PARPi Therapy: “Game-changing” for BRCA 1/2 Ovarian Cancer

High progression-free survival rates form an ethical mandate for genetic testing.

The SOLO 1 study published in December of 2018 demonstrated unprecedented leaps in progression-free survival (PFS) for patients with BRCA-mutated ovarian and related (primary peritoneal or fallopian tube) cancers treated with the PARP inhibitor olaparib. While other trials have investigated the efficacy of olaparib for relapsed disease, SOLO 1 represents the first to test it on newly diagnosed patients who have a BRCA mutation.

The results should have turned the oncology world upside down, says Marta Crispens, M.D., director of gynecologic oncology at Vanderbilt University Medical Center. “This carefully executed international study told us that a PARP inhibitor has the capability of extending median progression-free survival by an additional 36 months. That is a game-changer of a scope we rarely see in this field,” Crispens said.

However, the path to germline and somatic testing to identify this mutation is fraught with stumbling blocks. “Determining BRCA 1 and 2 should be part of the patient’s initial evaluation, particularly now that we know how substantially we can extend life if we identify these patients up front,” Crispens said. “Still, there are a lot of good data saying that not everyone gets tested, even in top centers.”

Dramatic Findings

The SOLO 1 study group consisted of patients with a breast cancer susceptibility gene (BRCA 1 or BRCA 2) mutation, representing five to 15 percent of women with ovarian cancer.

Following chemotherapy, 260 study patients took 300 mg olaparib twice daily, while 131 took a placebo. The primary end point was PFS, with the olaparib group exceeding placebo by 36 months. After a median follow-up of 41 months, disease progression or death was 70 percent lower in the olaparib group.

“You’ll notice the curves never approximate each other for as far out as they go.”

Referencing the comparative PFS graphs that extend past 48 months, Crispens said, “You’ll notice the curves never approximate each other for as far out as they go. You just don’t see curves like this in cancer.”

Olaparib’s Modus Operandus

Most patients treated for ovarian, primary peritoneal or fallopian tube cancer have a recurrence in two to three years, Crispens said. The cancer cells that remain behind after cytoreduction and chemotherapy  reproduce and spread. However, in a BRCA-mutated cell, the first-line homologous recombinant DNA repair mechanism is inoperative. This forces the cancerous cell to fall back on a secondary mechanism for survival and reproduction. PARP inhibitors like olaparib work by inhibiting this back-up mechanism, leading to the accumulation of damage and either apoptosis or the inability to divide.

SOLO 1 demonstrates that, rather than waiting until relapse to treat with olaparib, administering PARP inhibitors following initial cytoreductive surgery and chemotherapy helps cripple the back-up mechanism early.

Not only is it effective, but it also substitutes a less toxic maintenance drug for more chemotherapy. Patients in the SOLO 1 study tolerated olaparib well, with health-related quality of life scores approximating those of the placebo group.

Pushing through Barriers

While the need for BRCA 1 and 2 testing may seem obvious, Crispens says the obstacles are neither minor nor arbitrary. “At many centers, genetic testing is only done in the context of genetic counseling, and we don’t have enough genetic counselors,” she said. It is also a costly test requiring insurance clearance that is far from straightforward, because these tests are not yet considered standard of care. In addition, some patients are wary of how their genetic information might be used.

Crispens urges providers to push through these barriers and make upfront testing the standard of care. “Patients with this mutation stand to benefit dramatically. Overall survival hasn’t been looked at yet, but I can’t imagine you’re going to have a 44-month increase in PFS and not have an improvement in overall survival. And the median PFS for the treated group wasn’t even reached,” Crispens said.