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Ongoing Developments

There are many ongoing trials exploring the use of PARP inhibitors in other ovarian cancer settings or using alternative treatment strategies. These include investigating other disease and treatment settings, improving drug delivery, more effectively identifying patients who will be responsive to treatment, and combining PARP inhibitors with other treatments such as immunotherapy, angiogenesis inhibitors or other DDR pathway-targeting agents in order to improve outcomes and/or overcome resistance.

Click on each item below to find out more about these areas of research:

Different disease settings

The phase III, open-label SOLO3 trial evaluated olaparib versus physician’s choice non-platinum chemotherapy in patients with a germline BRCA mutation in platinum-sensitive, relapsed ovarian cancer in patients with ≥2 prior treatments (NCT02282020)[1]. The ORR was 72% with olaparib versus 51% with chemotherapy (odds ratio: 2.53, 95% CI 1.40–4.58; p=0.002). Median progression-free survival was 13.4 versus 9.2 months, respectively by blinded independent central review (HR: 0.62 (95% CI 0.43–0.91; p=0.013), and 13.2 months versus 8.5 months by investigator assessment (HR: 0.49: 95% CI 0.35–0.70; p<0.001). There were no new safety signals in this disease setting.

The phase II, open-label, single-arm QUADRA trial evaluated niraparib in 463 patients with relapsed ovarian cancer after ≥3 lines of chemotherapy (NCT02354586) regardless of platinum sensitivity or BRCA status [2]. In this population, in whom <20% had a BRCA mutation, 28% had an objective response and the disease control rate was 69%.

A phase III trial is evaluating the investigational PARP inhibitor veliparib in combination with chemotherapy in the first-line setting as ongoing maintenance treatment in patients with serous epithelial ovarian, fallopian tube or primary peritoneal cancer (NCT02470585).

The phase III ARIEL 4 trial is investigating rucaparib versus chemotherapy after ≥2 lines of treatment in patients with BRCA-mutant ovarian, fallopian tube, or primary peritoneal cancer (NCT02855944).

The phase III placebo-controlled PRIMA trial is evaluating niraparib maintenance following first-line platinum-based chemotherapy in patients with ovarian cancer (NCT02655016). 

Combination Strategies

The aim of combination therapy is to improve efficacy and combat resistance. The many biological functions of PARPs underscore the rationale for using PARP inhibitors as combination partners with other agents [3-6].

Examples include:

Combining with angiogenesis inhibitors. A phase II trial evaluated olaparib in combination with cediranib in 90 patients with relapsed platinum-sensitive ovarian cancer (NCT01116648) and reported a median progression-free survival of 16.5 months with the combination versus 8.2 months with olaparib alone (HR: 0.50; p=0.007)[7]. The placebo-controlled, phase III PAOLA-1 trial is assessing maintenance treatment with olaparib + bevacizumab following first-line platinum-based chemotherapy in patients with advanced ovarian cancer (NCT02477644).

Combining with immunotherapies. Preclinical studies have demonstrated cross-talk between PARP inhibition/DDR and tumour-associated immunosuppression, providing a rationale for combining PARP inhibitors with immune checkpoint blockade agents such as PD-L1 or PD-1 [8, 9]. A number of trials are underway to explore these combinations, including (but not limited to):

  • The phase I/II MEDIOLA trial of olaparib plus the anti-PD-L1 antibody durvalumab in solid tumours, including ovarian, breast, small cell lung cancer and gastric cancer (NCT02734004) [10].
  • The phase I/II TOPACIO/KEYNOTE-162 trial of niraparib plus pembrolizumab in patients with advanced triple-negative breast cancer or recurrent ovarian cancer (NCT02657889) [11].
  • The phase III (DUO-O) trial of durvalumab plus standard-of-care platinum-based chemotherapy and bevacizumab, followed by maintenance therapy with durvalumab and bevacizumab with or without olaparib in women with newly-diagnosed advanced ovarian cancer (NCT03737643)[12]

Combining with other DDR-targeting agents. Another area of research is the combination of PARP inhibition with targeting other parts of the DDR machinery such as AZD-6738 (ATR) and AZD-1775 (WEE1). For more information on these, click here. 

References

  1. Penson RT, Valencia RV, Cibula D et al. Olaparib monotherapy versus (vs) chemotherapy for germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase III SOLO3 trial. J Clin Oncol 37, 2019 (suppl; abstr 5506).
  2. Moore KN, Secord AA, Geller MA et al. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 2019; 20: 636-648.
  3. O'Connor MJ. Targeting the DNA Damage Response in Cancer. Mol Cell 2015; 60: 547-560.
  4. Pearl LH, Schierz AC, Ward SE et al. Therapeutic opportunities within the DNA damage response. Nat Rev Cancer 2015; 15: 166-180.
  5. Gourley C, Balmana J, Ledermann JA et al. Moving from PARP Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy. J Clin Oncol 2019; doi: 10.1200/JCO.1218.02050. [Epub ahead of print].
  6. Jubin T, Kadam A, Jariwala M et al. The PARP family: insights into functional aspects of poly (ADP-ribose) polymerase-1 in cell growth and survival. Cell Prolif 2016; 49: 421-437.
  7. Liu JF, Barry WT, Birrer M et al. Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer. Ann Oncol 2019; 30: 551-557.
  8. Jiao S, Xia W, Yamaguchi H et al. PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression. Clin Cancer Res 2017; 23: 3711-3720.
  9. Mouw KW, Konstantinopoulos PA. From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation. Br J Cancer 2018; 118: 933-935.
  10. Drew Y, de Jonge M, Hong SH et al. An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed (PSR) ovarian cancer (OC). Gynecol Oncol 2018; 149 Suppl 1: 246-247.
  11. Konstantinopoulos PA, Waggoner SE, Vidal GA et al. A phase 1/2 study of niraparib + pembrolizumab in patients (pts) with advanced triple-negative breast cancer or recurrent ovarian cancer (ROC)—Results from ROC cohort. J Clin Oncol 2018; 36 (suppl; abstr 106).
  12. Harter P, Bidziński M, Colombo N et al. DUO-O: A randomized Phase III trial of durvalumab (durva) in combination with chemotherapy and bevacizumab (bev), followed by maintenance durva, bev and olaparib (olap), in newly diagnosed advanced ovarian cancer patients. J Clin Oncol 37, 2019 (suppl; abstr TPS5598).

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