PARP inhibitor and chemotherapy combination trials for the treatment of advanced malignancies: does a development pathway forward exist?

Abstract

Poly (ADP ribose) polymerase (PARP) inhibitor combinations are currently being developed as a treatment strategy for advanced cancers with partial, potential, or no known DNA repair deficits in order to augment the anti-cancer potential of both the PARP inhibitor and the chemotherapy partner. The phase III development of PARP inhibitors in ovarian cancer has focused on single agents. As such, PARP inhibitors have demonstrated their greatest efficacy in cancers with underlying DNA repair deficits, such as deleterious mutations inBRCA1 orBRCA2, or when used in clinical situations when homologous recombination deficiency (HRD) is operative, such as recently described results for niraparib in platinum-sensitive high-grade serous ovarian cancer [1.Bryant H.E. Schultz N. Thomas H.D. et al.Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.Nature. 2005; 434: 913-917Crossref PubMed Scopus (3628) Google Scholar, 2.Kaufman B. Shapira-Frommer R. Schmutzler R.K. et al.Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.J Clin Oncol. 2015; 33: 244-250Crossref PubMed Scopus (1275) Google Scholar, 3.Fong P.C. Boss D.S. Yap T.A. et al.Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.N Engl J Med. 2009; 361: 123-134Crossref PubMed Scopus (2945) Google Scholar, 4.Audeh M.W. Carmichael J. Penson R.T. et al.Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial.Lancet. 2010; 376: 245-251Abstract Full Text Full Text PDF PubMed Scopus (1164) Google Scholar]. Single-agent PARP inhibitors have less activity inBRCA wildtype, especially platinum resistant, or HR proficient cancers [5.Gelmon K.A. Tischkowitz M. Mackay H. et al.Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study.Lancet Oncol. 2011; 12: 852-861Abstract Full Text Full Text PDF PubMed Scopus (942) Google Scholar]. In the accompanying phase I trial, Thaker et al. attempt to combine veliparib, a potent oral inhibitor of PARP, with DNA damaging chemotherapy. Working under the umbrella of NRG Oncology, the triplet of cisplatin/paclitaxel/veliparib was studied in women with persistent or recurrent cervical cancer. The rationale for adding the PARP inhibitor veliparib to cisplatin was to augment cisplatin’s anti-cancer potential and because PARP-1 expression is higher in cervical cancer cells than in normal cells [6.Thaker P.H. Salani R. Brady W.E. et al.A phase I trial of paclitaxel, cisplatin, and veliparib in the treatment of persistent or recurrent carcinoma of the cervix: an NRG Oncology Study (NCT#01281852).Ann Oncol. 2017; 28: 505-511Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar,7.Nguewa P.A. Fuertes M.A. Cepeda V. et al.Poly(ADP-ribose) Polymerase-1 inhibitor 3-Aminobenzamide enhances apoptosis induction by platinum complexes in cisplatin-resistant tumor cells.Med Chem. 2006; 2: 47-53Crossref PubMed Scopus (52) Google Scholar]. Additionally, the complex pathogenesis of cervical cancer and the interaction of PARP, HPV, DNA repair, and inflammation make the study of PARP inhibition in cervical cancer rational [8.Kotsopoulos I.C. Kucukmetin A. Mukhopadhyay A. et al.Poly(ADP-ribose) polymerase in cervical cancer pathogenesis: mechanism and potential role for PARP Inhibitors.Int J Gynecol Cancer. 2016; 26: 763-769Crossref PubMed Scopus (9) Google Scholar]. Thaker et al. [6.Thaker P.H. Salani R. Brady W.E. et al.A phase I trial of paclitaxel, cisplatin, and veliparib in the treatment of persistent or recurrent carcinoma of the cervix: an NRG Oncology Study (NCT#01281852).Ann Oncol. 2017; 28: 505-511Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar] dose escalated veliparib up to 400 mg BID, the maximal tolerated dose (MTD) for the single agent, and veliparib was administered for 7 days rather than continuously. Response rates for this PARP inhibitor and chemotherapy combination in advanced cervical cancer across all dose levels were 34%, reaching responses of 60% at the highest dose of veliparib tested. During the conduct of this study, the US Food and Drug Administration gave regulatory approval for cisplatin/paclitaxel/bevacizumab for advanced/recurrent cervical cancer [9.Tewari K.S. Sill M.W. Long 3rd, H.J. et al.Improved survival with bevacizumab in advanced cervical cancer.N Engl J Med. 2014; 370: 734-743Crossref PubMed Scopus (933) Google Scholar], thus making pursuit of cisplatin/paclitaxel/veliparib less compelling for this indication. However, the triplet under study did have a numerically higher overall response rate (ORR) at the MTD compared with the bevacizumab triplet with an identical chemotherapy backbone [6.Thaker P.H. Salani R. Brady W.E. et al.A phase I trial of paclitaxel, cisplatin, and veliparib in the treatment of persistent or recurrent carcinoma of the cervix: an NRG Oncology Study (NCT#01281852).Ann Oncol. 2017; 28: 505-511Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar,9.Tewari K.S. Sill M.W. Long 3rd, H.J. et al.Improved survival with bevacizumab in advanced cervical cancer.N Engl J Med. 2014; 370: 734-743Crossref PubMed Scopus (933) Google Scholar]. Granted, cross trial comparisons with this small PARP inhibitor combination phase I trial are near impossible. Ideally, there should be a predefined understanding of the mechanisms of augmentation of anti-cancer activity of the combination and whether or not additive or synergistic effects are predicted to occur clinically. PARP inhibitors have several known mechanisms of action including inhibition of DNA single strand break (SSB) repair [by inhibiting base excision repair (BER)] leading to double strand breaks (DSB); alteration of non-HR DNA repair pathways, such as promotion of classic non-homologous end joining (classic-NHEJ)–a more error prone mechanism of DNA repair, and disruption of alternative end joining (alt-EJ) which is essential for HR-deficient cells, and PARP trapping; PARP inhibitors trap PARP on DNA, and these PARP-DNA complexes are lethal to HR deficient cells [10.Konstantinopoulos P.A. Ceccaldi R. Shapiro G.I. D'Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer.Cancer Discov. 2015; 5: 1137-1154Crossref PubMed Scopus (493) Google Scholar]. PARP trapping can induce increased cell killing compared with unrepaired SSBs and also varies amongst PARP inhibitors; veliparib has weaker PARP trapping than olaparib, rucaparib, and niraparib, while talazoparib induces the most potent PARP trapping, though all five agents can potently inhibit PARP catalytic activity [11.Murai J. Huang S.N. Brata Das B. et al.Trapping of PARP1 and PARP2 by clinical PARP inhibitors.Cancer Res. 2012; 72: 5588-5599Crossref PubMed Scopus (1337) Google Scholar,12.Murai J. Huang S.Y. Renaud A. et al.Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib.Mol Cancer Ther. 2014; 13: 433-443Crossref PubMed Scopus (510) Google Scholar]. Mechanisms leading to synergy or additive activity of a combined PARP inhibitor and chemotherapy are likely multifactorial and differ based on the combination (i.e. chemotherapy can increase DNA damage, and PARP inhibitors diminish the PARP enzymes ability to repair DNA damage) and tumor studied [7.Nguewa P.A. Fuertes M.A. Cepeda V. et al.Poly(ADP-ribose) Polymerase-1 inhibitor 3-Aminobenzamide enhances apoptosis induction by platinum complexes in cisplatin-resistant tumor cells.Med Chem. 2006; 2: 47-53Crossref PubMed Scopus (52) Google Scholar,13.Patel A.G. Flatten K.S. Schneider P.A. et al.Enhanced killing of cancer cells by poly(ADP-ribose)Polymerase inhibitors and Topoisomerase I inhibitors reflects poisoning of both enzymes.J Biol Chem. 2012; 287: 4198-4210Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 14.Murai J. Zhang Y. Morris J. et al.Rationale for poly(ADP-ribose)polymerase (PARP) inhibitors in combination therapy with camptothecins or temozolomide based on PARP trapping versus catalytic inhibition.J Pharmacol Exp Ther. 2014; 349: 408-416Crossref PubMed Scopus (200) Google Scholar, 15.Ihnen M. zu Eulenburg C. Kolarova T. et al.Therapeutic potential of the poly(ADP-ribose) Polymerase inhibitor rucaparib for the treatment of sporadic human ovarian cancer.Mol Cancer Ther. 2013; 12: 1002-1015Crossref PubMed Scopus (86) Google Scholar]. The chemotherapy agent and the PARP inhibitor selected for testing will also influence the mechanisms of action of cell death as well as the efficacy of the combination [7.Nguewa P.A. Fuertes M.A. Cepeda V. et al.Poly(ADP-ribose) Polymerase-1 inhibitor 3-Aminobenzamide enhances apoptosis induction by platinum complexes in cisplatin-resistant tumor cells.Med Chem. 2006; 2: 47-53Crossref PubMed Scopus (52) Google Scholar,13.Patel A.G. Flatten K.S. Schneider P.A. et al.Enhanced killing of cancer cells by poly(ADP-ribose)Polymerase inhibitors and Topoisomerase I inhibitors reflects poisoning of both enzymes.J Biol Chem. 2012; 287: 4198-4210Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 14.Murai J. Zhang Y. Morris J. et al.Rationale for poly(ADP-ribose)polymerase (PARP) inhibitors in combination therapy with camptothecins or temozolomide based on PARP trapping versus catalytic inhibition.J Pharmacol Exp Ther. 2014; 349: 408-416Crossref PubMed Scopus (200) Google Scholar, 15.Ihnen M. zu Eulenburg C. Kolarova T. et al.Therapeutic potential of the poly(ADP-ribose) Polymerase inhibitor rucaparib for the treatment of sporadic human ovarian cancer.Mol Cancer Ther. 2013; 12: 1002-1015Crossref PubMed Scopus (86) Google Scholar]. For example, PARP inhibitor combinations with topoisomerase-I inhibitors such as camptothecin or topotecan are highly synergistic primarily due to catalytic PARP inhibition, suggesting that all PARP inhibitors would be similarly synergistic with topoisomerase-I inhibitors given their potent inhibition of PARP [13.Patel A.G. Flatten K.S. Schneider P.A. et al.Enhanced killing of cancer cells by poly(ADP-ribose)Polymerase inhibitors and Topoisomerase I inhibitors reflects poisoning of both enzymes.J Biol Chem. 2012; 287: 4198-4210Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar,14.Murai J. Zhang Y. Morris J. et al.Rationale for poly(ADP-ribose)polymerase (PARP) inhibitors in combination therapy with camptothecins or temozolomide based on PARP trapping versus catalytic inhibition.J Pharmacol Exp Ther. 2014; 349: 408-416Crossref PubMed Scopus (200) Google Scholar]. Conversely, PARP inhibitor combinations with alkylating agents such as temozolomide are highly synergistic due to both catalytic PARP inhibition as well as PARP trapping [14.Murai J. Zhang Y. Morris J. et al.Rationale for poly(ADP-ribose)polymerase (PARP) inhibitors in combination therapy with camptothecins or temozolomide based on PARP trapping versus catalytic inhibition.J Pharmacol Exp Ther. 2014; 349: 408-416Crossref PubMed Scopus (200) Google Scholar]. In this regard, olaparib is more synergistic with temozolomide compared with veliparib (which has weaker PARP trapping activity).In vitro preclinical assessments show differential cell killing dependent on choice of chemotherapy agent; highest synergism has been reported with topoisomerase-I inhibitors and alkylating agents as stated above, while less synergistic or only additive activity has been observedin vitro with platinum agents (such as cisplatin and carboplatin) and topoisomerase-II inhibitors such as etoposide and doxorubicin which is consistent with the relative lack of involvement of PARP in repair of platinum- and topoisomerase-II inhibitor-induced lesions [15.Ihnen M. zu Eulenburg C. Kolarova T. et al.Therapeutic potential of the poly(ADP-ribose) Polymerase inhibitor rucaparib for the treatment of sporadic human ovarian cancer.Mol Cancer Ther. 2013; 12: 1002-1015Crossref PubMed Scopus (86) Google Scholar]. Finally, the least combinatorial effect is observed with either a taxane or gemcitabine, although results differ based on experimental conditions [15.Ihnen M. zu Eulenburg C. Kolarova T. et al.Therapeutic potential of the poly(ADP-ribose) Polymerase inhibitor rucaparib for the treatment of sporadic human ovarian cancer.Mol Cancer Ther. 2013; 12: 1002-1015Crossref PubMed Scopus (86) Google Scholar,16.Wachters F.M. van Putten J.W. Maring J.G. et al.Selective targeting of homologous DNA recombination repair by gemcitabine.Int J Radiat Oncol Biol Phys. 2003; 57: 553-562Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. Combinations of PARP inhibitors and chemotherapy agents have unique strategic and development challenges because of overlapping toxicities such as myelosuppression, the array of schedule and drug dosing choices, and potential for drug interactions in humans not identified in pre-clinical models. A major issue with the strategy of enhancing the activity of chemotherapy using PARP inhibitors is its narrow therapeutic window, since the synergism via PARP inhibition is not selective for tumor cells. Rather, inhibition of PARP in normal cells abrogates an important mechanism of DNA repair in these cells thereby enhancing toxicity from chemotherapy including myelosuppression. Choice of drug(s) to be dose escalated should be determined based on planned toxicities such as myelosuppression; Thaker et al. [6.Thaker P.H. Salani R. Brady W.E. et al.A phase I trial of paclitaxel, cisplatin, and veliparib in the treatment of persistent or recurrent carcinoma of the cervix: an NRG Oncology Study (NCT#01281852).Ann Oncol. 2017; 28: 505-511Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar] dose escalated only veliparib and kept paclitaxel and cisplatin constant. How was the schedule of 7 days of veliparib (days 1–7) combined with paclitaxel day 1 and cisplatin day 2 determined? Intermittent versus continuous PARP inhibition may have implications on efficacy as well as toxicity. Drew et al. [17.Drew Y. Ledermann J. Hall G. et al.Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer.Br J Cancer. 2016; 114: 723-730Crossref PubMed Scopus (108) Google Scholar] showed that PARP inhibition is short-lived and recovers within 1 week of completion of a 7-day dosing schedule; thus oral continuous dosing is important to maintain in the single agent setting when long-term PARP inhibition is critical to efficacy, with shorter durations leading to reduced myelosuppression but an unknown effect on efficacy. In addition, sequence of agents may also be important for efficacy and tolerability. The phase I study of carboplatin and olaparib led to an MTD of olaparib 200 mg BID for 7 days (tablet formation) and carboplatin AUC 4 [18]. The group from the National Cancer Institute determined that administering carboplatin before olaparib led to faster olaparib clearance due to higher intracellular accumulation of olaparib, thus perhaps predicting greater efficacy [18.Lee J.M. Peer C.J. Yu M. et al.Sequence-specific pharmacokinetic and pharmacodynamic phase I/Ib study of olaparib tablets and carboplatin in women’s cancer.Clin Cancer Res. 2016; Google Scholar]. Other phase I studies of combined PARP inhibitors and chemotherapy have been performed showing enhanced myelosuppression (Table 1); dose escalation of olaparib/cisplatin/gemcitabine led to lowered doses of all three agents at the MTD: olaparib 100 mg once daily on day 1 only, cisplatin 60 mg/m2 on day 1 and gemcitabine 500 mg/m2 day 1 and 8 [19]. Topotecan and veliparib were tested in recurrent cervical cancer, and hematologic toxicities ≥grade 3 included anemia 59%, thrombocytopenia 44%, and neutropenia 19%, despite the use of myeloid growth factor [20.Kunos C. Deng W. Dawson D. et al.A phase I-II evaluation of veliparib (NSC #737664), topotecan, and filgrastim or pegfilgrastim in the treatment of persistent or recurrent carcinoma of the uterine cervix: an NRG Oncology/Gynecologic Oncology Group study.Int J Gynecol Cancer. 2015; 25: 484-492Crossref PubMed Scopus (42) Google Scholar]. Pre-clinicalin vitro synergy of topotecan and veliparib was demonstrated and occurred at veliparib combinations below those needed to kill HRD-deficient cells [13.Patel A.G. Flatten K.S. Schneider P.A. et al.Enhanced killing of cancer cells by poly(ADP-ribose)Polymerase inhibitors and Topoisomerase I inhibitors reflects poisoning of both enzymes.J Biol Chem. 2012; 287: 4198-4210Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar]; however, only 7% response rate was observed when this regimen was tested in recurrent cervical cancer [20.Kunos C. Deng W. Dawson D. et al.A phase I-II evaluation of veliparib (NSC #737664), topotecan, and filgrastim or pegfilgrastim in the treatment of persistent or recurrent carcinoma of the uterine cervix: an NRG Oncology/Gynecologic Oncology Group study.Int J Gynecol Cancer. 2015; 25: 484-492Crossref PubMed Scopus (42) Google Scholar].Table 1Examples of PARP inhibitor and chemotherapy combination clinical trialsClass of agentsMechanism of synergismTrialPhase of studyCancer studiedPARP inhibitorChemotherapy agent(s)OutcomeTopoisomerase-I inhibitorsPARP is critical for repair of topoisomerase-I cleavage complexes Catalytic PARP inhibition important – No PARP trapping involved [13.Patel A.G. Flatten K.S. Schneider P.A. et al.Enhanced killing of cancer cells by poly(ADP-ribose)Polymerase inhibitors and Topoisomerase I inhibitors reflects poisoning of both enzymes.J Biol Chem. 2012; 287: 4198-4210Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar,14.Murai J. Zhang Y. Morris J. et al.Rationale for poly(ADP-ribose)polymerase (PARP) inhibitors in combination therapy with camptothecins or temozolomide based on PARP trapping versus catalytic inhibition.J Pharmacol Exp Ther. 2014; 349: 408-416Crossref PubMed Scopus (200) Google Scholar]Kunos et al. [20.Kunos C. Deng W. Dawson D. et al.A phase I-II evaluation of veliparib (NSC #737664), topotecan, and filgrastim or pegfilgrastim in the treatment of persistent or recurrent carcinoma of the uterine cervix: an NRG Oncology/Gynecologic Oncology Group study.Int J Gynecol Cancer. 2015; 25: 484-492Crossref PubMed Scopus (42) Google Scholar]1/2CervicalVeliparibTopotecanTopotecan 0.6 mg/m2 days 1–5 and veliparib 10 mg BID resulted in 7% RR; >gr 3 tox: 19% neutropenia, 44% thrombocytopenia and 59% anemiaAlkylating agentsPARP is critical for repair of SSBs induced by alkylating agents. Both Catalytic PARP inhibition and PARP trapping are important because PARP-DNA complexes are formed at SSBs induced by alkylating agents such as temozolomide [14.Murai J. Zhang Y. Morris J. et al.Rationale for poly(ADP-ribose)polymerase (PARP) inhibitors in combination therapy with camptothecins or temozolomide based on PARP trapping versus catalytic inhibition.J Pharmacol Exp Ther. 2014; 349: 408-416Crossref PubMed Scopus (200) Google Scholar]Isakoff et al. [27.Isakoff S.J. Overmoyer B. Tung NM. Phase II trial expansion cohort of the PARP inhibitor veliparib (ABT888) and temozolomide in BRCA1/2 associated metastatic breast cancer.Cancer Res. 2011; 71Google Scholar]2Breast CancerVeliparibTemozolomideVeliparib [30 mg PO BID days 1–7) and TMZ (150 mg/m2 PO QD days 1–5). Responses in the subset of patients with a BRCA1 or BRCA2 mutation: total RR 25% (7/28)Kummar et al. [25.Kummar S. Oza A.M. Fleming G.F. et al.Randomized trial of oral cyclophosphamide and veliparib in high-grade serous ovarian, primary peritoneal, or fallopian tube cancers, or BRCA-mutant ovarian cancer.Clin Cancer Res. 2015; 21: 1574-1582Crossref PubMed Scopus (104) Google Scholar]2BRCA mutated ovarianVeliparibLow dose oral cyclophosphamideNo PFS or RR increase with Veliparib 60 mg and oral cyclophosphamide 50 mg versus cyclophosphamide alonePlatinum agentsPARP participates partly in repair of platinum lesions PARP inhibitors induce additional DNA damage along with platinum agents [7.Nguewa P.A. Fuertes M.A. Cepeda V. et al.Poly(ADP-ribose) Polymerase-1 inhibitor 3-Aminobenzamide enhances apoptosis induction by platinum complexes in cisplatin-resistant tumor cells.Med Chem. 2006; 2: 47-53Crossref PubMed Scopus (52) Google Scholar]Lee et al. [18.Lee J.M. Peer C.J. Yu M. et al.Sequence-specific pharmacokinetic and pharmacodynamic phase I/Ib study of olaparib tablets and carboplatin in women’s cancer.Clin Cancer Res. 2016; Google Scholar]1Breast and ovarianOlaparibOlaparib and carboplatinGiving carboplatin before olaparib increases olaparib clearance due to higher intracellular accumulation of olaparib: MTD was olaparib 200 mg BID (tab) days 1–7 and carboplatin AUC 4TaxanesMechanism not clear [15.Ihnen M. zu Eulenburg C. Kolarova T. et al.Therapeutic potential of the poly(ADP-ribose) Polymerase inhibitor rucaparib for the treatment of sporadic human ovarian cancer.Mol Cancer Ther. 2013; 12: 1002-1015Crossref PubMed Scopus (86) Google Scholar].In vitro additive or synergism has been reported, but synergism is less than with topoisomerase-I inhibitors, alkylating agents and platinumDent et al. [22.Dent R.A. Lindeman G.J. Clemons M. et al.Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer.Breast Cancer Res. 2013; 15: R88.Crossref PubMed Scopus (152) Google Scholar]1BreastOlaparibWeekly paclitaxelPaclitaxel dose was 90 mg/m2/week and Olaparib 200 mg BID daily; higher than expected neutropenia observedBang et al. [23.Bang Y. Boku N. Chin K. et al.LBA25: Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first line therapy: Phase III GOLD study. European Society of Medical Oncology.Ann Oncol. 2016; 27: 1-36Google Scholar]3GastricOlaparibWeekly paclitaxelNo benefit for OS, PFS or RR for O/P versus P aloneMultiple agentsCombination of mechanisms discussed above Gemcitabine has been reported to inhibit HR which may lead to sensitization to PARP-inhibition [16.Wachters F.M. van Putten J.W. Maring J.G. et al.Selective targeting of homologous DNA recombination repair by gemcitabine.Int J Radiat Oncol Biol Phys. 2003; 57: 553-562Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar] but the combination of PARPi with gemcitabinein vitro seems to be only additive [15.Ihnen M. zu Eulenburg C. Kolarova T. et al.Therapeutic potential of the poly(ADP-ribose) Polymerase inhibitor rucaparib for the treatment of sporadic human ovarian cancer.Mol Cancer Ther. 2013; 12: 1002-1015Crossref PubMed Scopus (86) Google Scholar]Oza et al. [24.Oza A.M. Cibula D. Benzaquen A.O. et al.Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial.Lancet Oncol. 2015; 16: 87-97Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar]2Platinum sensitive ovarianOlaparibCarboplatin and paclitaxelPFS improved for Carboplatin/paclitaxel/olaparib and olaparib maintenance versus carboplatin/paclitaxel; dose of C reduced to AUC 4 from 6 and Olaparib dose (capsules) was 200 mg BID x 10 days for triplet regimenHan et al. [26.Han H.S.S. et al.Abstract S2-05. San Antonio Breast Cancer Symposium, 6–10 December. 2016Google Scholar]2BRCA mutated advanced breast cancerVeliparibCarboplatin and paclitaxelNo difference in PFS between carboplatin/paclitaxel/veliparib versus carboplatin/paclitaxel: veliparib was 120 mg BID for 7 daysThaker et al. [6.Thaker P.H. Salani R. Brady W.E. et al.A phase I trial of paclitaxel, cisplatin, and veliparib in the treatment of persistent or recurrent carcinoma of the cervix: an NRG Oncology Study (NCT#01281852).Ann Oncol. 2017; 28: 505-511Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar]1CervicalVeliparibCisplatin and paclitaxelMTD not reached and dosing stopped at Veliparib 400 mg BID d 1–7, cisplatin 50 mg/m2 and paclitaxel 175 mg/m2Rajan et al. [19.A Rajan , CACarter, RJKelly . A phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors. Clin Cancer Res18: 2344–2351.Google Scholar]1Solid TumorsOlaparibCisplatin and gemcitabineMTD = olaparib 100 mg once daily on day 1, cisplatin 60 mg/m2 on day 1 and gemcitabine 500 mg/m2 day 1 and 8 Open table in a new tab Additional PARP inhibitor and chemotherapy combinations have been tested in randomized studies which are critical to determine if the synergy of the combination can overcome the reduced activity of the attenuated doses and prove benefit beyond standard of care [21.Paller C.J. Bradbury P.A. Ivy S.P. et al.Design of phase I combination trials: recommendations of the Clinical Trial Design Task Force of the NCI Investigational Drug Steering Committee.Clin Cancer Res. 2014; 20: 4210-4217Crossref PubMed Scopus (45) Google Scholar] (Table 1). Combined weekly paclitaxel and olaparib was tested in metastatic triple negative breast cancer [22.Dent R.A. Lindeman G.J. Clemons M. et al.Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer.Breast Cancer Res. 2013; 15: R88.Crossref PubMed Scopus (152) Google Scholar] with significant myelosuppression noted (Table 1). This regimen was subsequently tested in a phase 3 study in advanced gastric cancer, and despite encouraging randomized phase 2 data, olaparib and weekly paclitaxel did not improve overall survival nor progression-free survival (PFS) compared with weekly paclitaxel alone [23.Bang Y. Boku N. Chin K. et al.LBA25: Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first line therapy: Phase III GOLD study. European Society of Medical Oncology.Ann Oncol. 2016; 27: 1-36Google Scholar]. Pre-clinical PARP inhibitor and taxane studies showed littlein vitro benefit, perhaps foreshadowing the lack of success of paclitaxel and olaparib combination in advanced gastric cancer [15.Ihnen M. zu Eulenburg C. Kolarova T. et al.Therapeutic potential of the poly(ADP-ribose) Polymerase inhibitor rucaparib for the treatment of sporadic human ovarian cancer.Mol Cancer Ther. 2013; 12: 1002-1015Crossref PubMed Scopus (86) Google Scholar]. In another randomized study, the paclitaxel/carboplatin/olaparib triplet followed by olaparib maintenance was tested against carboplatin and paclitaxel in platinum sensitive recurrent ovarian cancer [24.Oza A.M. Cibula D. Benzaquen A.O. et al.Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial.Lancet Oncol. 2015; 16: 87-97Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar] demonstrating improved PFS for the olaparib containing arm. The carboplatin dose was dose reduced to AUC 4 and the olaparib dose to 200 mg BID, days 1–10, when combined with chemotherapy. However, this PARP inhibitor/chemotherapy combination has not been moved forward for further clinical development. Lower doses of chemotherapy have also been tested in combination with PARP inhibitors; Kummar et al. [25.Kummar S. Oza A.M. Fleming G.F. et al.Randomized trial of oral cyclophosphamide and veliparib in high-grade serous ovarian, primary peritoneal, or fallopian tube cancers, or BRCA-mutant ovarian cancer.Clin Cancer Res. 2015; 21: 1574-1582Crossref PubMed Scopus (104) Google Scholar] performed a randomized trial of oral cyclophosphamide 50 mg PO daily alone or combined with veliparib 60 mg daily in patients with BRCA mutated recurrent ovarian cancer. Pre-clinically, PARP inhibitors were found to augment DNA damage caused by cyclophosphamide; however, adding the PARP inhibitor to oral cyclophosphamide did not improve ORR nor PFS [25.Kummar S. Oza A.M. Fleming G.F. et al.Randomized trial of oral cyclophosphamide and veliparib in high-grade serous ovarian, primary peritoneal, or fallopian tube cancers, or BRCA-mutant ovarian cancer.Clin Cancer Res. 2015; 21: 1574-1582Crossref PubMed Scopus (104) Google Scholar]. InBRCA mutated metastatic breast cancer patients, carboplatin/paclitaxel/veliparib was compared with carboplatin/paclitaxel, and there was no difference in PFS between two groups [26.Han H.S.S. et al.Abstract S2-05. San Antonio Breast Cancer Symposium, 6–10 December. 2016Google Scholar]; the chemotherapy in both arms was standard dose but the dose of veliparib was 120 mg BID for 7 days. PARP inhibitor combinations with chemotherapy are a novel, potentially therapeutically promising but challenging strategy used to enhance the anti-cancer effects of both a PARP inhibitor and chemotherapy agents, thus expanding the patient population eligible to receive a PARP inhibitor. However, multiple factors will influence clinical trial design including choice of PARP inhibitor and its pharmacokinetic and pharmacokinetic properties, combination partner(s), goals of combining a PARP inhibitor and chemotherapy, which agent(s) to dose escalate, schedule of agents, patient population and clinical situation as well as a changing drug approval and regulatory landscape—further development of velparib/carboplatin/paclitaxel was complicated by the FDA approval of cisplatin/paclitaxel/bevacizumab. In gaining regulatory approval, the importance of each of the different components of treatment will need to be compared with the combination, with the combination showing superiority [21.Paller C.J. Bradbury P.A. Ivy S.P. et al.Design of phase I combination trials: recommendations of the Clinical Trial Design Task Force of the NCI Investigational Drug Steering Committee.Clin Cancer Res. 2014; 20: 4210-4217Crossref PubMed Scopus (45) Google Scholar]. Development of PARP inhibitor/chemotherapy combinations, if pursued, will require strong pre-clinical data to support human clinical trial testing, commitment and patience from investigators, sponsors, and patients given the time needed to sort through these factors, and adaptability because of changing clinical landscapes.