- PARP inhibitors represent a success story for DNA-repair targeted therapies in ovarian cancer.
- Important unanswered questions remain, including the comparative efficacy of different PARP inhibitors, the degree of their cross-resistance, and their optimal incorporation into the management of ovarian cancer.
- PARP inhibitor resistance is also emerging as an important problem in the clinic; the ideal treatment of patients who progress after PARP inhibitor therapy remains to be defined and should depend on a thorough understanding of the underlying mechanism(s) of resistance.
The synthetic lethal interaction between PARP inhibition and HRR deficiency is being successfully exploited therapeutically in ovarian cancer whereby three PARP inhibitors—olaparib, rucaparib, and niraparib—have received U.S. Food and Drug Administration (FDA) approval as monotherapy either in patients with germline or somatic BRCA1/2 mutations, or as maintenance therapy after platinum chemotherapy in platinum-sensitive recurrent disease, regardless of BRCA mutation status. The Table (page 9C) provides a clinical overview (dosing, approval indications, and toxicities) of the three PARP inhibitors that are currently FDA approved in ovarian cancer; two additional PARP inhibitors—veliparib and talazoparib—are in clinical development. Thus far, no study has directly compared the efficacy of olaparib, niraparib, and rucaparib. However, based on already reported studies on similar patient populations with ovarian cancer, it is reasonable to assume that all three drugs have comparable efficacy. Another important unanswered question is the degree of cross-resistance between these agents (i.e., whether resistance to one agent automatically confers resistance to the other two).
HRR alterations have also been identified, albeit less frequently, in other human malignancies, including melanoma and triple-negative breast, prostate, and pancreatic cancers, which has prompted evaluation of PARP inhibitors in other clinical contexts beyond ovarian cancer. In January, the FDA approved olaparib for patients with germline BRCA-mutated HER2-negative metastatic breast cancer previously treated with chemotherapy. Furthermore, olaparib has been granted breakthrough therapy designation as a single agent for the treatment of BRCA or ATM gene–mutated, castration-resistant metastatic prostate cancer in patients who have received a prior taxane-based chemotherapy and at least one newer hormonal agent. HRR alterations have also been reported in uterine cancer, such as BRCA1/2 mutations in high-grade serous endometrial cancers. Furthermore, PTEN loss, which is prevalent in endometrioid endometrial cancer, has been reported under certain contexts to be synthetically lethal with PARP inhibition or compound PARP-PI3K inhibition.3,4
Although PARP inhibitors have shown striking responses in HRR-deficient ovarian cancer, a substantial fraction of patients develop resistance or do not respond to these agents, highlighting that de novo and acquired resistance to PARP inhibitors is a significant clinical problem. The most common mechanism of PARP inhibitor resistance in HRR-deficient tumors is secondary genetic and epigenetic events that cancel the original HRR alteration and restore HRR proficiency.2 HRR proficiency may also be restored in BRCA1-deficient tumors by rescue of DNA-end resection ability through loss of 53BP1 or REV7, which increases HRR capacity and confers resistance to PARP inhibitors. Interestingly, PARP inhibitor resistance may still develop without restoration of HRR proficiency through reduced uptake and increased efflux of the drugs (e.g., through ABCB1 upregulation) or through a complex mechanism where the DNA replication fork is protected by downregulation of proteins such as PTIP or CHD4, which typically facilitate recruitment of nucleases involved in degradation of stalled replication forks.5,6
PARP Inhibitor Combinations in Ovarian Cancer
Building on the success of PARP inhibitor monotherapy in ovarian cancer, many combination strategies of PARP inhibitors with chemotherapy, antiangiogenic agents, molecular targeted agents, or immunotherapy are actively being explored in this disease and other cancers. Several rationales exist behind these combinations, including expansion of PARP inhibitor use in non–HRR-deficient tumors, overcoming PARP inhibitor resistance, potentiating the activity of chemotherapy through inhibition of DNA repair, or priming the immune system with PARP inhibitors to facilitate response to immune checkpoint blockade.
Combination of PARP Inhibitors With Chemotherapy
Several combinations of PARP inhibitors with conventional double-strand break (DSB)–inducing chemotherapy agents (i.e., platinum analogues, temozolomide, and topoisomerase I or II inhibitors), as well as with antimitotic agents (taxanes), have been evaluated. The rationale behind these combinations is that by disrupting base excision repair and trapping PARP-DNA complexes at the replication fork, PARP inhibitors may potentiate the action of chemotherapy, particularly of DSB-inducing agents. However, PARP inhibitors have been challenging to combine with chemotherapy, mainly because of overlapping myelosuppression requiring dose reductions of the PARP inhibitors and/or the chemotherapy agents or an abbreviated, noncontinuous treatment schedule of the PARP inhibitors.7,8 In non–small cell lung cancer, veliparib has been evaluated in combination with carboplatin and paclitaxel chemotherapy (NCT02106546); in breast cancer, veliparib has been evaluated in combination with carboplatin in triple-negative breast cancer (NCT02032277); and in gastric cancer, olaparib has been evaluated in combination to weekly paclitaxel (NCT01924533; GOLD trial).8 These trials, as well as other combination regimens, have not demonstrated superior activity compared with chemotherapy alone, which has tempered the enthusiasm for further development of PARP inhibitors in combination with chemotherapy. This is also one of the reasons PARP inhibitor use has been focused in the maintenance setting after administration of platinum-based chemotherapy in ovarian cancer.
Combination of PARP Inhibitors With Antiangiogenic Agents
Several lines of evidence indicate that hypoxia can suppress HRR and that PARP inhibitor sensitivity is enhanced under hypoxic conditions. This research has prompted evaluation of the combination of PARP inhibitors with antiangiogenic agents, including both monoclonal antibodies and tyrosine-kinase inhibitors. Unlike chemotherapy agents, combining PARP inhibitors with antiangiogenic agents has been much more straightforward given the nonoverlapping toxicities between the two classes of drugs. In phase I studies, both olaparib and niraparib have been safely combined with bevacizumab while maintaining their FDA-recommended doses and schedules.9,10 Olaparib is now being evaluated in combination with bevacizumab as maintenance therapy after first-line platinum chemotherapy in ovarian cancer in the randomized phase III PAOLA-1 trial (ENGOT-ov25; NCT02477644), and niraparib is being evaluated in combination with bevacizumab as maintenance therapy in platinum-sensitive recurrent ovarian cancer in the randomized phase II AVANOVA trial (ENGOT-ov24; NCT02354131).
Olaparib has also been combined with cediranib, an oral VEGFR1, VEGFR2, and VEGFR3 tyrosine-kinase inhibitor, with the recommended phase II dose found to be cediranib 30 mg once daily and olaparib 200 mg twice daily. Strikingly, in a randomized, open-label, phase II study, the combination of olaparib plus cediranib significantly improved progression-free survival in recurrent platinum-sensitive epithelial ovarian cancer compared with olaparib alone,11 with the greatest benefit observed among patients without germline BRCA1/2 mutations, suggesting there may be greater synergism between these two agents in the setting of HRR-proficient tumors. Of note, VEGFR3 inhibition has been shown to downregulate BRCA gene expression, reverse chemotherapy resistance, and restore chemosensitivity in resistant cell lines in which a BRCA2 mutation had reverted to wild-type, raising the possibility that through VEGFR3 inhibition, cediranib may sensitize HRR-proficient tumors to olaparib. These results have led to phase III studies comparing olaparib plus cediranib to standard therapies in both platinum-resistant and platinum-sensitive ovarian cancer (NCT02502266 and NCT02446600, with the latter having completed accrual in November 2017).
Combination of PARP Inhibitors With Other Targeted Agents
The promise of PARP inhibitors in the management of ovarian cancer is tempered by the fact that HRR-proficient ovarian carcinomas do not respond well to these agents.12 Furthermore, the most prevalent mechanism of PARP inhibitor resistance in HRR-deficient cancers is acquired HRR proficiency whereby secondary genetic or epigenetic events (e.g., secondary mutations in BRCA1/2 or RAD51C/D, as well as reversal of BRCA1 promoter methylation) cancel the original HRR alteration, restore HRR proficiency, and confer PARP inhibitor resistance.13,14 Therefore, de novo HRR proficiency (i.e., ovarian cancers that are not initially HRR deficient) and acquired HRR proficiency (which represents the most important mechanism of PARP inhibitor resistance) pose a significant challenge for the successful use of PARP inhibitors in this disease.
Combining PARP inhibitors with molecular targeted agents that inhibit HRR may represent an effective strategy to sensitize HRR-proficient (de novo or acquired) ovarian cancers to PARP inhibitors and thus potentially expand use of these agents beyond patients with HRR-deficient tumors. Many of these combinations are also being evaluated in other tumor types, including triple-negative breast cancer. Strategies under investigation include combinations of PARP inhibitors with CDK1 inhibitors (inhibition of CDK1 induces HRR deficiency through inhibition of phosphorylation of BRCA1 by CDK1); PI3K or AKT inhibitors (inhibition of the PI3K pathway leads to ERK activation/phosphorylation, increased activation of ETS1, and suppression of BRCA1/2 expression and of HRR); CDK12 inhibitors (abrogation of CDK12 leads to downregulation of HRR genes as discussed above); and HDAC inhibitors and HSP90 inhibitors, which both induce coordinated downregulation of HRR pathway genes. Combinations of PARP inhibitors with cell cycle checkpoint inhibitors (i.e., ATR inhibitors, WEE1 inhibitors, and CHK1 inhibitors) to sensitize HRR-proficient cells to PARP inhibitors and to overcome PARP inhibitor resistance are also under development, although there is concern for overlapping myelosuppression with these agents. Of all these approaches, combined PI3K and PARP inhibition represents the most mature combination strategy, as it has now completed phase I evaluation in ovarian and triple-negative breast cancer (using the pan-PI3K inhibitor BKM120 and the alpha-specific PI3K inhibitor BYL719 in combination with olaparib) with promising results among ovarian cancers enriched for HRR proficiency and no alarming signals besides the expected nonoverlapping toxicities of these agents.15,16
Combinations of PARP Inhibitors With Immune Checkpoint Inhibitors
Although immune checkpoint inhibitors (e.g., anti–CTLA-4 and anti–PD-1/PD-L1 antibodies) have demonstrated potent clinical activity across multiple tumor types, only modest effectiveness in ovarian cancer has been observed. Development of strategies to improve efficacy of immune checkpoint inhibitors in ovarian cancer while minimizing immune-related toxicity is a high priority for ovarian cancer treatment. Several lines of evidence indicate that DSBs created by damaging agents such as PARP inhibitors can result in somatic mutations that act as neoantigens if HRR is deficient, and these DSBs are repaired by error-prone repair pathways such as nonhomologous end-joining or alternative end-joining. Furthermore, DNA damage induced by PARP inhibitors can also activate the innate immune system through the STING pathway, and this DSB-mediated immune activation is balanced by concomitant inhibitory signaling, including upregulation of PD-L1 expression through STAT1/STAT3/IRF3 activation.17,18 These data suggest that PARP inhibitors may prime the immune system to facilitate response to immune checkpoint blockade and provide the preclinical rationale for combinations of PARP inhibitors with immune checkpoint inhibitors. In this regard, all PARP inhibitors (olaparib, niraparib, rucaparib, veliparib, and talazoparib) are being evaluated in various combinations with immune checkpoint inhibitors, including anti–PD-1 antibodies (nivolumab and pembrolizumab), anti–PD-L1 antibodies (durvalumab, atezolizumab, and avelumab), and anti–CTLA-4 antibodies (ipilimumab and tremelimumab) in ovarian cancer, both in HRR-deficient and HRR-proficient tumors. Similar combinations are also being evaluated in other disease types, including triple-negative breast, non–small cell lung, urothelial, and prostate cancers. Of note, the addition of antiangiogenic agents to these combinations is also being explored, such as the combination of olaparib/durvalumab/cediranib and the combination of rucaparib/nivolumab/bevacizumab, which will be opening shortly in our institution.
PARP inhibitors represent a success story for DNA-repair targeted therapies in ovarian cancer. However, important unanswered questions remain, including the comparative efficacy of different PARP inhibitors, the degree of their cross-resistance, and their optimal incorporation into the management of ovarian cancer (i.e., after first-line treatment or in the recurrent setting). PARP inhibitor resistance (de novo and acquired) is also emerging as an important problem in the clinic; the ideal treatment of patients who progress after PARP inhibitor therapy remains to be defined and should depend on thorough understanding of the underlying mechanism(s) of resistance.
Development of rational combinations of PARP inhibitors with other agents represents the next step for using PARP inhibitors for treatment of cancers that are non-HRR deficient; for overcoming PARP inhibitor resistance; and for priming the immune system to facilitate response to immune checkpoint blockade. Careful clinical trial design and evaluation of these combinations will be required, with increased focus on proof-of-mechanism pharmacodynamic studies so that PARP inhibitor combinations can be tailored for specific patient populations and for specific mechanisms of PARP inhibitor resistance.
About the Authors: Dr. Konstantinopoulos is a medical oncologist and director of translational research, Gynecologic Oncology Program, with the Dana-Farber
Cancer Institute. Dr. Matulonis is a medical oncologist and director of the Gynecologic Oncology Program with the Dana-Farber Cancer Institute.