An update on the progress of PARP inhibitors in the clinic


An article published at the beginning of 2016 titled ‘ PARP Inhibitors: The race is on’, describes the race to exploit single agent PARP inhibitors for the treatment of cancer by exploiting the concept of synthetic lethality to selectively target cancer cells deficient in the repair of DNA double strand breaks by the homologous recombination (HR) pathway1. The most studied defects in HR are associated with inactivating mutations in the proteins BRCA1 and BRCA2, which have essential roles in the pathway. Inhibition of PARP during the repair of damaged DNA bases by the base excision repair (BER) pathway causes single strand breaks in DNA that later become double strand breaks during DNA replication. The breaks are repaired by the error prone non-homologous end joining (NHEJ) pathway in cells deficient in homologous recombination (HR) repair mechanisms. The high burden of mutations in the DNA of rapidly proliferating cells caused by error prone NHEJ leads to cell death. Therefore, in accordance with the synthetic lethality concept, PARP inhibition in tumours that have deleterious mutations in BRAC1/2 should lead to cancer cell death and tumour shrinkage.2 Olaparib is the first example of a PARP inhibitor that is well tolerated in patients and clinically validates the synthetic lethality concept 3,4. The drug has been approved as a monotherapy for the treatment of ovarian cancer patients with germline BRCA mutations. Its success has encouraged the development of other PARP inhibitor programmes from Clovis, Tesaro, AbbVie and Medivation. So, as we end the first quarter of 2017, who is leading the race?

Clovis took an early lead with Rucaparib after submitting a new drug application to the FDA in June 2016 for patients with advanced ovarian cancer that have been treated with two or more chemotherapies and have either somatic or germline BRCA1/2 mutations. An efficacy study measuring the percentage of patients to experience complete or partial shrinkage of their tumors (progression free survival) was completed in a cohort of 106 patients with Rucaprib dosed twice per day (600mg). The company posted favorable comparative data showing a high response rate (54% vs 34% for Olaparib) with a marginally longer duration of response at 9.7 months compared to Olaparib’s 7.2 months. In December 2016 the FDA granted accelerated approval for Rucaparib. Furthermore, unlike Olaparib that is restricted to germline BRCA mutations, Rucaparib was approved for germline and/or somatic mutations in ovarian tumours.

In October 2016 Tesaro presented data on Niraparib at ESMO from a Phase III randomized clinical trial in patients with platinum responsive ovarian cancer. The study assessed progression free survival (PFS) in a cohort of 533 patients with or without BRCA mutations.5 Consistent with previous studies on PARP inhibitors, patients with germline BRCA1/2 mutations showed the greatest PFS at 21 months compared to placebo (5 months). Crucially, a statistically significant effect was demonstrated in non-germline BRCA mutant cancers with a PFS of 9.3 months vs 3 months for placebo. In December the FDA granted Niraparib priority review status and last week gave approval for the maintenance treatment for recurrent ovarian cancer in patients who are in complete or partial response to platinum based chemotherapy. Furthermore, the approval is not restricted to ovarian cancer patients with BRCA mutations, making the drug available to a larger population of ovarian cancer patients than either Rucaparib or Olaparib.

While PARP inhibitors have been tested in several types of solid tumour, the greatest response has been observed in ovarian cancer 6. AbbVie’s approach with Veliparib has focused on demonstrating sensitisation of classical chemotherapy drugs to combinations with PARP inhibitors in the more prevalent non-small cell lung cancer and breast cancer patient groups. The use of platinum based agents like carboplatin cause apoptosis of cancer cells by cross linking DNA, leading to tumour cell shrinkage 7. However, the DNA damage response can limit the effect of these agents. The resulting lesions are recognized by the DNA damage sensors and repaired by the base or nucleotide excision repair pathways. Inhibiting the role of PARP in these DNA repair pathways leads to the formation of single strand breaks, which are synthetically lethal in HR deficient cells. Studies in preclinical mouse models of breast cancer demonstrated a pronounced potentiation of cisplatin efficacy in combination with Veliparib 8. While PARP inhibitors are well tolerated, combination therapies risk narrowing the therapeutic window for both Veliparib and the chemotherapeutic agent. At the San Antonio Breast Cancer Symposium in December last year, AbbVie presented results from its phase II study of Veliparib in patients with locally recurrent or metastatic breast cancer with BRCA1 or BRCA2 mutations. While the addition of Veliparib to paclitaxel and carboplatin resulted in an improved overall response rate without an increase in adverse events, the study failed to show statistical significance in progression free survival. Despite the disappointing PFS data, the higher responder rate has encouraged continuation with the phase III trial (BROCADE) appropriately powered to detect improvements in PFS and overall survival. In addition to trails in Breast Cancer, AbbVie was given orphan drug status for Veliparib in NSCLC.

Of all the PARP inhibitors in late stage clinical trials, the most potent and selective is Talazaporib, recently acquired by Pfizer after its take-over of Medivation. While PARP inhibitors have been developed to potently inhibit the enzymatic activity of PARP, recent evidence suggests that the ability of the compounds to trap PARP at the DNA single strand break closely correlates with efficacy in preclinical models 9. Talazaporib has superior trapping ability than any other PARP inhibitor on the market, and with the promise of superior efficacy at a lower dose with fewer side effects, there is significant interest in the ongoing clinical studies. The drug is in a phase III clinical study for advanced and/or metastatic breast cancer with a BRCA mutation. Results from the study are keenly awaited.

PARP inhibitors are widely accepted as a clinically proven target class that validates the synthetic lethality concept. The future growth of PARP inhibitors will depend on the ability to combine it with other targeted approaches that can demonstrate synthetic lethality in tumour cell backgrounds while sparing normal cells. The good tolerability of PARP inhibitors in combination with other chemotherapy bodes well. Studies are ongoing for PARP inhibitors in different cancer populations in combination with radiation, Wee1 inhibitors, ATR inhibitors, Hsp90 inhibitors and drugs targeting the PI3K/Akt pathway. Studies may complete in 2017/18 and the results are eagerly awaited.

Blog written by Darren Le Grand

References

  1. Brown, J. S., Kaye, S. B. & Yap, T. A. PARP inhibitors: the race is on. Br. J. Cancer 114, 713–715 (2016).
  2. Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–21 (2005).
  3. Ledermann, J. et al. Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer. N. Engl. J. Med. 366, 1382–1392 (2012).
  4. Ledermann, J. A. et al. Articles Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Oncol (2016). doi:10.1016/S1470-2045(16)30376-X
  5. Mirza, M. R. et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N. Engl. J. Med. 375, 2154–2164 (2016).
  6. Ledermann, J. A. PARP inhibitors in ovarian cancer. Ann. Oncol. 27, i40–i44 (2016).
  7. Kelland, L. The resurgence of platinum-based cancer chemotherapy. Nat. Rev. Cancer 7, 573–584 (2007).
  8. Donawho, C. K. et al. ABT-888, an Orally Active Poly(ADP-Ribose) Polymerase Inhibitor that Potentiates DNA-Damaging Agents in Preclinical Tumor Models. Clin. Cancer Res. 13, (2007).
  9. Murai, J. et al. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res. 72, 5588–99 (2012).

 

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s