Danielle Bucco

Patients with renal cell carcinoma (RCC) have seen a change in standard of care as novel therapies and combinations are quickly approved, says Toni K. Choueiri, MD.

In December 2017, the FDA approved cabozantinib (Cabometyx) based on practice-changing data from the phase II CABOSUN trial. The multikinase inhibitor reduced risk of progression or death by 52% compared with sunitinib (Sutent) while the median progression-free survival was 8.6 months with cabozantinib versus 5.3 months for sunitinib (HR, 0.48; 95% CI, 0.31-0.74;

Median overall survival (OS) after a 30.8 month follow-up was 26.6 months (95% CI, 14.6-not evaluable) versus 21.2 months (95% CI, 16.3-27.4) in cabozantinib and&nbsp;sunitinib arms, respectively. There was a nonstatistically significant 20% reduction in the risk of death (HR, 0.80; 95% CI, 0.53-1.21;

The field is also pushing toward immunotherapy combinations, Choueiri adds. Combination nivolumab (Opdivo) plus ipilimumab (Yervoy) reduced risk of death by 37% compared with sunitinib in patients with intermediate- and poor-risk RCC (HR, 0.63;

<.0001), according to results from the CheckMate-214 trial.

In April 2018, this regimen was approved by the FDA for frontline treatment of this patient population.

, Choueiri, director of the Lank Center for Genitourinary Oncology and of the Kidney Cancer Center at Dana-Farber Cancer Institute, discussed the recent advancements in RCC. He also shared his insight on the future outlook of this treatment landscape.

: Can you speak to the success of the CABOSUN trial?

We are beyond single-agent VEGF receptors and TKIs. We still use other single agents, such as nivolumab or cabozantinib. In the frontline setting against sunitinib, cabozantinib showed superior response rates and an improved PFS.

This randomized phase II trial was essentially for patients in the poor- and intermediate-risk subgroups. Cabozantinib was approved in December 2017 in the frontline setting.

: What does the future look like? Will it include combinations of immunotherapies and targeted therapies?

Almost all of the large phase III trials are comparing combinations, such as immunotherapy plus VEGF inhibition, plus another immunotherapy regimen, or plus sunitinib. However, these studies are not head to head, so hopefully we will eventually have a head-to-head study. It is extremely important to compare combinations with the new standard of care. The combinations, especially with the high response rates that we are seeing, are going to be a significant part of the standard of care. However, the combination of nivolumab and ipilimumab has a higher response rate than sunitinib.

Also, with earlier studies, we are seeing TKIs such as axitinib (Inlyta) and lenvatinib (Lenvima). Additionally, the combination of pembrolizumab (Keytruda) and [axitinib] was very well tolerated, resulting in response rates between 50% to 70% and higher. There are also studies with 2 antibodies, the PD-L1 inhibitor atezolizumab (Tecentriq) and bevacizumab (Avastin), which were presented at the 2018 Genitourinary Cancers Symposium. The PD-L1positive population demonstrated a higher response rate with the combination when compared with sunitinib. However, it is still too early to determine the OS benefit.

: Can you discuss any new biomarker development?

We are still trying to come up with a biomarker for single-agent PD-1/PD-L1 inhibitors as well as VEGF TKIs. It is not easy, as we do not have anything to guide our clinical decision in practice. PD-L1 via immunohistochemistry was prognostic for nivolumab but when it was combined with ipilimumab in the CheckMate-214 study, it responded differently when looking at PD-L1 status. There was a much higher benefit for patients who were PD-L1 positive. This biomarker could tell us something. It has been integrated in most phase III trials but is still not ready for prime time.

Choueiri TK, Hessel C, Halabi S, et al. Progression-free survival (PFS) by independent review and updated overall survival (OS) results from Alliance A031203 trial (CABOSUN): Cabozantinib versus sunitinib as initial targeted therapy for patients (pts) with metastatic renal cell carcinoma (mRCC). In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA38.

Escudier B, Tannir NM, McDermott DF, et al. CheckMate214: efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naive advanced or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA5. 2013;369(18):1691-1703. doi:10.1056/NEJMoa1304369.

Articles

Patients with renal cell carcinoma have seen a change in standard of care as novel therapies and combinations are quickly approved, says Toni K. Choueiri, MD.

Expert Highlights Changes in the Treatment Landscape of RCC

The frontline treatment of patients with ovarian cancer may potentially change in the near future, with targeted and immunotherapy strategies showing promising signals of activity.

For example, the combination of chemotherapy plus the PD-1 inhibitor pembrolizumab (Keytruda) followed by pembrolizumab maintenance&nbsp;appeared to be safe and feasible for patients with advanced ovarian cancer, according to preliminary data from a small clinical trial that were presented at the 2018 Society for Gynecologic Oncology Annual Meeting.

In the study, 6 of 10 patients exhibited no evidence of disease during follow-up for as long as 14 months after debulking surgery, including 1 patient who had suboptimal results. No new or unexpected adverse events (AEs) occurred.

However, further data need to be collected before knowing what role immunotherapy should have in the frontline setting, Heather Dalton, MD, says. Other strategies being explored include PARP inhibitors, checkpoint inhibitor monotherapy, and bevacizumab (Avastin). In October 2017, the FDA accepted a supplemental biologics license application for bevacizumab, in combination with carboplatin and paclitaxel, followed by bevacizumab alone, for the first-line treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. The FDA is expected to make a decision on the application by June 25, 2018.

, Dalton, a gynecologic oncologist at Arizona Oncology, discussed the developing standard of care for the frontline treatment of patients with ovarian cancer.

What is the standard first-line treatment option for patients with ovarian cancer?

This is a controversial subject. There were many times where we thought we had it all figured out. With every trial, the water seems to get muddier regarding the standard of care. With the initial dose-dense regimen, we were excited about the improvement in overall survival that we saw that rivaled intraperitoneal (IP) chemotherapy. Everyone was understandably embracing of that regimen, but the results of the GOG 252 trial complicated that significantly as there was no difference in survival between the regimens.

I would say, for suboptimally debulked patients, most would agree that the dose-dense regimen or an appropriate clinical trial are good choices. For patients who are not the most robust, consideration of fractionated treatments, such as dose-dense carboplatin and paclitaxel, are good options. For patients with a good performance status, IP chemotherapy is still a reasonable option, although there is no true standard of care. There are lots of controversies there.

Are there emerging strategies that could be looked at as a frontline option?

A lot of exciting things are going on right now in ovarian cancer. There are 6 new FDA appointment dates for potential approvals for drugs in the frontline setting. The addition of PARP inhibitors in the frontline setting [could be] exciting. We are seeing that in multiple clinical trials and it will be exciting to see the results.

Additionally, we are seeing the introduction of checkpoint inhibitors in the frontline setting. Those are all very exciting, so it will be interesting to see what comes out of those trials because there are [encouraging] data in the second-line setting.

Are there any concerns or unanswered questions that we have with PARP inhibitors or immunotherapy in the frontline setting?

We are learning more about these medications and the class-specific AEs associated with them. With regimens such as PARP inhibitors, some patients have more hematologic or gastrointestinal-related toxicities, but those are generally manageable. We are getting better at making appropriate adjustments to dosing as we become familiar with these regimens.

With checkpoint inhibitors, we are at a time where there is potential with modulating the immune system, but these also have anticipated AEs. Those are often serious, but are usually manageable and can be recognized earlier. As time goes on, we can learn more about these medications so that we can handle things more effectively.

What are your thoughts on pembrolizumab (Keytruda) being combined with chemotherapy in the frontline setting?

I do not think that there are enough data with that combination to say that patients shouldn&rsquo;t get the standard of care, which is cytotoxic chemotherapy. As we learn more about these trials with checkpoint inhibitors and PARP inhibitors, we will have more data on how efficacious those can be in the frontline setting. It is too early to abandon the treatments that we know work without definitive evidence. Certainly, in some cancer types, we are moving to immunotherapy as a frontline setting and hopefully for patients with ovarian cancer that will be an optionbut we are not there yet.

Have we defined the role of adding bevacizumab (Avastin) to the treatment landscape?

There is definitely a benefit in patients who are suboptimally debulked, which has been supported by numerous data. As far as its addition in the frontline setting, there are new data coming out demonstrating the potential benefit of it in the frontline setting. Although those studies have been criticized, there is a pending FDA evaluation of the regimen in the frontline setting. We will see how the indication changes, but many people are using it.

If we get to a point where PARP inhibitors are looked at in the frontline setting, will we run into sequencing challenges?

As more patients are exposed to PARP inhibitors, it will be interesting to see the data that have come out on the efficacy of these agents. Hopefully, depending on how long it has been since the patient received a PARP inhibitor, it could be given to them again, but those data are forthcoming.

Uyar D, Bishop EA, Bradley WH, Rader JS. Preliminary data on the use of combination carboplatin, paclitaxel and pembrolizumab therapy for ovarian cancer. In: Proceedings from the 2018 SGO Annual Meeting; March 24-27, 2018; New Orleans, LA. Abstract 100.

Expert Discusses Evolving Treatment of Ovarian Cancer in the Frontline Setting

While PARP inhibitors have demonstrated success in ovarian cancer previously, they are finally impacting the treatment paradigm for patients with

-positive breast cancers, according to Nadine M. Tung, MD.

The FDA approved olaparib (Lynparza) in January 2018 for treatment of patients with germline

-positive, HER2-negative metastatic breast cancer who have received a prior treatment of chemotherapy. Based on results from the phase III OlympiAD trial, olaparib reduced risk of disease progression or death by 42% and improved progression-free survival (PFS) by 2.8 months versus standard chemotherapy in previously treated patients

-positive, HER2-negative disease. These promising results led to the FDA approval.

Phase III findings also demonstrated potential benefit with talazoparib, another PARP inhibitor. Talazoparib was reduced the risk of disease progression or death by 46% in patients with

-positive advanced breast cancer in the EMBRACA trial.

At a median follow-up of 11.2 months, the median PFS was 8.6 months with talazoparib versus 5.6 months with physician&rsquo;s choice of therapy (HR, 0.54; 95% CI, 0.41-0.71;

Tung, associate professor of medicine at the Harvard Medical School and director of the Cancer Risk and Prevention Program at Beth Israel Deaconess Medical Center, Dana-Farber Cancer Institute, discussed the emerging role PARP inhibitors have for patients with

-positive breast cancer and the importance of genetic testing.

What is the current treatment landscape of PARP inhibitors for patients with breast cancer?

The newest development is the OlympiAD trial and the FDA approval of olaparib for patients with germline

mutations who have metastatic, HER2-negative breast cancer. The FDA approved use of olaparib in January 2018, so that is available now for patients who have metastatic HER2-negative breast cancer. Those patients also have a germline

mutation and have seen chemotherapy at some pointeither in the initial setting, adjuvant, neoadjuvant, or metastatic setting

What other PARP inhibitors are being investigated?

Firstly, the OlympiAD trial investigated olaparib compared with nonplatinum standard chemotherapy. Olaparib led to a significant improvement in PFS.

A similar study was presented at the 2017 San Antonio Breast Cancer Symposium using a different PARP inhibitor, talazoparib, in the EMBRACA trial. It was a very similar design with the same population, comparing the PARP inhibitor monotherapy with standard chemotherapy choices. Interestingly, the results were very similar with a significant improvement in PFS by approximately 3 months. It will be interesting to see if a second PARP inhibitor does get FDA approval.

Are there any thoughts of bringing PARP inhibitors to earlier lines of therapy?

Both of the studies I mentioned were for patients who had seen standard chemotherapyanthracyclines or taxanes&mdash;either in the initial or metastatic setting. Now, PARP inhibitors are also being studied in an earlier setting. There are studies, such as OlympiA, looking at [olaparib in] the adjuvant setting for patients with germline

mutations who have higher risk of disease after they complete standard chemotherapy and local therapy.

Could this benefit patients without BRCA mutations?

That is an important goal we are working on. We want to find patients who do not have germline

mutations, but whose tumors may be sensitive to PARP inhibitors. The way that investigators are trying to approach that topic is to identify breast cancers that also have the same DNA repair defect as the breast cancers in patients with germline

-associated breast cancers have a defect in homologous recombination. That is the pathway that repairs double-strand DNA breaks. How can we identify other breast cancers that have this defect? There are various tools being developed. None of them are in clinical use yet, but some of them are interesting. Some look at genomic loss in the tumor, whereas others look at mutational signatures to find those with a defect in homologous recombination. The other approach is to look at patients who either have a germline mutation or whose tumors have a somatic mutation in other genes that work with

In metastatic prostate cancer, patients with germline or somatic mutations in the other genes, such as

, respond to PARP inhibitors. That approach is being looked at with breast cancer. We are looking at patients who have some other mutations, such as

How do you typically identify these mutations?

For some patients, we do germline testing. If they have a personal or family history that is suggestive of having an inherited

mutation, we do multigene panels. For many patients, we are rarely just testing for

. We are looking for these other DNA repair genes.

In metastatic patients, we do a lot of tumor somatic testing that looks at targets of therapy. You pick up a lot of germline mutations by testing the tumor in the metastatic setting. There are about 4% of patients with breast cancer whose tumors will have a

mutation that do not have an inherited germline mutation.

mutation is found in the tumor, that should trigger germline testing so that it is known whether the patient has an inherited mutationas that has other implications for risk management for other cancers and family members. It is also important to say that even if the tumor testing does not show a

mutation, a patient should undergo germline testing if they qualify for it.

When is it best to conduct germline testing?

Even though PARP inhibitors are not yet approved in an earlier setting, if a patient qualifies for germline

testing, they should always have it at initial diagnosis. It has implications for their local treatment, surgery, what chemotherapy is being chosen, prophylactic mastectomies, and risk management. In the initial setting, if someone meets criteria for germline testing, they should always have it.

At recurrence or at metastatic disease, we are almost always doing tumor testing. If the patient missed it or qualifies for germline testing and never had it, they should get it at that point.

Is there anything else you would like to add?

There is a lot of debate about how much genetic testing to do in a patient who is diagnosed with breast cancer. Should it just be the high-risk breast cancer genes? Should it be high- and moderate-risk breast cancer genes? Should it be a multigene panel that looks for cancer susceptibility genes for other cancers? I do not think there is complete agreement among experts in this field, but we are increasingly using panels. Identifying the breast cancer susceptibility genes has implications for treatment and surveillance in our own patients, identifying their risks for other cancers, and also for their relatives.

Now that there are some new ovarian cancer susceptibility genes, such as

identifying those mutations warrants a discussion about prophylactic mastectomy in our patients with breast cancer. For me, I am virtually always testing for the breast and ovarian cancer susceptibility genes. However, if the patient and the clinician feel that there is merit in finding other cancer susceptibility genes, then a multigene panel for established cancer risk genes is appropriate.

We know now that when we test patients with breast cancer, we do find Lynch syndrome genes in patients who do not have a personal or family history that would have suggested it. If the patient and clinician feel this is important information, then a multigene panel makes sense.

Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA&nbsp;mutation. 2017;377:523-533.&nbsp;

Litton JK, Rugo HS,&nbsp;Ettl J, et al. A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician&rsquo;s choice of therapy in patients with advanced breast cancer and a germline BRCA-mutation. In: Proceedings from the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, Texas. Abstract GS6-07.

While PARP inhibitors have demonstrated success in ovarian cancer previously, they are finally impacting the treatment paradigm for patients with <em>BRCA</em>-positive breast cancers, according to Nadine M. Tung, MD.&nbsp;

Expert Highlights Advancements With PARP Inhibitors in Breast Cancer

While relapsed/refractory mantle cell lymphoma (MCL) is considered an aggressive disease, new findings show patients may benefit from adding chimeric antigen receptor (CAR) T-cell therapy to their treatment regimen. ZUMA-2, a currently ongoing trial, aims to understand the potential benefits with axicabtagene ciloleucel (axi-cel; Yescarta), an anti-CD19 CAR T-cell product, for&nbsp;patients with relapsed/refractory MCL (NCT02601313).

The ZUMA-2 trial set a primary endpoint of safety and efficacy of axi-cel, measured by overall response rate (ORR). Secondary endpoints were selected as duration of response, best objective response, and progression-free survival. It was required that patients in the trial had prior therapy with an anthracycline- or bendamustine-containing chemotherapy, anti-CD20 monoclonal antibody therapy, and either ibrutinib (Imbruvica) or acalabrutinib (Calquence). Researchers estimate a primary completion date for this study in July 2018.

The FDA has approved axi-cel for patients with non-Hodgkin lymphoma (NHL) based on findings from the ZUMA-1 trial. The approval was specified for patients with large B-cell lymphoma that had received 2 prior lines of therapy, also including diffuse large B-cell lymphoma (DLBCL). An ORR of 82% was reached with Axi-cel, as well as a CR rate of 54%. With an 8.7 month follow-up, 39% of the patients in the ZUMA-1 trial remained in CR. Median duration of response was not reached, though, at the time of assessment (95% CI, 8.1-not estimable).

In an interview with Targeted Oncology,&nbsp;Frederick L. Locke, MD, a medical oncologist at Moffitt Cancer Center, investigator on ZUMA-2, and co-lead investigator on ZUMA-1, discussed the ongoing ZUMA-2 trial investigating axi-cel for patients with MCL. He also highlights the impact this trial and its results will have on the treatment landscape of this disease.

Can you discuss the rationale behind conducting the ZUMA-2 trial for patients with MCL?

The ZUMA-2 trial is a Kite Pharma/Gilead Sciences-sponsored multicenter clinical trial to evaluate the anti-CD19 CAR T-cell therapy called axi-cel as a treatment for patients with MCL.&nbsp;

MCL is a B-cell cancer that can act indolently or aggressively. When the disease becomes refractory, it can grow very quickly. Newer FDA-approved medications with efficacy for late-stage MCL, such as the oral medication ibrutinib, have proven very effective to control disease for many patients. Unfortunately, for patients whose lymphoma grows while on ibrutinib, or the similar medication acalabrutinib, there are not many good options. This trial is attempting to investigate if that set of patients could go into remission for a prolonged period of time with axi-cel.

What are the main challenges that exist for this patient population?

Once ibrutinib stops working or if patients come off ibrutinib, we know that the disease may progress rapidly. These patients have very little time to be referred and enrolled onto the trial, so they could get CAR T cells manufactured.ery quickly. That is one of the big challenges for patients with MCL refractory to ibrutinib; patients need treatment [right away].

If this trial investigating axi-cel is successful, what impact could this type of therapy have on the MCL landscape?

We saw the FDA-approved indication for axi-cel in patients with DLBCL who have relapsed after 2 lines of therapy, but MCL is another lymphoma [that expresses CD19]. There are clearly patients who die of progressive MCL and need new therapies. If we can prove that axi-cel is safe and effective to use, the study has the potential to save lives.

Is it possible for axi-cel to be brought into the frontline setting for patients with MCL?

This is also a question that we have in DLBCL. I would not say that it is impossible, but we have to be deliberate and first answer the question of its safety and efficacy in refractory patients. We can then compare it to other earlier lines of therapy, which is the logical next step.

Patients with MCL can be in remission for many years with upfront chemotherapy, anti-CD20 monoclonal antibodies. If patients are in CR and are consolidated with an autologous stem cell transplant, they could potentially remain in remission for a decade. To say that CAR T-cell therapy can compete with those preexisting responses in MCL is a big leap so we have a ways to go.

It is important that people are aware of existing trials, not only for MCL but also for DLBCL, so they can determine whether their patients are eligible for a referral to a center that has clinical trials, especially in the CAR T-cell space and at first relapse. Referring patients at first relapse is important. Waiting for a second relapse or third relapse creates issues of getting those patients onto trials. There are study eligibility criteria, including while blood cell count and platelet count, which can be quite low for patients with MCL, especially if the patients have a large spleen or bone marrow involvement. Early referral is always better.

Locke FL, Neelapu SS, Bartlett NL, et al. Primary results from ZUMA-1: a pivotal trial of axicabtagene ciloleucel (Axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). In: Proceedings from the 2017 AACR Annual Meeting; April 1-5, 2017; Washington, DC. Abstract CT019.

While relapsed/refractory mantle cell lymphoma (MCL) is considered an aggressive disease, new findings show patients may benefit from adding chimeric antigen receptor T-cell therapy to their treatment regimen. ZUMA-2, a currently ongoing trial, aims to understand the potential benefits with axicabtagene ciloleucel, an&nbsp;anti-CD19 CAR T-cell product, for&nbsp;patients with relapsed/refractory MCL.

Expert Discusses ZUMA-2 Trial Investigating CAR T-Cell Therapy in MCL

According to Neil E. Kay, MD, novel agents, such as&nbsp;ibrutinib (Imbruvica), venetoclax (Venclexta), idelalisib (Zydelig), and acalabrutinib (Calquence), are revolutionizing treatment for patients with chronic&nbsp;lymphocytic leukemia (CLL). However, the best way to sequence these agents to maximize the benefit to patients is still unclear.

, Kay, a professor of medicine at the Mayo Clinic, discussed options available to oncologists hoping to use these therapies for their patients with relapsed/refractory CLL. He also explains his opinion on how this field will advance.

: Please discuss the evolution of personalized medicine and sequencing in CLL.

: [There is a lot to discuss with] the sequencing of treatment options for relapsed/refractory CLL. Since there are so many options available for CLL, it is not as straightforward because we still do not have all the data we need to definitively say which agent would go in which order.

: Can you discuss the role of molecular testing for determining the sequence of treatments?

: That is a critical step. For patients with

mutations who have relapsed and do not have a 17p deletion or

mutation, they could theoretically be treated with chemoimmunotherapy, such as FCR. The treatment is a reasonable choice for the rare few patients who are relapsed/refractory; however, they need to meet the criteria for not having those adverse prognostic factors.

What are some challenges facing these relapsed patients?

: Based on prior clinical trials and prior drugs that were available, once a patient relapses after primary therapy, their responses were short lived. This causes mortality to be much closer [for them].

However, with newer drugs such as ibrutinib, idelalisib, rituximab, and venetoclax, which are all FDA approved for patients with relapsed/refractory CLL, there is much less emphasis on these prognostic factors being criteria that would prevent patients from receiving them. While it is important to know these parameters, it means less to a practitioner if they wanted to use ibrutinib or venetoclax for a patient even if they had an adverse prognostic factor.

However, these parameters still play a role. For example, if a patient relapsed and had 17p deletion as shown via fluorescence in situ hybridization (FISH), they would respond to these novel agents nicelyparticularly ibrutinib, idelalisib, or rituximab. However, their responses would be less robust than if they did not have that defect.

To be specific, I believe the current data for patients receiving ibrutinib with 17p deletion is a progression-free survival (PFS) of around 26 months. Whereas, for the more favorable-risk groups, like 13q deletion or patients with no abnormalities, the PFS has not been reached. While this is an improvement over prior drugs, having that specific genetic defect would suggest that these patients will not respond for as long.

: Can you discuss emerging combination strategies?

: There will always be a role for single-agent ibrutinib. The ability to tolerate 1 drug is always better than having to tolerate 2. For the individual who is older, such as in their late 70s or early 80s, being on ibrutinib for 4 or 5 years with a good response would be quite reasonable.

However, ibrutinib alone does not induce a high level of complete responses (CRs). If a patient has a CR, ibrutinib will not give them a minimal residual disease (MRD)-negative status. Therefore, combinations will be necessary if the goal is to get to a CR with MRD-negative status.

There are ongoing trials that are investigating those combinations with preliminary data that look promising. The combinations are encouraging.

: What is the role of acalabrutinib in this setting?

: Acalabrutinib is the cousin of ibrutinib. It works in the same mechanism, but has less off-target effects compared with ibrutinib in terms of enzyme targets. The toxicity profile is likely to be less than it is for ibrutinib. To summarize, ibrutinib&rsquo;s major issue has not been the response level, since over 90% of patients respond to ibrutinib, but the chronic low-grade toxicity, such as arthralgia, diarrhea, rash, hypertension, and the occurrence of fibrillation. [It will lead to] a significant number of patients to ultimately go off ibrutinib.

However, as acalabrutinib continues to be developed, if in fact there is less chronicity of these lower-level toxicities, it will likely become a reasonable option for patients.

: Could acalabrutinib ever replace ibrutinib?

: If it has a toxicity profile that is consistently less than ibrutinib, it might. However, there are a lot of clinical trial data that are needed. There are so many patients who have been treated with ibrutinib either on or off clinical trials; there is a long road to go for acalabrutinib.

What are some of the main takeaways that you would physicians to understand about personalized therapy in CLL?

: There is a potential hierarchy for the big salvage therapies for patients with relapsed/refractory CLL. In my opinion, based on clinical trials, these are ibrutinib, venetoclax, idelalisib, rituximab, and also allogeneic bone marrow transplant.

There is no clear way to decide which order to give these to patients, but you can make wise decisions based on age, comorbidities, and what patients&rsquo; goals are. Regarding clinical trials, I am hoping that oncologists realize that these are reasonable choices, although bone marrow transplants might be the further down the road due to the morbidity and mortality associated with that approach. The other drugs can be chosen wisely based on the parameters I have reviewed.

According to Neil E. Kay, MD, novel agents,&nbsp;such as&nbsp;ibrutinib (Imbruvica), venetoclax (Venclexta), idelalisib (Zydelig), and acalabrutinib (Calquence), are revolutionizing treatment for patients with chronic&nbsp;lymphocytic leukemia. However, the best way to sequence these agents to maximize the benefit to patients is still unclear.

Expert Discusses Novel Treatment Options for Relapsed/Refractory CLL

PARP inhibitors continue to advance the treatment landscape of ovarian cancer, but there is still debate over which agent is the most optimal to use in the maintenance setting.

For patients who progress on earlier lines of therapy, practice-changing treatment options have come with the recent additions of olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca). Olaparib and niraparib have an additional FDA indication in the maintenance setting, with rucaparib showing efficacy in this setting, as well. Rucaparib has been submitted to the FDA for approval in the maintenance setting and was granted a priority review designation in December 2017, explains David O'Malley, MD.

In the randomized phase III ARIEL3 study, rucaparib increased progression-free survival (PFS) in the maintenance setting for patients with platinum-sensitive, high-grade ovarian, fallopian tube, or primary peritoneal cancer. The median PFS with rucaparib was 16.6 months (95% CI, 13.4-22.9) compared with 5.4 months for placebo (95% CI, 3.4-6.7). Similar PFS benefits were observed in patients with

wild-type tumors and those with homologous recombination deficiency (HRD) or low to high loss of heterozygosity.

mutations, there was a 77% reduction in the risk of progression or death with rucaparib versus placebo (HR, 0.23; 95% CI, 0.16-0.34;

<.0001). In the HRD group, risk reduction with rucaparib was 68% (HR, 0.32;

at the 2018 Society of Gynecologic Oncology Annual Winter Meeting, O'Malley, a professor in the Department of Obstetrics and Gynecology at The Ohio State University Comprehensive Cancer Center, discussed the excitement surrounding PARP inhibitors for patients with ovarian cancer.

Please provide an overview of your presentation at the meeting. You were part of a debate on maintenance therapy, correct?

The debate I was involved in is looking at maintenance therapy in patients with platinum-sensitive ovarian cancer. We each took one of the agents, which had been tested in clinical trials. We have rucaparib, olaparib, and niraparib. I was given the responsibility of discussing rucaparib.

Can you discuss the current role of PARP inhibitors and where you see them headed in the future?

The current role of PARP inhibitors are in a couple of different patient populations. One of those populations are

mutations, either in the germline or in the somatic of the tumor. Both of those have indications. Olaparib has an indication in 3 or more prior lines of therapy in those with germline mutations, while rucaparib has indications of more than 2 lines of prior therapy in both somatic and germline.

There are now 2 drugs that are approved in the platinum-sensitive maintenance setting. Those are olaparib and niraparib. Rucaparib has been submitted to the FDA, but we have not yet heard if it will receive approval. In this population of patients, many of the trials concentrated on BRCA mutations as well as HRD status. Both current drugs are approved in all-comers, no matter what their somatic or germline status is.

How do you determine which agent to give a patient? Are there any biomarkers?

Trying to determine which drug to give was the format of the debate. Currently, there are 2 drugs that are approved and we think there will be a third drug. Looking at those drugs and trying to figure out what to use is not yet possible. I do not think those drugs will ever be compared. They all seem to have similar efficacy, and a lot of this comes down to balancing toxicity, dosing schedules, convenience, and other factors.

Can you discuss the combination of niraparib and bevacizumab (Avastin)?

Right now, we can say that there are multiple trials ongoing at the phase III level, both in upfront first-line therapy, as well as in the recurrent and platinum-sensitive settings. These drugs are difficult to combine with other classic cytotoxic therapies, especially the alkylating agents, such as platinum-based therapies.

When we are looking at combining these drugs, we are looking at other biologic therapies. They seem to be much better tolerated in the combination. We have seen some interesting results. For example, there was a phase III trial investigating the combination of cediranib and olaparib. That was the NRG-GYN 005 trial. Yet, we do not have the results on this and we are hoping to enroll patients in those trials. Since there are so many clinical trials out there, we hope to have any eligible patient treated on a clinical trial.

Can you discuss olaparib and durvalumab (Imfinzi) in combination?

PARP inhibitors are being looked at in multiple levels to include antivascular, checkpoint inhibitors, and all 3 together. There are currently trials that are being designed. We have approximately 14 clinical trials, which are utilizing PARP inhibitors in the upfront and recurrent settings in the United States and worldwide. We are considering every possible conceivable combination, mostly in the maintenance phase, determining how the checkpoint inhibitors are placed, as well as the antivascular therapies in the treatment phase.

Overall, how are PARP inhibitors tolerated?

The toxicity is somewhat of a challenging question. When you are taking agents daily, particularly oral agents, patients find that very convenient. The problem of taking the agent is you have therapy every day. We have looked at adverse events such as fatigue, gastrointestinal related, and hematologic related, which can limit the quality of life in patients. However, we have looked at patient-reported outcomes and if we can keep the disease from coming back in the maintenance phase in platinum-sensitive disease, those patients do better.

When you look at comparison treatment from placebo versus PARP inhibitors, there is not much difference when treating these patients. There are clearly side effects that we need to balance and we need to look at patient-reported outcomes as we move forward in trying to ascertain the best place to use these drugs. Overall, they are well tolerated but there are some side effects that can impact a patient's quality of life, specifically, the fatigue and gastrointestinal side effects.

Ledermann J, Oza AM, Lorusso D, et al. ARIEL3: a phase 3, randomised, double-blind study of rucaparib vs placebo following response to platinum-based chemotherapy for recurrent ovarian carcinoma (OC).

. 2017;28 (suppl_5) doi:10.1093/annonc/mdx440.034.

David O&#39;Malley, MD,&nbsp;discusses the excitement surrounding PARP inhibitors for patients with ovarian cancer.