PARP inhibitors are changing the face of treatment
Poly(adenosine diphosphate-ribose) polymerases (PARPs) are a family of enzymes that play a critical role in DNA damage repair. These enzymes promote DNA repair by recruiting proteins involved in repairing single-strand and double-strand DNA breaks and in protecting and restarting stalled DNA replication forks.13 The predominant mechanisms of action of PARP inhibitors in cells with homologous-recombination deficiency (HRD) include inhibiting repair of single-strand DNA breaks and trapping PARP-DNA complexes at stalled DNA replication forks.14
Germline or somatic BRCA1/2 mutations and genetic alterations resulting in HRD are present in about 20% and 30% of ovarian carcinomas, respectively, and increase the susceptibility of tumors to platinum-based agents and PARP inhibitors.15,16 Based on multiple clinical trials that demonstrated the efficacy of single-agent PARP in the treatment of recurrent ovarian carcinoma and as maintenance therapy after an initial response to platinum-based therapy, the US Food and Drug Administration approved olaparib, niraparib, and rucaparib for the treatment of high-grade epithelial ovarian cancer.17-19 Only olaparib is approved for maintenance therapy after initial adjuvant therapy in patients with BRCA mutations.20
Given the robust response to PARP inhibitors, there has been great interest in using these agents earlier in the disease course in combination with chemotherapy.
Efficacy of veliparib with chemotherapy and as maintenance monotherapy
In a randomized, double-blind, placebo-controlled phase 3 trial, Coleman and colleagues sought to determine the efficacy of the PARP inhibitor veliparib when administered with first-line carboplatin and paclitaxel induction chemotherapy and subsequently continued as maintenance monotherapy.21
Women with stage III or IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal carcinoma were eligible for the study. Cytoreductive surgery could be performed prior to the initiation of trial treatment or after 3 cycles of chemotherapy.
Participants were randomized in a 1:1:1 ratio: 371 women received carboplatin and paclitaxel plus placebo followed by placebo maintenance (control arm); 376 received chemotherapy plus veliparib followed by placebo maintenance (veliparib combination-only arm); and 377 received chemotherapy plus veliparib followed by veliparib maintenance therapy (veliparib-throughout arm). Combination chemotherapy consisted of 6 cycles, and maintenance therapy was an additional 30 cycles.
Progression-free survival extended
At a median follow-up of 28 months, investigators observed a significant improvement in progression-free survival in the veliparib-throughout (initial and maintenance therapy) arm compared with the control arm in 3 cohorts: the BRCA-mutation cohort, the HRD cohort, and the intention-to-treat population (all participants undergoing randomization).
In the BRCA-mutation cohort, the median progression-free survival was 12.7 months longer in the veliparib-throughout arm than in the control arm. Similarly, in the HRD cohort, the median progression-free survival was 11.4 months longer in the veliparib-throughout arm than in the control group. In the intention-to-treat population, the median progression-free survival increased from 17.3 to 23.5 months in the veliparib-throughout arm compared with the control arm.
Women who received veliparib experienced increased rates of nausea, anemia, and fatigue and were more likely to require dose reductions and treatment interruptions. Myelodysplastic syndrome was reported in 1 patient (BRCA1 positive) in the veliparib combination-only arm.
WHAT THIS EVIDENCE MEANS FOR PRACTICE
For women with newly diagnosed, previously untreated stage III or IV high-grade serous ovarian carcinoma, carboplatin, paclitaxel, and veliparib induction therapy followed by single-agent veliparib maintenance therapy resulted in a significant improvement in median progression-free survival compared with induction chemotherapy alone. However, veliparib use was also associated with a higher incidence of adverse effects that required dose reduction and/or interruption during both the combination and maintenance phases of treatment.
For women with newly diagnosed, previously untreated stage III or IV high-grade serous ovarian carcinoma, carboplatin, paclitaxel, and veliparib induction therapy followed by single-agent veliparib maintenance therapy resulted in a significant improvement in median progression-free survival compared with induction chemotherapy alone. However, veliparib use was also associated with a higher incidence of adverse effects that required dose reduction and/or interruption during both the combination and maintenance phases of treatment.
Secondary cytoreductive surgery or chemotherapy alone for platinum-sensitive recurrent ovarian carcinoma?
Coleman RL, Spirtos NM, Enserro D, et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N Engl J Med. 2019;381:1929-1939.
Primary surgical cytoreduction combined with platinum and taxane-based chemotherapy remains the mainstay of ovarian cancer treatment.11 The role of surgery for women with recurrent ovarian cancer, so-called secondary cytoreduction, remains controversial.22
Data have shown that among women who undergo secondary surgery, those with little or no postoperative residual disease benefit the most from a secondary debulking.23-26 Prior work largely is based on small retrospective reports and is limited by substantial bias in the selection of patients undergoing surgery. Additionally, with the availability of targeted therapies such as bevacizumab and PARP inhibitors as maintenance—medical interventions with a demonstrated benefit in progression-free survival17-19,27—the role of secondary cytoreduction in the treatment of ovarian carcinoma needs to be clarified.
Continue to: Overall survival after secondary cytoreduction followed by chemotherapy...