the platinum-sensitive recurrent setting, where our goal is to truly extend that chemotherapy-free interval, incorporation of a maintenance PARP inhibitor is also an attractive option. I would argue that maintenance therapy in ovarian cancer is here to stay, both in the frontline setting and in the platinum-sensitive recurrent setting.

Maintenance Therapy for Advanced Ovarian Cancer

 The use of PARP inhibitors such as rucaparib always has to be balanced against potential treatment-related adverse events, especially because it’s our hope that these patients can continue on treatment for long periods. With rucaparib, the main treatment-related adverse events are fatigue and hematologic toxicity, particularly anemia. When you look at the clinical trials, ARIEL2 Part 1 as well as ARIEL3, one of the more common grade greater than or equal to 3 adverse events was anemia. We also are concerned about GI [gastrointestinal] adverse effects. What I mean by that is abdominal pain, cramping, or nausea, and sometimes constipation or diarrhea.

And then lastly, you can see an elevation in the AST [aspartate aminotransferase] and ALT [alanine aminotransferase], or the creatinine. We believe these elevations on rucaparib are not reflective of end organ damage, but rather are reflective of issues with transporters—for example, the MATE [multidrug and toxic compound extrusion] transporters—and the impact on creatinine. So you want to follow these laboratory test results. You may see a rise in the AST and ALT initially, but that should plateau when a patient is on treatment. Their creatinine may rise at initial therapy but then should plateau. You should not have a patient with a rising bilirubin level. That would concern many of us for disease progression, potentially. And certainly, you can get a 24-hour creatinine clearance if you’re worried about the creatinine to assess renal function.

Mitigation for these adverse effects on treatment is really important, and I think of this as a 3-pronged approach. First is education, because it’s key for patients to be aware of the potential adverse events. Second is close communication, both with the provider and the staff. And third is early mitigation strategies. For us, the fatigue, for example, patients are going to experience fatigue. You prepare them, you counsel them, and you educate them on that it’s a possibility. You have them take a nap if they need to. But in parallel, you make sure it’s not another issue. You make sure they’re not hypothyroid, and that they’re getting physical activity as tolerated during the day. You make sure they’re not anemic, because anemia can cause fatigue.

With the GI adverse effects, make sure they have antiemetics prescribed for them and available for use. If they get significant nausea on treatment, they can use that medication. With respect to the anemia, follow their blood counts. And ultimately, with the hematologic toxicities, use dose interruptions and dose reductions as deemed clinically appropriate based on laboratory evaluations.

We shouldn't be reluctant or shy to dose interrupt or dose reduce with rucaparib if needed. Based on hematologic assessments, these drugs do have a rare but potentially life-threatening adverse effect for the development of MDS [myelodysplastic syndrome] and AML [acute myeloid leukemia], so we don’t want to ignore longstanding hematologic toxicity if it doesn’t correct with time.

Rucaparib for Relapsed Ovarian Cancer: Safety Profile

 What we know about PARP inhibitors is not only do we think about them as a maintenance strategy, but many of us think about ovarian cancers in remission as microscopic tumor sites that reside in the peritoneal cavity. So, maintenance really has some treatment component to it. Additional studies that were done looked at efficacy in a prespecified patient population, in a cohort of patients who emerged from Study 10, a rucaparib study, as well as a cohort of patients who were adopted from ARIEL2 Part 1. These were patients with 

In that cohort of patients for efficacy data, they saw an overall response rate of 54%. In addition to that, 61% had greater than or equal to 3 prior lines of therapy. So you have a heavily pretreated patient population with an objective response rate above 50%, which is really exciting data for us. As we discussed previously, with each disease recurrence the magnitude of benefit declines. If we have patients who have had 3 or more prior lines of treatment with an overall response rate of greater than 50%, it suggests efficacy of this regimen even in that population.

There are additional data important to highlight when we talk about efficacy of rucaparib. The ARIEL3 study, which was in the platinum-sensitive recurrent setting, allowed patients who had a partial response with what we call 

, or disease left over that was greater than 2 cm after completion of their cytotoxic chemotherapy. Even in that population, we saw a meaningful response rate, suggesting that the PARP inhibitor is effective therapeutically even for those patients who have measurable disease that remains after the cytotoxic combination chemotherapy is completed.

Loss of heterozygosity [LOH] is one of the markers that we would consider reflective of genomic instability. The theory behind the assays that we do to evaluate for what we call homologous recombination deficiency, which LOH, or loss of heterozygosity, is a component of, when we are doing these assays, is that we are trying to determine whether we’re going to identify a vulnerability in the tumor that helps identify patients who may benefit from a PARP inhibitor such as rucaparib. Again, ARIEL2 Part 1 specifically incorporated an LOH assessment in that population with a cutoff of 14%. That was revised in ARIEL3.

The relevance of this is that patients who have an elevated LOH score or who have homologous recombination deficiency appear to benefit or have a greater magnitude of benefit over what we would call a 

 mutated by definition are homologous recombination deficient. So the LOH score doesn’t really apply to a patient who has a known germline or somatic 

But there is a caveat here, and that caveat stems from the fact that this is not a perfect assay. LOH is not predictive of response with a sufficient sensitivity to define patients who would benefit only by that mode of assessment. There are patients who are 

 wild-type and who are LOH low or homologous recombination proficient who will still benefit and have a meaningful response. In fact, in the ARIEL3 study, I think among that cohort 30% were responders to rucaparib versus 5% in the placebo arm. So you can see that it’s not perfect in predicting response, because patients who are LOH low and 

 wild-type may still respond to PARP inhibition. That ties to the FDA approval of niraparib in the frontline setting for all-comers, which is based on the data that were released after the PRIMA trial.

Rucaparib: Clinical Activity in Relapsed Ovarian Cancer

 ARIEL2 Part 1 was an important trial. It was an informative trial not just because of the outcomes data when you look at median progression-free survival in the cohorts, but it also took a purposeful assessment of a biomarker, specifically loss of heterozygosity [LOH], and looked at the implications on treatment response. That’s specifically looked at in ARIEL2 Part 1.

This was an international multicenter 2-part phase 2 trial. A total of 206 patients were enrolled on that trial between 2013 and 2014. And when we look at these patients in Part 1, they were defined to be recurrent platinum-sensitive patients.

So we were looking at platinum-sensitive patients, and we split them into 3 cohorts. We looked at patients who had a 

 mutation, either germline, inherited; or somatic, acquired. We looked at patients who had an LOH-high score as well as a cohort of patients who had an LOH-low score. Importantly, for ARIEL2 Part 1, the LOH cutoff of 14% was derived from a retrospective analysis of data from the TCGA [The Cancer Genome Atlas] study. That 14% cutoff was subsequently incorporated into the clinical trial, and it was used as a way to stratify these patients.

And what we saw, if you looked at the 3 cohorts who were exposed to rucaparib given at 600 mg orally twice a day, was the median progression-free survival in the 

 mutation population was 12.8 months. The median progression-free survival in the LOH-high population was 5.7 months. In the LOH-low population, it was 5.2 months. There was a significant improvement in the median progression-free survival for both the 

-mutated population and the LOH-high population when compared to the LOH-low population.

And in parallel, from the ARIEL2 Part 1 study, we saw that the median duration of response was also significantly higher in the 

-mutated and LOH-high versus LOH-low groups, and that was 9.2 months versus 10.8 months in the LOH-high population. In the LOH-low population, it was 5.6 months. And something that I think is important to look at from the ARIEL2 Part 1 study was that they evaluated the patients with germline and the somatic 

 mutations and looked at the response in these 2 populations. What they saw was a similar response in patients with germline or somatic 

 mutations, suggesting that whether it’s an inherited mutation in the germline or an acquired mutation in the tumor, the anticipated response to rucaparib and the magnitude of benefit is similar.

This study was very informative because it helped us learn more about the relevance of loss of heterozygosity, especially with respect to monotherapy PARP inhibition with rucaparib given at 600 mg twice a day. And in parallel, it also helped us try to refine this loss of heterozygosity cutoff score. As many may be aware, when ARIEL3 was designed, that LOH cutoff transformed from 14% to 16%. That was based on a retrospective assessment of the data from ARIEL2 Part 1.

ARIEL2 Part 2 is a slightly different trial. ARIEL2 Part 2 is specifically looking at an all-comers population. Patients are platinum-sensitive, platinum-resistant, or platinum-refractory. The investigators are looking at response to treatment with rucaparib. What’s going to be informative about ARIEL2 Part 2 when those data emerge is, how can we expand the patient population that may benefit beyond the platinum-sensitive disease recurrence that was reported in ARIEL2 Part 1? We await the results of ARIEL2 Part 2, but the hope is that we have therapeutic options available for more of our patients based on efficacy data from these trials.

Ramez N. Eskander, MD | Authors

Articles

Future Directions in High-Risk Ovarian Cancer

Rucaparib Maintenance Therapy for High-Risk Ovarian Cancer

Maintenance Therapy for Advanced Ovarian Cancer

Rucaparib for Relapsed Ovarian Cancer: Safety Profile

Rucaparib: Clinical Activity in Relapsed Ovarian Cancer

Rucaparib Explored for High-Risk Ovarian Cancer