WASHINGTON -- The FDA on Friday approved the first PARP inhibitor for , a fourth-line option for , and a frontline immunotherapy combination for .
Rucaparib for BRCA-Mutated Prostate Cancer
Support for approval of rucaparib (Rubraca) was based on findings from TRITON2, a single-arm trial of patients with metastatic castration-resistant prostate cancer (mCRPC) with germline or somatic BRCA mutations who had received prior chemotherapy and androgen receptor-directed therapy.
Among 115 patients who had undergone bilateral orchiectomy or were on a gonadotropin-releasing hormone analog, 55% had a prostate-specific antigen response following treatment with oral rucaparib (600 mg twice daily).
Moreover, in 62 patients with evaluable disease, 44% had an objective response to the PARP inhibitor. Median duration of response was not evaluable (range: 1.7 to 24-plus months), and 27 patients achieved a response of 6 months or beyond.
"Rubraca is the first in a class of drugs to become newly available to patients with mCRPC who harbor a deleterious BRCA mutation," TRITON2 investigator Wassim Abida, MD, of Memorial Sloan Kettering Cancer Center in New York City, said in a manufacturer . "Given the level and duration of responses observed with Rubraca in men with mCRPC and these mutations, it represents an important and timely new treatment option for this patient population."
Common adverse events (AEs) in the trial included anemia, constipation, decreased appetite, diarrhea, fatigue, increased liver enzymes, nausea and vomiting, rash, and thrombocytopenia.
GIST Gets Fourth-Line Option
The tyrosine kinase inhibitor (TKI) ripretinib (Qinlock) snagged its first approval, for adults with advanced GISTs whose tumors progressed on three prior TKIs, including imatinib (Gleevec).
"Despite the progress that has been made over the past 20 years in developing treatments for GIST, including four FDA-approved targeted therapies -- imatinib in 2002, sunitinib [Sutent] in 2006, regorafenib [Stivarga] in 2013 and avapritinib [Ayvakit] earlier this year -- some patients don't respond to treatment and their tumors [continue] to progress," Richard Pazdur, MD, director of the FDA's Oncology Center of Excellence, said in a . "Today's approval provides a new treatment option for patients who have exhausted all FDA-approved therapies for GIST."
Approval for the fourth-line agent was based on the international phase III INVICTUS trial, which randomized 129 patients 2:1 to oral ripretinib (150 mg once daily) or placebo until disease progression or unacceptable toxicity.
Patients on ripretinib had improved progression-free survival (PFS), at 6.3 months versus 1.o month with placebo (HR 0.15, 95% CI 0.09-0.25, P<0.0001). Overall survival (OS) was 15.1 months in the investigational arm versus 6.6 months with placebo, with crossover permitted in the placebo arm following disease progression.
Common AEs with ripretinib included abdominal pain, alopecia, constipation, decreased appetite, diarrhea, fatigue, hand-foot syndrome, myalgia, and nausea and vomiting. FDA warned that ripretinib was also associated with the development of cardiac dysfunction, hypertension, and new skin cancers.
Opdivo Notches First-Line NSCLC Approval
The PD-1 inhibitor nivolumab (Opdivo), the first immune checkpoint inhibitor to be approved in non-small cell lung cancer (NSCLC), finally landed a first-line indication, in combination with the CTLA-4-directed agent ipilimumab (Yervoy) for patients with metastatic PD-L1-positive disease (≥1%).
In part 1a of the phase III CheckMate-227 trial, treatment with the combination demonstrated an improvement in OS for PD-L1-positive NSCLC patients without EGFR mutations or ALK rearrangements over a platinum doublet (17.1 vs 14.9 months; HR 0.79, 95% CI 0.67-0.94, P=0.0066). Landmark analyses of OS favored the immunotherapy combination over chemotherapy at all time points:
- 1 year: 63% vs 56%
- 2 years: 40% vs 33%
- 3 years: 33% vs 22%
In the nivolumab-ipilimumab arm, 36% of patients responded versus 30% with chemotherapy, and the median duration of response was 23.2 and 6.2 months, respectively. Median PFS was similar between the two arms, at 5.1 months in the nivolumab-ipilimumab arm and 5.6 months in the chemotherapy arm.
"Patients with metastatic lung cancer remain in need of new treatment options that may provide durable responses," study investigator Matthew Hellmann, MD, also of Sloan Kettering, said in a . "The results from the CheckMate-227 trial show that a dual immunotherapy approach offers a chance at long-term survival for appropriate patients with metastatic NSCLC."
Common AEs among patients treated with the immunotherapy combination included cough, decreased appetite, diarrhea/colitis, dyspnea, fatigue, hepatitis, musculoskeletal pain, nausea, pruritus, and rash.
Nivolumab-ipilimumab is also approved for the first-line treatment of advanced or metastatic melanoma and renal cell carcinoma.