Amid PARP Advances, Chemo Remains Critical in Ovarian Cancer

Heather Dalton, MD

In the frontline setting, chemotherapy regimens are still the go-to option for patients with ovarian cancer—and likely will be for years to come, explains Heather Dalton, MD.

While PARP inhibitors, such as rucaparib (Rubraca) and niraparib (Zejula), have demonstrated impressive results in later lines of therapy, a carboplatin/paclitaxel regimen is still holding the reigns as a first-line treatment.

Dalton adds that researchers continue to wait for long-term survival data from the Gynecologic Oncology Group (GOG)-252 trial, in which preliminary findings did not demonstrate that intraperitoneal (IP) chemotherapy was superior to an intravenous (IV) regimen.

OncLive: What are the options for patients in the first-line setting with ovarian cancer?

In an interview during the 2017 OncLive^® State of the Science Summit on Ovarian Cancer, Dalton spoke about the first-line treatment options currently available for patients, pivotal data that have solidified standard approaches, and why chemotherapy will likely always remain critical in the ovarian cancer sphere.Dalton: Unfortunately, most of our patients with ovarian cancer are advanced when they are diagnosed, so we are always left with a conundrum on how to treat them. There has been a lot of research done about the best way to treat these patients. We have moved a long way from initially doing cytotoxic doxorubicin, to around 2003 where carboplatin and paclitaxel became the backbone for our ovarian cancer treatment. Since then, we’ve been looking at different ways to give it and ways to improve progression-free survival (PFS).

Unfortunately, some of those trials have had more success than others. The trial that led to our new standard of therapy was GOG-172, which looked at IV carboplatin and paclitaxel versus IP therapy. The IV method results in significant PFS and (overall survival) OS. That became our new standard of care and we were very excited about.

Subsequently, we have tried to combine that with different types of chemotherapy and different ways to give it. One of those was first actually done in Japan; they looked at giving standard IV chemotherapy compared with what we called dose-dense therapy—which is giving weekly paclitaxel in combination with carboplatin on day 1. We saw a significant improvement with PFS and OS in that study, so we were all very excited about that because the OS difference was even more so than we initially saw in GOG-172.

That was a little bit limited because it was a Japanese study, so how much does that directly apply to our populations here? That population has more clear cell histology, while Americans have more serous histology. Those are some constant criticisms of the study.

Therefore, we repeated that study here in the form of GOG-262, but we added bevacizumab (Avastin). Unfortunately, the bevacizumab seems to have muddied the waters. Most patients got bevacizumab; however, those patients did not experience that big of a difference in OS that we were hoping for. In the subgroup that didn’t actually receive bevacizumab, that improvement in OS was still significant. Basically, we concluded that bevacizumab doesn’t really help in this setting.

Now, we have 2 kinds of conflicting studies—dose-dense and IP—that have never been compared. That was the trial that we were all looking forward to so much, which was GOG-252, that compared standard chemotherapy versus IP chemotherapy plus the dose-dense therapy. We thought this would answer all of our questions that we had and, because bevacizumab saw good results in some trials, we added bevacizumab to the mix. Unfortunately, while the data is not mature, there doesn’t look to be any improvement in PFS in those groups.

Are you looking to combine chemotherapy with some novel agents, such as the PARP inhibitors, in the frontline setting?

What other interesting ongoing trials are being conducted in this area?

Do you foresee chemotherapy always having such a significant role for these patients?

Is it worth testing another angiogenesis inhibitor in some of these trials, such as ramucirumab (Cyramza)?

What else could the future treatment landscape of ovarian cancer hold?

The initial enthusiasm for IP chemotherapy has waned somewhat because, now, we haven’t been able to replicate what we saw in GOG-172. Dose-dense therapy is a more tolerable regimen for a lot of people, so now there is no great consensus on how to best treat those patients in the upfront setting. Dose-dense therapy is reasonable, but IP chemo is not unreasonable. We need more data; that is where we are up to speed in the ovarian cancer clinical trials world. There are currently multiple ongoing trials in the frontline setting coming out about maintenance PARP inhibitors after receiving frontline standard chemotherapy. Most of the data is still accruing, so we don’t have a great answer. Certainly, our hope is that we will get some great benefit. Most clinical trials start in the recurrence setting, and then move into the frontline setting as we get better and better results. We have seen good results in the recurrent settings. We were hoping to move some of that forward to the initial setting and hopefully be able to benefit some of our patients, in terms of maintenance. I will be interested to see what matures out of GOG-252; that survival data is not yet mature. We still don’t have a great answer. Really, a lot of us would like to see a head-to-head comparison of dose-dense therapy versus IP chemo without bevacizumab. That would really answer our question because those trials are very hard to accrue. The more moderate thinking with PARP inhibitors and bevacizumab is hard. I don’t know if we will ever be able to answer that question, but it would be awesome if we could. I do think it will always have a role, unfortunately. Especially in the upfront setting, cytotoxic therapy is so important. Targeted therapies and immunotherapies are going to have a big role, but it will be adjunct to the initial backbone. Then, hopefully, we can really implement those as maintenance strategies, especially with things like PARP inhibitors and all of these others that are coming down the pipelines—like immune modulators that regulate the tumor microenvironment. I don’t know if, in my lifetime, we will see standard chemotherapy go away. We have looked at other angiogenic drugs; most of those trials have been in the recurrent setting and not upfront. Much like bevacizumab, we were all very excited about it initially. We have realized that it is a good adjunct in some situations, but I don’t think angiogenesis alone is going to be the answer. This also goes for targeting members of the VEGF family or the receptor, or other members of the TKI family that affect angiogenesis. The tumors are smart, it’s complex, and we need more than that. It will still be a backbone of a platinum-based therapy and paclitaxel. It is going to move more toward a dose-dense setting and that is an easier regimen for patients to tolerate.

We are going to move much more toward a maintenance setting and, with BRCA, the PARP inhibitors coming out, and the homologous recombination deficiency families of mutations that we’re able to target now we hope that we will have a solid maintenance strategy to offer these patients. Ideally, we are then starting to move the PARP inhibitors and other agents into the frontline setting with initial chemotherapy followed by maintenance. That is where things are going to head over the next few years.

Walker JL, Brady MF, DiSilvestro PA, et al. A phase III clinical trial of bevacizumab with IV versus IP chemotherapy in ovarian, fallopian tube and primary peritoneal carcinoma NCI-supplied agent(s): bevacizumab (NSC #704865, IND #7921) NCT01167712 a GOG/NRG trial (GOG 252). Presented at: 2016 SGO Annual Meeting. March 19-22, 2016. San Diego, CA. Late-breaking abstract.