PARP Inhibitors: The Journey From Research Hypothesis to Clinical Approval

Kishan AT Naipal; Dik C van Gent

Personalized Medicine. 2015;12(2):139-154.

PARP Inhibitors in the Clinic

Several PARP inhibitors have been developed over the past decades, but only recently a number of PARP inhibitors have shown potential in clinical trials (Table 1 & Table 2).

Olaparib

Olaparib (AZD-2281) manufactured by AstraZeneca showed clinical potential as monotherapy in tumors from BRCA mutation carriers with oral dosing of 100–400 mg twice daily.^[23–28] These dosage regimens had relatively mild adverse effects compared with classic chemotherapy and showed proof of concept that most tumors of BRCA mutation carriers have antitumor response, in some cases even complete remission. In addition to monotherapy, several combination strategies have been tested. Unfortunately, severe hematological adverse effects were detected in combination with Topotecan, an oral Topoisomerase 1 inhibitor and Cediranib, a potent VEGF inhibitor.^[29,30] These dose-limiting toxicities resulted in termination of these combination trials. Combination strategies with Decarbazine, an alkylating agent, and Bevacizumab, a VEGF-A inhibitor, did not result in dose limiting adverse effects but also did not show an advantage over Decarbazine monotherapy.^[31,32] Finally, combinations with Gemcitabine, a nucleoside analog, and Cisplatin, a DNA cross-linking agent, revealed severe myelosuppression and bone marrow toxicity.^[33]

BRCA1/2 mutated ovarian tumors that were sensitive to Cisplatin in their first round of treatment also showed sensitivity to Olaparib, whereas platinum insensitive tumors showed no reaction to the inhibitor, suggesting that both therapies depend on the same tumor characteristics.^[23] This was exploited further in a scheme where Olaparib was given as maintenance treatment after prior successful rounds of platinum treatment. This strategy significantly extended progression free survival in patients with high-grade serous ovarian cancer, independent of BRCA germ line status.^[34]

Rucaparib

Developed by Clovis Oncology, Rucaparib (AG 014699) was first introduced to the clinic in combination with the alkylating agent Temozolamide. It was well tolerated and showed no dose-limiting toxicities.^[35] In the first trials Rucaparib was administered intravenously but afterwards this was achieved orally and the addition of Rucaparib to Temozolamide treatment in patients with advanced metastatic melanoma increased progression-free survival compared with historical controls treated with Temozolamide as monotherapy.^[36] Proof of concept trials of Rucaparib in BRCA1/2 mutated tumors were not conducted. However, analysis of epithelial ovarian cancers that were exposed to several rounds of Cisplatin therapy revealed that clinical Cisplatin sensitivity correlated with ex vivo Rucaparib sensitivity and HR deficiency.^[37,38]

Veliparib

The PARP inhibitor manufactured by Abbvie, Veliparib (ABT-888), showed functional PARP inhibition in tumor samples and mononuclear blood cells at concentrations of 10–50 mg single dose orally administered.^[39] This directly led to conduction of Phase I trials for chemopotentiation in combination with other chemotherapeutic agents. However, combining Veliparib with Topotecan resulted in dose limiting toxicities that demanded dose reductions of Topotecan.^[40] On the other hand the combination of Veliparib with a low dose of Cyclophosphamide was well tolerated and showed promising antitumor activity in BRCA mutation carriers.^[41] These results led to a Phase II trial of this combination strategy in patients with locally advanced or metastatic breast cancer and is currently ongoing.

Niraparib

Niraparib (MK4827) was developed by Merck an further exploited by Tesaro Inc. For this PARP inhibitor first trials have been performed where an oral dose of 300 mg/day was determined to be well tolerated. Furthermore, some antitumor activity was noted in patients included in this Phase I trial, however, significance has to be validated in Phase III trials.^[42]

BMN-673

This very potent and highly efficient PARP inhibitor manufactured by BioMarin Pharmaceuticals was found to selectively inhibit PARP activity at much lower concentrations compared with the drugs described above.^[43,44] BMN-673 clinical trials in patients with advanced hematological malignancies and patients with advanced metastatic breast cancer are ongoing and results have yet to be published (Table 1 & Table 2).

Iniparib

A small molecule claimed to have PARP inhibitory activity from Sanofi – Aventis, Iniparib (BSI-201), showed very promising results in patients with metastatic triple negative breast cancer. The addition of Iniparib to treatment with Gemcitabine and Carboplatin improved clinical response, progression-free survival and overall survival without exerting any toxic side effects.^[45] This resulted in the first Phase III clinical trial to be conducted with PARP inhibitors. Unfortunately, this drug failed in Phase III clinical trials in patients with squamous non-small-cell lung cancer and also failed other trials with platinum resistant ovarian cancer.^[46] The drug did not show selective tumor cell killing of BRCA mutated tumors, which has been found for the other PARP inhibitors. Extensive investigation revealed that cytotoxic effects of Iniparib were most probably not caused by PARP inhibition.^[47] At this moment, Iniparib is still being investigated as an anticancer drug. The precise mechanism of action is under investigation, but this drug is not considered to be important for the field of PARP inhibitors anymore.

1 2 3 4 5 6 7 8 9 10 11 12

Next Section

Table 1. Poly-(ADP-ribose) polymerase inhibitors in clinical studies.
PARP inhibitor	Number of completed or ongoing studies	Type of studies completed or ongoing	Specific tissue cancers that were studied	Combination therapy studied
Olaparib (AZD2281)	52	Phase I, II and III	Breast, ovarian (including fallopian tube, uterine and peritoneal), prostate, gastric, pancreatic, head and neck, lung and colorectal carcinoma; Solid metastatic tumors; Ewings sarcoma; Melanoma	Paclitaxel, Carbo/Cis-platin, Cetuximab, Bevecizumab, Irinotecan, Topotecan, Decarbazine, Doxorubicin, Gemcitabine, Temozolamide
Rucaparib (AGO14699)	7	Phase I, II and III	Breast, ovarian (including fallopian tube, uterine and peritoneal) and pancreatic carcinoma; Solid metastatic tumors; Melanoma	Carboplatin, Cisplatin
Veliparib (ABT-888)	73	Phase I, II and III	Breast, ovarian (including fallopian tube, uterine, cervical and peritoneal), prostate, pancreatic, head and neck, lung, urothelial, biliary, liver and colorectal carcinoma; Solid metastatic tumors; Melanoma; Childhood gliomas and glioblastomas; Lymphomas, Multiple myeloma and Leukemia	Paclitaxel, Carbo/Cis/Oxali-platin, Cetuximab, Rituximab, Bevecizumab, Irinotecan, Topotecan, Decarbazine, Doxorubicin, Gemcitabine, Capecitabine, Temozolamide, Etoposide, Bendamustine, Dinaciclib, MitomycinC, Cyclophosphamide, Floxuridine, Bortezomib
Niraparib (MK4827)	3	Phase I and III	Breast and ovarian carcinoma; Ewings sarcoma	Temozolamide
BMN-673	9	Phase I, II and III	Breast, ovarian (including fallopian tube, uterine and peritoneal), prostate, pancreatic and lung carcinoma; Solid metastatic tumors; Ewings sarcoma; Leukemia	Temozolamide

PARP:Poly-(ADP-ribose) polymerase.
Data taken from [22].

Table 2. Poly-(ADP-ribose) polymerase inhibitors currently in Phase III trials.
PARP inhibitor	Phase III trials (registration number)	Condition	Combination therapy	Randomized	Double blind
Olaparib (AZD2281)	1. NCT02000622	Metastatic breast cancer	Olaparib monotherapy	Yes	No
	2. NCT02032823	Germline BRCA1/2 mutated and high-risk HER2-negative primary breast cancer who have completed definitive local treatment and neo-adjuvant or adjuvant chemotherapy	Olaparib monotherapy	No	No
	3. NCT01874353	Platinum Sensitive BRCA Mutated Relapsed Ovarian Cancer Following Complete or Partial Response to Platinum-Based Chemotherapy	Olaparib monotherapy	Yes	Yes
	4. NCT01844986	Newly Diagnosed Advanced Ovarian Cancer with BRCA Mutation and Complete or Partial Response to First Line Platinum Chemotherapy	Olaparib monotherapy	Yes	Yes
	5. NCT01924533	Advanced Gastric cancers that have progressed during first line chemotherapy	Olaparib + Paclitaxel	Yes	Yes
Rucaparib (AGO14699)	1. NCT01968213	Ovarian Cancer, Fallopian Tube Cancer and Peritoneal Cancer stratified by gene mutation status	Rucaparib monotherapy	Yes	Yes
Veliparib (ABT-888)	1. NCT02032277	Early stage Triple Negative Breast Cancer.	Veliparib + Carboplatin (neo-adjuvant therapy)	Yes
Niraparib (MK4827)	1. NCT01847274	Platinum sensitive ovarian cancer	Niraparib monotherapy	Yes	Yes
	2. NCT01905592	Advanced metastatic breast cancer with germline BRCA1/2 mutation	Niraparib monotherapy	Yes	No
BMN-673	1. NCT01945775	Breast Neoplasms with germline BRCA 1/2 mutation	BMN-673 monotherapy	Yes	No

PARP: Poly-(ADP-ribose) polymerase.
Data taken from [22].

Sidebar

Executive Summary

Cancer epidemiology & therapy

Healthcare systems will be burdened with increasing numbers of cancer patients in the near future. Therefore, optimization of current treatment strategies and development of new strategies, such as targeted therapies, are needed to sustain our healthcare system.

Genetic concepts for targeted cancer treatment

Two different concepts for targeted treatment are currently used: oncogene addiction and synthetic lethality. Synthetic lethality can be achieved when tumor cells have sustained mutations that inactivate one pathway, thereby making the tumor dependent on a compensatory pathway. Inhibition of this compensatory pathway can then kill tumor cells without harming normal cells.

Targeting the DNA damage response

Genetic instability caused by DNA damage response (DDR) defects is frequently observed in tumors. DDR defects not only predispose to cancer, but also provide targets for therapy as a form of personalized medicine.

PARP inhibitors target the DDR

PARP enzymes support single strand break repair and prevent formation of DNA double strand breaks (DSBs) during replication. Repair of these DSBs requires homologous recombinaion (HR) for efficient repair, a process which is defective in hereditary breast cancer caused by inactivation of the BRCA1 or BRCA2 gene. Therefore, PARP inhibition kills these HR-deficient tumor cells without killing normal cells, which still retain an intact copy of the gene.

PARP inhibitors in the clinic

Poly-(ADP-ribose) polymerase (PARP) inhibitors have shown strong potential during early clinical development. Currently, five PARP inhibitor drugs are running in clinical trials for approval. All have shown proof of concept success in germline BRCA mutation carriers. Furthermore, several combinations with other drugs are being investigated.

Clinical PARP inhibitors: where are we now?

All PARP inhibitors are running in Phase III clinical trials for approval. Inclusion criteria are germline BRCA1 or BRCA2 mutations or ovarian cancer patients having successfully completed platinum-based chemotherapy. In two Phase III trials the chemo potentiating effect of PARP inhibitors on other drugs is being investigated.

Predictive biomarkers for PARP inhibitor sensitivity

Current patient selection is based on germline BRCA1 and BRCA2 status. Furthermore, many single-gene predictive biomarkers for PARP inhibitor response have been identified in a research setting, which may help to increase the number of eligible patients. Other promising approaches to identify PARP inhibitor sensitive tumors are functional ex vivo assays and identification of specific signatures using massive omics techniques. All approaches still need validation in prospective clinical studies.

Sensitizing tumors for PARP inhibitors

The recent observation that HR can be downregulated by hyperthermia treatment holds great promise for sensitizing even HR-proficient tumors to PARP inhibitors.

Resistance mechanisms

PARP inhibitor treatment can induce various resistance mechanisms, including re-activating BRCA mutations, mutations in HR-inhibiting genes and upregulation of drug efflux pumps. Clinical relevance of these mechanisms remains to be confirmed.

Conclusion

PARP inhibitors are expected be approved for specific tumors soon. However, biomarker discovery should be maintained to increase the number of patients that may benefit from the treatment. Also emerging resistance should be closely monitored and methods to counter this resistance should be developed.