Improved understanding of the molecular basis of gynecologic cancers in addition to the availability of faster and less expensive technologies for genetic analysis of cancers has led to the exciting field of targeted biologic agents in ovarian, endometrial, cervical, and vulvar cancer. These agents include antiangiogenic therapies, poly (ADP-ribose) polymerase inhibitors, phosphoinositide 3-kinase pathway inhibitors, notch inhibitors, and epidermal growth factor receptor inhibitors. This article provides an update on the state of targeted therapy testing in gynecologic cancers.
With the development of molecularly targeted therapies, the availability of faster and less expensive technologies for genetic analysis of cancers, and the increasing molecular understanding of gynecologic malignancies, novel targeted biologic approaches are being tested in patients with gynecologic cancers, representing an exciting chapter in the treatment of gynecologic cancers. This article discusses several new areas of therapeutics in gynecologic malignancies: antiangiogenesis agents, poly-ADP-ribose polymerase (PARP) inhibitors, hedgehog (Hh) inhibitors, folate receptor (FR) antagonists, phosphoinositide 3-kinase (PI3K) pathway inhibitors, and inhibitors of the epidermal growth factor receptor (EGFR) family.
Antiangiogenesis therapies
Antiangiogenic therapies have been tested in ovarian, endometrial, and cervical cancer, and these agents have demonstrated antitumor activity as monotherapy and combined with cytotoxic chemotherapy.
Ovarian Malignancies
Angiogenesis has an important role in ovarian cancer pathogenesis. Epithelial ovarian cancer overexpresses proangiogenic factors, such as vascular endothelial growth factor (VEGF), fibroblast growth factor, platelet-derived growth factor (PDGF), and angiopoietin, supporting the role of angiogenesis in this cancer. In preclinical models, the expression of VEGF provides a survival advantage to transformed cells of the ovary. Several studies have found an association between higher preoperative serum VEGF and decreased overall survival (OS).
Several antiangiogenic agents have been studied in ovarian cancer; these agents are divided into tyrosine kinase inhibitors (TKIs) targeting VEGF receptor (VEGFR), and other kinases and antibody-based approaches, such as bevacizumab and VEGF-Trap.
Single-agent phase II studies of antiangiogenic agents for ovarian cancer
Table 1 lists single-agent antiangiogenic agents that have been tested in recurrent ovarian cancer and results of these studies. Bevacizumab, a recombinant humanized monoclonal IgG1 anti-VEGF antibody, has been studied in two separate single-agent phase II trials for recurrent ovarian cancer. In a Gynecologic Oncology Group (GOG) study, 62 patients with recurrent platinum-resistant or -sensitive (up to 12 months platinum-free interval) ovarian cancer received bevacizumab, 15 mg/kg intravenously (IV) once every 3 weeks. A total of 21% of patients achieved a clinical response, and 40.3% patients had a progression-free survival (PFS) of greater than or equal to 6 months. Median PFS was 4.7 months, and OS was 16.9 months. Clinical activity was observed in platinum-resistant and -sensitive tumors. Toxicities included 9.7% grade 3 hypertension, 22.6% grade 2 proteinuria, and 1.6% grade 3 venous thromboembolism, and there were no reports of gastrointestinal (GI) perforation. A second study that enrolled patients with platinum-resistant ovarian cancer who had received two or three prior lines of therapy tested bevacizumab, 15 mg/kg IV once every 3 weeks. The response rate was 15.9%, median PFS was 4.4 months, OS was 10.7 months, and the 6-month PFS was 27.8%. However, this study was stopped early because of an 11.4% GI perforation rate. Risks for GI perforation included receipt of more than two lines of therapy in the recurrent setting; bowel wall thickening on radiographic imaging or bowel obstruction were also identified as potential risk factors, but the association was not statistically significant. Grade 3 and 4 toxicities included 9.1% hypertension and 15.9% proteinuria. Three patients died on this study with toxicities related to bevacizumab including one episode each of myocardial infarction and cerebrovascular ischemia, intestinal perforation, and convulsion and hypertensive encephalopathy. Additional toxicities observed in single-agent bevacizumab studies were consistent with known bevacizumab toxicities. Aflibercept (VEGF-Trap), a fusion protein that acts as a VEGF sink by combining the Fc portion of human IgG1 with the principal extracellular ligand-binding domains of VEGFR, demonstrated a response rate of 11% in a phase II trial.
| Agent Tested | Regimen/Schedule | Patient Population | Outcomes | Notable Toxicities |
|---|---|---|---|---|
| Bevacizumab | 15 mg/kg q 3 wk IV | Platinum-free interval <12 mo | CR 3% PR 18% SD 52% Median PFS 4.7 mo 6-mo PFS 40.3% | 9.7% grade 3 HTN 22.6% grade 2 proteinuria 1.6% grade 3 venous thromboembolism No episodes of GIP |
| 15 mg/kg q 3 wk IV | Platinum resistant | PR 16% SD 61% Median PFS 4.4 mo 6-mo PFS 27.8% | 11.4% risk of GIP Grades 3 and 4 toxicities: 9.1% HTN 15.9% proteinuria 2.3% bleeding and wound healing complications | |
| Aflibercept | Either 2 or 4 mg/kg q 2 wk | Platinum-resistant, two or three prior lines for recurrence allowed | RR 11% | 9% grades 3 and 4 HTN 4% proteinuria 2% renal failure and encephalopathy 2 patients had GIP |
| Cediranib | 45 mg PO daily; dose reduced to 30 mg daily for toxicity | Platinum resistant | PR 17% SD 13% Median PFS 5.2 mo 6-mo PFS 17% | No GIP or fistulas 46% grade 3 HTN 24% grade 3 fatigue 13% grade 3 diarrhea 43% grade 2 hypothyroidism Grade 4: one episode each of CNS bleed, dehydration, elevated cholesterol |
| Sorafenib | 400 mg PO BID | Platinum-free interval <12 mo | PR 3.4% SD 34% Median PFS 2.1 mo 6-mo PFS 24% | 19.7% grade 3 dermatologic 14% grade 3 metabolic 1.4% grade 3 HTN 25% grade 2 GI |
| Sunitinib | Stage 1 (17 patients): 50 mg daily 4 wk on/2 wk off Stage 2 (14 patients): 37.5 mg daily | Platinum sensitive or resistant | RR 3.3% SD 53% Median PFS 4.1 mo | No incidence of GIP 10% grade 3 for each granulocytes, platelets, hemoglobin Fatigue, diarrhea, hand-foot |
| Pazopanib | 800 mg daily | Platinum sensitive or resistant; must have had CA125 CR to initial platinum-based chemotherapy | CA125 response 31% RR by RECIST 18% 6-mo PFS 17% | 8% grade 3 ALT elevation 11% grade 3 fatigue 11% grade GGT elevation 8% grade 3 diarrhea |
| ENMD2076 | Starting dose of 375 mg/day was reduced to 275 mg/day | Platinum resistant | PR 7% SD 30% 6-mo PFS 19% | Grade 3 hypertension (46%) Grade 3+ fatigue (24%) Grade 3+ diarrhea (13%) One grade 4 CNS hemorrhage |
| Cabozantinib (XL184) | 100 mg PO q day | Platinum sensitive or resistant | Platinum sensitive: (10 patients) PR 40%, SD 60% Platinum resistant/refractory: (17 patients) PR 29% SD 41% | Toxicities ≥ grade 3: 12% PPE syndrome 7% diarrhea 5% fatigue 5% vomiting 3% HTN |
Multiple single-agent TKIs have been tested in recurrent ovarian cancer and single-agent results are listed in Table 1 . Agents that have been tested include cediranib (targets VEGFR and c-Kit); sunitinib (targets VEGFR, c-Kit, PDGFR, RET, and FLT-3); sorafenib (targets VEGFR, c-Kit, RAF, and PDGFR-β); ENMD2076 (targets VEGFR and aurora A); pazopanib (targets VEGFR, PDGFR, and c-Kit); and cabozantinib (targets VEGFR and c-MET). These studies have demonstrated response rates between 3% and 29% in recurrent platinum-resistant ovarian cancer. In a recent study of cabozantinib (XL184), which targets VEGFR and c-MET, there was a 29% confirmed partial response (PR) rate in platinum-resistant or -refractory ovarian cancer and 40% response rate in platinum-sensitive cancers.
Randomized phase II studies have also been performed. Ledermann and colleagues conducted a randomized double-blind phase II study of maintenance BIBF 1120 (which has activity against VEGFR, PDGFR, and fibroblast growth factor receptor) versus placebo for up to 9 months in 83 patients with recurrent ovarian cancer who had experienced response to their last chemotherapy in the second-line or greater setting. Thirty-six–week PFS rates were 16.3% and 5% in the BIBF 1120 and placebo groups, respectively (hazard ratio [HR] = 0.65; 95% confidence interval [CI], 0.42–1.02; P = .06), suggesting that maintenance antiangiogenic therapy can delay disease progression in this setting. These positive results have led to the testing of this drug combined with carboplatin and paclitaxel in the newly diagnosed setting, and this study is described next.
Combination chemotherapy plus antiangiogenic agents for ovarian cancer
Phase II studies
Single-agent phase II studies of combination chemotherapy with antiangiogenic drugs have been performed. These include combinations of bevacizumab with oral cyclophosphamide, bevacizumab with carboplatin and paclitaxel, bevacizumab with docetaxel and oxaliplatin, bevacizumab with nab-paclitaxel, cediranib with carboplatin and paclitaxel, and aflibercept plus docetaxel. Certain combinations (ie, carboplatin, paclitaxel and bevacizumab) have been or are being tested in randomized phase II or III studies. A recent report testing cediranib added to carboplatin-based chemotherapy in recurrent ovarian cancer resulted in acceptable toxicities. In the safety portion of ICON6, 60 patients were enrolled and subsequently randomized (2:3:3) to receive six cycles of carboplatin-based chemotherapy with placebo followed by placebo maintenance, carboplatin-based chemotherapy plus cediranib with placebo maintenance, or carboplatin-based chemotherapy plus cediranib with cediranib maintenance. Grade 3 and 4 toxicities were observed in 50% and 5% of patients, respectively, and no GI perforations were observed. The investigators concluded that the addition of cediranib to platinum-based chemotherapy was tolerable enough to expand the ICON6 trial to stage II.
AMG386 is a selective angiopoietin 1/2-neutralizing peptibody that inhibits angiogenesis by targeting a parallel angiogenic pathway from VEGFR. AMG386 was tested in a randomized phase II study of weekly paclitaxel plus AMG386 versus weekly paclitaxel alone in patients with recurrent platinum-resistant ovarian cancer. The results of this study demonstrated a nonsignificant prolongation of PFS from 4.6 months for paclitaxel and placebo to 7.2 months observed for paclitaxel and AMG386 at a dose of 10 mg/kg ( P = .23). These results have led to a phase III study, described next. The activity of sorafenib as a maintenance therapy is also being studied in a phase II study comparing a regimen of carboplatin, paclitaxel, and sorafenib for six cycles followed by 12 months of sorafenib maintenance to carboplatin and paclitaxel alone ; results of this study are currently pending.
Phase III studies
Bevacizumab combined with carboplatin and paclitaxel chemotherapy has been tested in two separate randomized phase III trials in newly diagnosed advanced ovarian cancer ( Table 2 ). GOG218 is a double-blind placebo-controlled trial that enrolled 1873 advanced FIGO stage III or IV patients (optimal or suboptimally debulked) who were randomized in a 1:1:1 ratio to one of three arms: Arm 1 (control) consisted of carboplatin AUC 6, paclitaxel, 175 mg/m 2 , and placebo every 3 weeks × six cycles, followed by maintenance placebo every 3 weeks for an additional 16 cycles; Arm 2 consisted of carboplatin AUC 6, paclitaxel, 175 mg/m 2 , and bevacizumab, 15 mg/kg every 3 weeks × 6 cycles, followed by maintenance placebo; and Arm 3 consisted of carboplatin AUC 6, paclitaxel, 175 mg/m 2 , and bevacizumab, 15 mg/kg every 3 weeks, followed by maintenance bevacizumab, 15 mg/kg every 3 weeks. The original endpoint of this study was OS, but this was changed to PFS midway through the study. When Arm 2 was compared with Arm 1, no significant benefit in PFS was seen (median PFS 10.3 months control vs 11.2 months treatment; HR = 0.908; P = .080). However, when Arm 3 was compared with Arm 1 (prespecified comparisons), Arm 3 showed a statistically significant improvement in PFS compared with Arm 1 (median PFS 10.3 months control vs 14.1 months treatment; HR = 0.717; P <.0001). OS data are not yet mature, but to date no OS benefit has been noted in any of the arms; OS is 39.3 months in Arm 1, 38.7 months in Arm 2, and 39.7 months in Arm 3. Grade 2 or higher hypertension and GI fistula and perforation were higher in the bevacizumab arms compared with Arm 1, which did not contain bevacizumab.
| Setting | Study | Accrual | Dose of Bev | Treatment Regimens | Primary Endpoint | Results |
|---|---|---|---|---|---|---|
| First-line | GOG218 | N = 1873 | 15 mg/kg q 3 wk |
| PFS | PFS arm 3: 14.1 mo PFS arm 1: 10.3 mo (HR = 0.717; P <.0001). OS not different |
| ICON7 | N = 1528 | 7.5 mg/kg q 3 wk |
| PFS | PFS arm 1: 17.3 mo PFS arm 2: 19 mo (HR = 0.81; P = .0041) OS not different | |
| Recurrent | OCEANS | N = 484 | 15 mg/kg q 3 wk |
| PFS | PFS arm 1: 8.4 mo PFS arm 2: 12.4 mo (HR = 0.484; P <.0001) OS not different |
ICON7 is a randomized open-label phase III trial that randomized 1528 women 1:1 to either carboplatin AUC 6 and paclitaxel, 175 mg/m 2 , every 3 weeks for six cycles or carboplatin AUC 6 and paclitaxel, 175 mg/m 2 , every 3 weeks for six cycles, with the addition of bevacizumab, 7.5 mg/kg, every 3 weeks starting in cycle 2 and continuing for an additional 12 cycles of maintenance therapy. Eligible patients included FIGO stages I or IIA (grade 3), IIB or C, III, and IV. PFS was improved in the bevacizumab arm with a median PFS of 17.3 months in the nonbevacizumab control arm and 19 months in the treatment arm (HR = 0.81; P = .0041). As in GOG218, OS was not significantly different between the two arms in ICON7. In an updated analysis of ICON7, a significant OS benefit was observed with bevacizumab treatment in patients who were suboptimally cytoreduced (>1 cm of cancer remaining at initial cytoreductive surgery) or had stage IV cancer (median OS 28.8 vs 36.6 months; HR = 0.64; P = .002).
Results are pending in other phase III studies of antiangiogenic drugs in newly diagnosed patients. A placebo-controlled randomized phase III trial investigating the antiangiogenic small molecule BIBF 1120 with carboplatin and paclitaxel is ongoing with PFS as the primary endpoint. Pazopanib is being tested in a randomized placebo-controlled phase III study as maintenance after initial surgical debulking and chemotherapy. Two additional ongoing phase III trials are incorporating bevacizumab with different chemotherapy strategies (ie, IP and dose-dense chemotherapy), but neither of these studies is testing the benefit of adding bevacizumab to front-line chemotherapy. GOG252 is open to patients with stages II, III, or IV cancer that is either optimally (≤1 cm residual cancer) or suboptimally (>1 cm residual cancer) cytoreduced, randomizes patients to one of three arms, and all of these arms contain bevacizumab followed by maintenance bevacizumab therapy: (1) IV carboplatin AUC 6 Day 1 and IV paclitaxel, 80 mg/m 2 , Days 1, 8, and 15; (2) IP carboplatin AUC 6 Day 1 and IV paclitaxel, 80 mg/m 2 , Days 1, 8, and 15; or (3) IV paclitaxel, 135 mg/m 2 over 24 hours Day 1, IP cisplatin, 75 mg/m 2 , Day 2, and IP paclitaxel, 60 mg/m 2 , Day 8. GOG262 is open to suboptimally debulked stages III or IV patients and randomizes patients to either IV carboplatin AUC 6 and IV paclitaxel, 175 mg/m 2 , Day 1 or IV carboplatin AUC 6 Day 1 and IV paclitaxel, 80 mg/m 2 , Days 1, 8, and 15. In this study, the use of bevacizumab is optional, and if used, is continued until either disease progression or unacceptable toxicity occurs.
Several randomized phase III trials have been performed and others are ongoing that test the role of antiangiogenic agents in recurrent ovarian cancer. The OCEANS study tested bevacizumab in combination with platinum-based chemotherapy in patients with recurrent platinum-sensitive ovarian cancer (see Table 2 ). In this trial, 484 women with platinum-sensitive ovarian cancer with no prior chemotherapy for recurrent cancer were randomized to receive carboplatin AUC 4 Day 1 and gemcitabine, 1000 mg/m 2 , Days 1 and 8 with either bevacizumab, 15 mg/kg, or placebo given IV every 3 weeks. The primary endpoint was PFS, and median PFS was 8.4 months in the control arm and 12.4 months with the addition of bevacizumab (HR = 0.484; P <.0001). Response rates were 57.4% in the control group and 78.5% in the treatment arm ( P <.0001). OS data are not yet mature, but OS was not statistically significant between the groups. Increased toxicities observed in patients receiving bevacizumab included hypertension, proteinuria, bleeding, and thromboembolic events. No GI perforations were observed during the study, but two patients developed GI perforations after completion of bevacizumab.
Other phase III studies are ongoing in recurrent ovarian cancer. GOG213 is testing the roles of secondary cytoreductive surgery and bevacizumab in combination with carboplatin and paclitaxel in recurrent platinum-sensitive ovarian cancer. ICON6 is testing the role of cediranib in recurrent platinum-sensitive ovarian cancer, described previously. AMG386 is being tested along with chemotherapy in a phase III study in the partially platinum-sensitive or in platinum-resistant patients. Patients are being randomized to either AMG386 with weekly paclitaxel or weekly paclitaxel alone.
Endometrial Cancer
Angiogenesis also has a role in endometrial cancer, and elevated levels of VEGF and other markers of angiogenesis have correlated with a poorer outcome in patients with endometrial cancer. To date, however, treatment of recurrent endometrial cancer with antiangiogenic agents has revealed mixed results. Agents that have been tested include bevacizumab, sunitinib, sorafenib, and thalidomide. Bevacizumab was studied as part of a GOG study in patients with recurrent or persistent endometrial cancer after receiving one or two prior cytotoxic regimens with measurable cancer. Fifty-two patients met eligibility and were evaluable. A total of 13.5% of patients had an objective response (one complete response and six PRs); 40.4% of patients survived progression-free for at least 6 months. Median PFS was 4.2 months, and OS was 10.5 months. No GI perforations or fistulas were reported. Two episodes of grades 3 and 4 hemorrhage were reported and two episodes of grades 3 or 4 thrombosis and embolism.
Other antiangiogenic agents have been tested with less positive results. Sunitinib was tested in patients with recurrent or metastatic endometrial cancer who have received up to one prior chemotherapy regimen for metastatic disease, and sunitinib was given at 50 mg daily for 4 consecutive weeks followed by 2 weeks off. Of the 20 patients evaluable for response, PR was achieved by three patients (overall response rate [ORR] = 15%) and four of these patients remained progression-free for greater than or equal to 6 months (20%). Sorafenib was tested in a cohort of 39 patients with endometrial cancer with the starting sorafenib dose of 400 mg orally twice daily. Two (5%) patients had a PR and 17 (42.5%) achieved stable disease (SD). The 6-month PFS rate for patients with carcinoma was 29%, and the median OS was 11.4 months. The authors concluded that sorafenib had minimal activity in endometrial cancer. Thalidomide was tested in a GOG study in patients with recurrent endometrial cancer using a thalidomide dose of 200 mg orally each day and dose escalated up to 1000 mg/day if tolerated. Response rate was 12.5%, and 8.3% of patients had SD. The investigators believe that thalidomide is an inactive drug in endometrial cancer.
Cervical Cancer
Angiogenesis has several roles in cervical cancer pathogenesis including the finding of elevated intratumoral levels of VEGF, human papilloma virus enhancement of VEGF production by upregulation of the E6 oncoprotein, and VEGF expression and increased vascularization predicts poorer outcomes in cervical cancer.
Single-agent bevacizumab has been studied in patients with recurrent or persistent squamous cell carcinoma of the cervix who received one or two prior cytotoxic regimens. Of 46 patients enrolled, 11 (23.9%) survived progression free for at least 6 months, and five patients (10.9%) had a response, all PRs. Toxicities were as expected and included grades 3 or 4 hypertension (N = 7), thromboembolism (N = 5), GI (N = 4), anemia (N = 2), cardiovascular (N = 2), vaginal bleeding (N = 1), neutropenia (N = 1), and fistula (N = 1), with one grade 5 infection observed. Median PFS was 3.40 months. An ongoing phase III study in recurrent cervical cancer through the GOG is testing the efficacy of adding bevacizumab to chemotherapy, and patients are being randomized to one of four arms: (1) pacliltaxel and cisplatin, (2) paclitaxel/cisplatin and bevacizumab, (3) paclitaxel and topotecan, and (4) paclitaxel/topotecan and bevacizumab. OS is the primary endpoint of this study.
Other oral TKIs have been tested in cervical cancer. Single-agent sunitinib was tested in 19 patients with locally advanced or metastatic cervical carcinoma. No objective responses were observed but 84% of patients had SD (median duration, 4.4 months). Four patients developed fistulae while receiving sunitinib, and an additional patient developed a fistula 3.5 months after she had discontinued therapy. The authors concluded that the 26.3% rate of fistula formation was higher than expected and concerning and sunitinib as a single agent had insufficient activity to warrant further exploration of this drug in cervical cancer.
In a randomized phase II study testing the TKI pazopanib in advanced cervical cancer, pazopanib was given either alone or in combination with lapatinib, a combined inhibitor of EGFR and HER2. Patients with measurable persistent or recurrent cervical carcinoma who had received at least one prior regimen in the metastatic setting were randomized in a ratio of 1:1:1 to pazopanib, 800 mg once daily, lapatinib, 1500 mg once daily, or a combination of lapatinib plus pazopanib in one of two regimens: lapatinib at 1000 mg plus pazopanib at 400 mg once daily; or lapatinib at 1500 mg plus pazopanib at 800 mg once daily. The primary end point was PFS. Interim analysis revealed an imbalance of toxicities in the combination arm and this arm was dropped. Median PFS for lapatinib was shorter compared with pazopanib (median PFS, 17.1 weeks vs 18.1 weeks; HR = 0.66; 90% CI, 0.48–0.91; P <.013). Grade 3 adverse events were 13% grade 3 diarrhea and 5% anemia in the lapatinib arm, 11% grade 3 diarrhea and 5% alkaline phosphatase elevation in the pazobanib arm, and 20% grade 3 diarrhea and 5% anemia in the combination arm. Grades 1 and 2 toxicities were not reported.
PARP inhibitors
One of the most promising advances in targeted therapy in ovarian cancer has been the discovery and use of PARP inhibitors. Table 3 lists selected PARP inhibitors currently undergoing testing. These agents inhibit the enzyme PARP and work synergistically with the deficiencies of DNA repair seen in cancers occurring in patients with germline BRCA1 or BRCA2-mutations. In addition, these agents also show activity in high-grade serous ovarian cancer in patients who do not harbor a germline BRCA1 or BRCA2 mutation likely because of the loss of BRCA function from deletion, somatic mutations, or methylation.
| Name of Agent | Company | Route of Administration | Examples of Ongoing Studies |
|---|---|---|---|
| Olaparib (AZD2281) | AstraZeneca | Both PO | Olaparib: single-agent studies and combination with chemotherapy |
| AZD2461 | AZ2461: single-agent phase I | ||
| MK4827 | Merck | PO | Single-agent and in combination with chemotherapy |
| Veliparib (ABT888) | Abbott | PO | Combination with chemotherapy |
| Rucaparib (PF-01367338) | Clovis | PO, IV | Single-agent and combination studies with chemotherapy |
| CEP-9722 | Cephalon | PO | Single-agent and in combination with chemotherapy |
| BMN673 | BioMarin | PO | Single-agent |
| E7016 | Eisai | PO | Combination with temozolomide |
Olaparib (AZD2281) is an oral PARP inhibitor that has undergone the most extensive investigation thus far of PARP inhibitors in ovarian cancer, in patients with germline BRCA mutations and in those with no mutations. Initial phase I testing of olaparib using doses from 10 mg orally daily 2 out of 3 weeks up to 600 mg twice a day dosed daily continuously demonstrated a maximally tolerated dose of 400 mg twice a day. Clinical benefit was demonstrated in 12 of 19 patients who were BRCA carriers with ovarian, breast, or prostate cancer. Table 4 lists selected studies of single-agent olaparib for the treatment of recurrent ovarian cancer, and phase II studies have demonstrated overall response rates up to 41% in patients with germline BRCA-1 or -2 associated cancers and 24% in sporadic high-grade serous cancers (HGSC) using the maximally tolerated dose of olaparib of 400 mg twice a day (capsule formulation). Toxicities of olaparib include fatigue, nausea, vomiting, decreased appetite, and myelosuppression.
| Study | No. of Patients | Study Design | Patient Population | Primary Outcome | Results |
|---|---|---|---|---|---|
| Audeh et al | 57 | 1st cohort: olaparib, 400 mg BID 2nd cohort: olaparib, 100 mg BID | All germline BRCA-1 or -2 mutation carriers | RR | 33% RR for 400-mg BID dose 13% RR for 100-mg BID dose |
| Gelmon et al | 65 | Phase II of olaparib, 400 mg BID | HGSC, ± germline BRCA mutation | RR | 41% RR in germline mutation carriers 24% RR in patients without mutations |
| Kaye et al | 97 | Randomized phase II to olaparib, 200 BID, 400 BID, or PLD 50 mg/m 2 (1:1:1 ratio) | All germline BRCA mutation carriers, recurrence within 12 mo of prior platinum, no prior anthra or PARP i | PFS | PFS not significant for olaparib arms vs PLD |
| Ledermann et al | 250 | Phase II randomized, double-blinded to either olaparib or placebo. Both penultimate and most recent platinum regimen showed platinum sensitivity | ± germline BRCA mutation. All patients had HGSC | PFS | 8.4 mo (olaparib) vs 4.8 mo (placebo) ( P <.00001) |
Olaparib has been compared with liposomal doxorubicin in patients who have recurrent ovarian cancer, a known germline BRCA mutation, and have never received pegylated liposomal doxorubicin (PLD). Patients were randomized 1:1:1 to PLD; olaparib, 200 mg twice a day; or olaparib, 400 mg twice a day. No significant differences in PFS were observed between PLD and the combined olaparib arms.
Olaparib has also been explored as maintenance therapy after patients with platinum-sensitive recurrent ovarian HGSC attained a clinical remission after platinum-based chemotherapy. After completion of platinum-based chemotherapy, patients were randomized to either placebo or olaparib, 400 mg twice a day, in this double-blinded study with PFS as the primary endpoint. There was a statistically significant difference between the PFS of the two groups in favor of olarapib compared with placebo (8.4 months vs 4.8 months; HR = 0.35; 95% CI, 0.25–0.49; P <.00001).
Olaparib has also been combined with chemotherapy and other studies are ongoing. In addition to PARP inhibitors, other agents are under development that inhibit various aspects of DNA repair pathways.
PARP inhibitors
One of the most promising advances in targeted therapy in ovarian cancer has been the discovery and use of PARP inhibitors. Table 3 lists selected PARP inhibitors currently undergoing testing. These agents inhibit the enzyme PARP and work synergistically with the deficiencies of DNA repair seen in cancers occurring in patients with germline BRCA1 or BRCA2-mutations. In addition, these agents also show activity in high-grade serous ovarian cancer in patients who do not harbor a germline BRCA1 or BRCA2 mutation likely because of the loss of BRCA function from deletion, somatic mutations, or methylation.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
