Genetic Analysis Helps Maximize Clinical Benefit with PARP Inhibitors in BRCA+ Ovarian Cancer

Saketh Guntupalli, MD

The use of genetic testing to identify homologous recombination deficiency (HRD) and BRCA mutations in ovarian cancer can better inform the selection of frontline maintenance therapies and improve the management of PARP inhibitor–related toxicities, according to Saketh Guntupalli, MD.

“We’re entering [a new] era of ovarian cancer molecularization,” said Guntupalli following an OncLive^® Institutional Perspectives in Cancer webinar on ovarian cancer, which he chaired. “We don’t want to give patients drugs that are going to make them feel bad if they’re not really efficacious. Knowing the markers for toxicity [can elucidate] what [treatment strategy] is going to work.” ​​

In an interview with OncLive^®, Guntupalli highlighted key topics discussed during the meeting, including data supporting PARP inhibitors as the standard-of-care frontline therapy, strategies for the management of PARP-related toxicities, and the importance of testing for HRD and BRCA status in patients with ovarian cancer.

Guntupalli is a professor and director of the Division of Gynecologic Oncology, Karen M. Jennison Endowed Chair in Gynecologic Oncology, and vice-chair for Faculty Affairs and Development in the Department of OB-GYN at the University of Colorado School of Medicine in Denver, Colorado.

OncLive^®: How have pivotal studies like the phase 3 SOLO-1 (NCT01844986) and PRIMA (NCT02655016) trials helped improve the use of up-front PARP inhibitors for patients with BRCA-positive ovarian cancer?

Guntupalli: Those seminal trials have established [the] need to know [HRD and BRCA mutation status]. The survival curves in those studies are impressive and [clearly show] that patients with BRCA or HRD [positivity] benefit the most from the use of PARP therapy vs placebo. SOLO-1 [in particular] is a remarkable study. We see patients [in this study] who were BRCA positive surviving years [after receiving] PARP inhibitors. The data are there [to support] the use of PARP therapy in those two groups.

Patients who are BRCA negative and HRD negative [also] seem to benefit from PARP inhibitors. In the PRIMA trial, [patients experienced some form of] benefit from PARP therapy whether they were BRCA positive or negative. [These trials contained] hazard ratios [between] 0.3 and 0.4 for BRCA-positive [patients] and [between] 0.5 and 0.6 for HRD-positive patients, [which] is great. [Still], the most benefit is seen in BRCA-positive and HRD[-positive] tumors.

Regarding the presentation given by your colleague Jill Alldredge, MD, of the University of Colorado Cancer Center, on the management of toxicity with PARP inhibitors, what strategies can be used to best address these effects while maximizing clinical benefit?

First and foremost, [it is vital to] talk to patients and find out what’s bothering them the most. The most [common] toxicity associated with PARP therapy is gastrointestinal toxicity, such as nausea, [which] begets some of the other toxicities, such as fatigue and anemia.

[Additionally,] seeing what strategies [patients have already] tried to ameliorate [adverse effects] can [inform the best approach]. Are they splitting the dose [in the] morning and afternoon? Are they taking it with food? [Are] they taking the maximum dose of 300 mg of niraparib [Zejula] every day? [If so], maybe they should go down a dose [level]. [If a patient has] thrombocytopenia, [it is also important to] ensure they’re not on other medications that [may negatively] interact [with PARP inhibitors. Consideration of these factors] is key to managing toxicities.

As noted in the presentation delivered by Yevegniya Ioffe, MD, of Loma Linda University Cancer Center, on antibody-drug conjugates in platinum-resistant ovarian cancer, what is the significance of the FDA approval of mirvetuximab soravtansine-gynx (Elahere) for this population?

[The accelerated approval] for mirvetuximab soravtansine is so great, because now we finally have something to treat patients with folate receptor alpha [expression]; [this is] a very difficult[-to-treat] patient population. The response rate [of mirvetuximab soravtansine] in the phase 3 SORAYA trial [NCT04296890] conducted by Kathleen Moore, MD, of Stephenson Cancer Center, was pretty good [compared with] other response rates [observed with] single-agent therapy.

The things to keep in mind are the toxicities associated with mirvetuximab soravtansine, [such as] ocular toxicity. [This] is not something [clinicians] can ignore, and I [do not] think someone losing visual acuity is acceptable on a large scale. [We] have to be very knowledgeable and cognizant of those toxicities.

What main message would you like to impart to colleagues regarding the importance of genetic testing in the treatment of ovarian cancer?

Knowing the HRD and BRCA [mutation] status of a patient with ovarian cancer is the single most important [factor for treatment selection] because that marker [can inform] the use of PARP inhibitors in those with serous ovarian cancer. We need to know that [information] so we can ensure patients are getting cutting-edge treatment.

It is [also] important to [understand] how and why we dose reduce, as well as things that we can do to ameliorate [and monitor] those toxicities. [Lastly,] it’s important to [be informed] about the new [available treatments] for platinum-resistant disease.

Are there any ongoing studies at the University of Colorado Cancer Center that you would like to highlight?

We have [several] things in the pipeline. We’re [currently] looking at combining mirvetuximab soravtansine with some other agents down the road. We are [also] examining PARP toxicity [in] the immune microenvironment and [trying to understand] what contributes to PARP [inhibitor] resistance in [patients with] BRCA-positive [disease].