PARP Inhibitors Continue to Flourish in Advanced Ovarian Cancer

Reagan M. Street, MD, MMS

PARP inhibitors have demonstrated progression-free survival (PFS) gains in the recurrent setting in women with BRCA-mutated advanced ovarian cancer, and now as frontline maintenance therapy in those with a wider scope of homologous recombination deficiencies (HRD), explained Reagan M. Street, MD, MMS.

“Treatment is rapidly evolving,” said Street. “There are three main PARP inhibitors right now that are constantly gaining new indications. These agents are being studied in conjunction with first-line therapy, in the recurrent setting, and in the maintenance setting in combination with different antiangiogenic drugs.”

The most recent data reflective of such benefit came from the phase III PAOLA-1,¹ PRIMA,^2,3 and VELIA^4,5 trials, which were all presented at the 2019 ESMO Congress. In PAOLA-1, patients with HRD-positive disease who received frontline maintenance with olaparib (Lynparza) and bevacizumab (Avastin) experienced a median PFS of 37.2 months versus 17.7 months with bevacizumab alone (HR, 0.33; 95% CI, 0.25-0.45). Similarly, in PRIMA, patients with HRD-positive disease who received frontline maintenance with niraparib (Zejula) derived a median PFS of 21.9 months versus 10.4 months, which translated to a 57% reduction in the risk of disease progression or death versus placebo (HR, 0.43; 95% CI, 0.50-0.76).

Furthermore, in VELIA, patients with HRD-positive disease experienced a median PFS of 31.9 months with the use of frontline veliparib in combination with platinum chemotherapy followed by veliparib maintenance versus 20.5 months with placebo (HR, 0.57; 95% CI, 0.43-0.76).

Although the PFS benefit was more pronounced in patients with BRCA mutations in all three trials, the results demonstrate the utility of PARP in a wider population of patients. As such, hierarchal testing for BRCA1/2, and if negative, HRD, should be implemented in routine practice, said Street.

In an interview during the 2019 OncLive State of the Science Summit on Precision Medicine, Street, gynecologic oncologist, Texas Oncology, discussed the shift toward targeted treatment in advanced ovarian cancer partly brought on by PARP inhibitors and the importance of hierarchical genomic testing.

OncLive: How is personalized medicine being used in ovarian cancer?

Street: Precision medicine and personalized targeted treatment is evolving in every kind of cancer. In ovarian cancer specifically, PARP inhibitors are the frontrunner of [personalized medicine]. Every tumor is different and every molecular environment is different. This previous approach of giving everyone blanket therapy with whatever standard-of-care drug was available at the time is changing. We are finding that different tumors have different markers that we can target and get better responses from. 

What are the key biomarkers and targets in this space right now?

[The key ones are] BRCA mutations and HRD, the latter of which is essentially an inability to repair DNA correctly. PARP inhibitors target these biomarkers.

Could you elaborate on hierarchal testing in ovarian cancer?

HRD encompasses BRCA plus a panel of other germline mutations. Once a patient is diagnosed with ovarian cancer, they will get tested for a BRCA1/2 mutation. If they test positive, they're done; they don't have to do any more testing. If they test negative, then they undergo panel testing for several other genes depending on the assay. If that comes back positive, they're done, but if that is negative, then they get their tumor tested for HRD. Overall, about 50% of ovarian cancers have some kind of HRD. 

What are the key challenges with testing?

There are always challenges. There are multiple different commercial assays and they’re not created equal. Deciding which one is the best is difficult. Also, should we test them multiple times? Do we test immediately upon diagnosis? If a patient recurs, should we test again? We don't know those answers yet. 

How are you approaching this in practice?

Once a patient is diagnosed, we have to decide whether to proceed with surgery or chemotherapy. By the time they are done with about 2 cycles of chemotherapy, they should have had their germline or blood tested for a BRCA mutation; that reflects the panel. If that is negative, we test for HRD or somatic [mutations] on the tumor itself.

In your presentation during the State of the Science Summit, you stated that PARP inhibitors are underused in practice. What could lead to greater widespread use?

If you ask a group of physicians if they're using them, 90% are going to say “yes”—that they’re using PARP inhibitors as indicated. However, market studies have shown that only 30% of physicians are actually doing that. There's clearly a disconnect in what we think we're doing and what is actually happening. That’s where the education comes in. That's why programs such as [the State of the Science Summit™] are very important. 

What key challenges remain in this space?

The number one challenge is ensuring that patients get treated appropriately from the beginning. That means that patients should be referred to gynecologic oncologists so they can get treated appropriately. Insurance [coverage] is an ongoing issue. Finally, [a challenge is] getting tested and not just stopping if a patient is negative for BRCA1/2.

What is your take-home message for your colleagues?

Every patient with ovarian cancer needs to undergo germline genetic testing. Every patient with ovarian cancer needs panel testing irrespective of whether or not they have a BRCA1/2 mutation. Moreover, everyone should receive HRD testing, which means tumor or somatic testing. 

References

1. Ray-Coquard IL, Pautier P, Pignata S, et al. Phase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients (pts) with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy (PCh) plus bev. Presented at: 2019 ESMO Congress; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA2_PR.
2. Gonzalez-Martin A, Pothuri B, Vergote I, et al. Niraparib therapy in patients with newly diagnosed advanced ovarian cancer (PRIMA/ENGOT-OV26/GOG-3012 study). Presented at: 2019 ESMO Congress; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA1.
3. González-Martin A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer [published online September 28, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1910962.
4. Coleman RL, Fleming GF, Brady MF, et al. VELIA/GOG-3005: Integration of veliparib (V) with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC). Presented at: 2019 ESMO Congress 2019, Barcelona, Spain, September 27 to October 1, 2019. Abstract LBA3.
5. Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer [published online September 28, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1909707.