Olaparib Induces Tumor Response as Single Agent in BRCA-Deficient Breast Cancer

A small, Phase II international multi-center study data presented during the 45th annual meeting of the American Society of Clinical Oncology (ASCO) for novel, oral anti-cancer treatment olaparib (AZD2281 / KU-0059436), demonstrate it is effective and well tolerated in women carrying the BRCA1 or BRCA2 gene mutation with advanced ovarian or breast cancer.

The study has been selected for inclusion in the ‘Best of ASCO’ scientific program and reports that more than a third of women with BRCA1 or BRCA2 mutations and advanced breast cancer that persisted despite prior treatment experienced tumor shrinkage after receiving the investigational PARP inhibitor olaparib.

Inhibition of PARP, short for poly [ADP-ribose] polymerases, is being explored as a new therapeutic approach in cancers with impaired DNA repair pathways, one example of which is cancers with BRCA deficiency.

Different cancers
Olaparib is a novel, potent inhibitor of poly [ADP-ribose] polymerases PARP-1 and PARP-2 that, in addition to undergoing clinical trials for the development of the treatment of BRCA1 and BCRA2-defective breast cancer, is being trialed in ovarian, pancreatic and colorectal tumors and melanoma. This targeted drug therapy candidate has the potential for use as a single agent or in combination with platinum-based DNA-damaging agents and cytotoxic drugs, as well as radiotherapy. Preliminary data supports the safety and oral bioavailability of the compound and warrant its further development as a potential clinical candidate in cancer therapy.

Hopeful News
About 8% of breast cancer cases are triggered by genetic factors. Although many of the exact causes remain unknown, defects on the BRCA-1 and BRCA-2 genes put women at much higher risk of developing aggressive cancers of the breast or ovaries. Increasingly women testing positive for BRCA1 or BECA2 mutations opt for drastic measures such as elective mastectomy as a precaution because they have an 80% risk of developing breast cancer.

Scientists feel that the preliminary results with olaparib may therefore represent good news. If the results of these first tests are to be believed, the new drug candidate may help thousands of women suffering from genetic breast cancer look for less extreme, targeted drug therapies.

Commenting on the results, lead author, Dr Andrew Tutt, MB ChB, PhD, director of the Breakthrough Breast Cancer Research Unit at Kings College in London, United Kingdom, confirms: “The findings of our study provide very promising evidence that the potent PARP inhibitor olaparib may be useful for treating BRCA-deficient breast cancers. However, this drug is in a very early stage of development, and additional clinical trials are necessary to determine the best way to use olaparib in women with BRCA-deficient breast cancer. We are actively discussing the design of future PARP inhibitor studies for women with BRCA1 and BRCA2 mutations.”

This study, which was carried out at hospitals in Britain, Europe, the United States and Australia, is the first to evaluate olaparib when used alone in women with BRCA-deficient breast cancer. A prior Phase II study showed that some women with BRCA-deficient ovarian cancers responded to olaparib. Tumors that arise in patients with BRCA mutations have a defect in their ability to repair DNA. By adding olaparib, the tumor cells are deprived of another DNA repair mechanism. It is thought that this added inhibition of DNA repair with olaprib then leads to cancer cell death.

Tutt and his colleagues examined the response rate to olaparib (as evidenced by tumor shrinkage) in 54 women with breast cancer that was deficient in BRCA1 or BRCA2 and that persisted despite several rounds of standard chemotherapy. An encouraging forty-one percent of the 27 evaluable patients responded to olaparib (experienced tumor shrinkage) at the higher, 400 mg , of the two doses used in the study. In one patient, the tumor seemed to have disappears completely. Furthermore, a 5.7 month progression free survival was noted

A phase I trial identified 400 mg bd as the maximum tolerated dose (MTD) with an initial signal of efficacy in BRCA-deficient ovarian cancers (ASCO 2008; abst 5510). The researchers in this trial concluded that olaparib at 400 mg 100mg monotherapy twice a day in women with advanced breast cancer was well tolerated, with the most common side effects being mild fatigue, nausea and vomiting.

“These encouraging data demonstrate the potential for olaparib to make a significant impact on the outcomes of patients with BRCA-deficient breast and ovarian cancer. AstraZeneca is fully evaluating the development of this drug in these diseases, and is exploring its potential in other populations of patients with cancers associated with defective DNA repair,” explained Alan Barge, Vice President and Head for Oncology and Infection at AstraZeneca, the manufacturer of the new drug.

A second study conducted in women with advanced ovarian cancer also showed encouraging activity, with objective responses observed in about one third of the women receiving olaparib 400mg monotherapy.

Safety and toxicity
Olaparib is highly active in advanced chemotherapy-refractory BRCA-deficient breast cancer. Toxicity in BRCA and BRCA2 carriers was similar to that reported previously in non-carriers. This first study in BRCA-deficient breast cancers provides positive proof-of-concept for high activity and tolerability of a genetically defined targeted therapy.

Rewarding results
These early, non comparative studies provide optimism about the role of PARP inhibition in certain cancers with DNA repair deficiency. Comments Tutt: “It is rewarding to see our earlier laboratory findings, showing that PARP inhibitors such as olaparib specifically kill BRCA-deficient cells, now seem to be holding true for our patients in the clinic. We are hopeful that olaparib could provide a targeted treatment for women with BRCA-deficient breast cancer.”

Olaparib was originally developed by the UK biotechnology company KuDOS Pharmaceuticals, which has been a wholly owned subsidiary of AstraZeneca since 2006.

ASCO 2009 Abstract:

• Audeh MW, Penson RT, Friedlander M, Powell B, et al. Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer. J Clin Oncol 27:15s, 2009 (suppl; abstr 5500).
• Tutt A, Robson M, Garber JE, Domchek S, et al. Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer. Abstract CRA501 presented at the 2009 American Society of Clinical Oncology annual meeting (ASCO) 29 May-2 June 2009; Orlando, Florida.
• Fong DS, Boss DS, Carden CP, Roelvink M, et al. AZD2281 (KU-0059436), a PARP (poly ADP-ribose polymerase) inhibitor with single agent anticancer activity in patients with BRCA deficient ovarian cancer: Results from a phase I study. J Clin Oncol 26: 2008 (May 20 suppl; abstr 5510)

Journal of Clinical Oncology (ASCO Post Meeting edition):

• Audeh MW, Penson RT, Friedlander M. et al. Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer. Journal of Clinical Oncology, 2009 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 27, No 15S (May 20 Supplement), 2009: 5500.

For more information, read these PubMed abstracts:

• Virag L and Szabo C. The therapeutic potential of Poly(ADP-Ribose)Polymerase Inhibitors. Pharm Rev. 2002; 54:375-429.
• Welcsh PL and King MC. BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum Mol Genet. 2001; 10:705-13.

More information:

• European Medicines Agency (EMEA) Pre-authorisation Evaluation of Medicines for Human Use. Public summary of positive opinion for orphan designation of olaparib for the treatment of ovarian cancer.

Clinical Trials:

• Efficacy and Safety of Olaparib in Pretreated Patients With Measurable Colorectal Cancer, Stratified by Microsatellite Instability (MSI) Status. (NCT00912743)

Photos courtesy of the American Society of Clinical Oncology.

PARP Inhibitors Show Promise for Hard-to-Treat (Breast) Cancers

Two studies, including one featured during the plenary session of the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO), report promising data on a new class of targeted drugs called PARP inhibitors. The plenary study reports that women with hard-to-treat 'triple-negative' breast cancer who received the PARP inhibitor BSI-201 along with conventional chemotherapy had better outcomes than women who received chemotherapy alone. A second study reports that women with BRCA-deficient advanced breast cancer experienced tumor shrinkage after receiving the PARP inhibitor olaparib as a single agent.

The two new studies report results on the effect of a new class of targeted therapy called PARP inhibitors on traditionally difficult-to-treat breast cancers – so-called 'triple-negative' breast cancer and BRCA1- and BRCA2 deficient breast cancers.

PARP is short for ‘poly (ADP-ribose) polymerase.’ Cancer cells use the PARP enzyme to repair DNA damage, including the damage inflicted by chemotherapy drugs. Preclinical studies indicate that PARP inhibitors could enhance the efficacy of radiation therapy and chemotherapies such as alkylating agents and platinum-based drugs by preventing malignant cells from repairing damaged DNA, ultimately leading to impaired tumor growth and apoptosis.

PARP Concept
The concept is based on the fact that BRCA1 and BRCA2 are tumor suppressor genes that help control normal cell growth and cell death by regulating the repair of double strand breaks in DNA. Mutations in the BRCA1 and BRCA2 genes can impair this function, leaving cells unable to repair their own DNA, as well as causing the uncontrolled growth that is characteristic of cancer cells. Women who inherit mutations in the BRCA1 or BRCA2 genes have significantly higher risks for breast and ovarian cancer

Exploiting impaired DNA repair function
PARP inhibitors work by exploiting the impaired DNA repair function inherent in BRCA-associated cancers. In this case, inhibition of PARP leads to failure to repair DNA single strand breaks, which in turn, result in DNA double strand breaks. These effects are particularly detrimental to BRCA-associated cancer cells. Ultimately, failure to repair both DNA single strand breaks and double strand breaks, leads to cancer cell death.

Researchers interested in understanding how to exploit the DNA damage on tumor cells inflicting by anti-cancer agents, are now examining whether drugs that inhibit the PARP enzyme will indeed diminish the self-repair mechanism and make cancer cells more sensitive to treatment and promote cancer cell death.

Currently, a number of PARP inhibitors are studied in Phase I, II and III trials for a variety of cancer indications. These include:

• ABT-888 in Metastatic melanoma (Abbott Laboratories). Preliminary trial results show that this drug candidate has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. Broad spectrum chemopotentiation and radiopotentiation makes this compound an attractive candidate for further clinical evaluation.
• AG-014699 in Breast cancer, ovarian cancer and melanoma (Agouron/Pfizer Inc.). Preliminary results of a phase II trial of AG-014699 and temozolomide in patients with metastatic melanoma indicated that the addition of AG-14699 enhanced temozolomide-associated myelosuppression, and that the response rate for combination treatment was higher than for temozolomide alone.
• Olaparib (AZD2281 / KU-0059436) in Breast cancer and ovarian cancer (AstraZeneca). Combination of AZD2281 with cisplatin or carboplatin increased the recurrence-free and overall survival, suggesting that AZD2281 potentiates the effect of these DNA-damaging agents. Preliminary results demonstrate in vivo sensitivity and efficacy of AZD2281, alone or in combination with cisplatin, and provide strong support for AZD2281 as a novel targeted therapeutic against BRCA-deficient cancers.
• BSI-201 in Breast cancer, ovarian cancer, uterine cancerand glioblastoma multiforme (BiPar Sciences Inc.). Data from a Phase II trial of BSI-201 in metastatic breast cancer patients whose tumors were negative for three common breast cancer markers: estrogen receptor, progesterone receptor, and HER2, confirmed that the patients' tumors had significant upregulation of PARP, compared with normal breast tissue, supporting the targeting of this enzyme with BSI-201.

ASCO 2009 Abstracts

• O'Shaughnessy J, Osborne C, Pippen J, Yoffe M, et al. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): Results of a randomized phase II trial. J Clin Oncol 27:18s, 2009 (suppl; abstr 3).

For more information, read these PubMed abstracts:

• Chalmers AJ. The potential role and application of PARP inhibitors in cancer treatment. Br Med Bull. 2009;89:23-40. Epub 2009 Feb 9.
• Dungey FA, Löser DA, Chalmers AJ. Replication-dependent radiosensitization of human glioma cells by inhibition of poly(ADP-Ribose) polymerase: mechanisms and therapeutic potential. Int J Radiat Oncol Biol Phys. 2008 Nov 15;72(4):1188-97.
• Chalmers AJ, Bentzen SM, Buffa FM. A general framework for quantifying the effects of DNA repair inhibitors on radiation sensitivity as a function of dose. Theor Biol Med Model. 2007 Jul 19;4:25.
• Kummar S, Kinders R, Gutierrez ME, Rubinstein L, et al. Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. J Clin Oncol. 2009 Jun 1;27(16):2705-11. Epub 2009 Apr 13.
• Donawho CK, Luo Y, Penning TD, Bauch JL, et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 2007 May 1;13(9):2728-37
• Palma JP, Rodriguez LE, Bontcheva-Diaz VD, Bouska JJ, et al. The PARP inhibitor, ABT-888 potentiates temozolomide: correlation with drug levels and reduction in PARP activity in vivo. Anticancer Res. 2008 Sep-Oct;28(5A):2625-35
• Daniel RA, Rozanska AL, Thomas HD, Mulligan EA, et al. Inhibition of poly(ADP-ribose) polymerase-1 enhances temozolomide and topotecan activity against childhood neuroblastoma. Clin Cancer Res. 2009 Feb 15;15(4):1241-9. Epub 2009 Jan 27.
• Plummer R, Jones C, Middleton M, Wilson R, Evans J, et al. Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res. 2008 Dec 1;14(23):7917-23.
• Calvert AH, Plummer R. The development of phase I cancer trial methodologies: the use of pharmacokinetic and pharmacodynamic end points sets the scene for phase 0 cancer clinical trials. Clin Cancer Res. 2008 Jun 15;14(12):3664-9.

For more information:

• Farmer H, McCabe N, Lord CJ et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917-921 (14 April 2005) doi:10.1038/nature03445.
• Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913-917 (14 April 2005) doi:10.1038/nature03443.

Also read:

• Investigational BSI-201 plus Chemotherapy May Offer New Treatment Option for Triple-Negative Breast Cancer
• Olaparib Induces Tumor Response as Single Agent in BRCA-Deficient Breast Cancer.
• O’Shaughnessy J, Osborne C, Blum J, Pippen J, Yoffe M, et al. Triple Negative Metastatic Breast Cancer: A Phase 2, Multi-Center, Open-Label, Randomized Trial of Gemcitabine/Carboplatin (G/C) With or Without BSI-201, a PARP Inhibitor. SABCS Poster 2120, December 2008

Progress Against Breast and Gynecologic Cancers: Highlights from ASCO

Advances in the treatment of cancers that primarily affect women, including breast and gynecologic cancers, were presented in Orlando at the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO), the world’s leading professional organization representing physicians who care for people with cancer.

“Studies presented during the 45th Annual Meeting of the American Society of Clinical Oncology demonstrate continued progress against breast, ovarian and cervical cancers, which are major causes of cancer mortality worldwide,” said Eric P. Winer, MD, Chair of ASCO’s Cancer Communications Committee and professor of medicine at Harvard Medical School. “One study tells us that women can safely avoid unnecessary blood tests and can delay toxic treatment for ovarian cancer recurrence without compromising their longevity. Others report on a promising new class of targeted drugs for some of the most difficult-to-treat breast cancers. And others provide more effective and less invasive options for treating cervical cancer, which is a particularly significant problem in developing countries.”

Studies highlighted during ASCO include:

• No survival advantage to treating ovarian cancer relapse based on rising CA125 levels, compared with waiting for symptoms. A study featured in ASCO’s plenary session reports that starting treatment immediately for an ovarian cancer relapse based on CA125 protein levels found in the blood does not improve overall survival, compared with delaying treatment until symptoms arise. The findings should allow women to avoid the anxiety and cost associated with frequent blood testing and the toxicity of early treatment.
• PARP inhibitors show promise for hard-to-treat breast cancers. Two studies, including one featured in ASCO’s plenary session, report promising data on a new class of targeted drugs called PARP inhibitors. Poly (ADP-ribose) Polymerase (PARP) has a well-established role in DNA repair processes, and small molecule inhibitors of PARP have been developed as chemotherapy sensitisers for the treatment of cancer. The subsequent demonstration that PARP inhibition is selective for BRCA1 or BRCA2 deficiency suggests that PARP inhibitors may be particularly useful for the treatment of cancer with BRCA mutations. The plenary study reports that women with hard-to-treat “triple-negative” breast cancer who received the PARP inhibitor BSI-201 (BiPar Sciences Inc) along with conventional chemotherapy had 60% better survival outcomes compared with chemotherapy alone than women who received chemotherapy alone. A second study reports that women with BRCA-deficient advanced breast cancer experienced tumor shrinkage after receiving the PARP inhibitor olaparib as a single agent.
• Gemcitabine plus chemoradiation improves cervical cancer survival. Adding the drug gemcitabine (Gemzar) to cisplatin-based chemotherapy and radiation therapy extends overall survival among women with locally advanced cervical cancer. This study was primarily conducted in developing countries, where cervical cancer screening programs are limited.
• Sentinel node biopsy is an effective option for early-stage cervical cancer. Most women with early-stage cervical cancer can safely undergo sentinel node biopsy – a technique in which only one or two lymph nodes are removed to determine whether cancer has spread – in lieu of the traditional, more invasive pelvic lymph node removal, which can lead to more significant side effects. Sentinel node biopsy was also as effective for detecting cancer spread to atypical areas of the pelvis.

For more information, read these PubMed abstracts

• Sivanesaratnam V. Third S. S. Ratnam Memorial Lecture 2007. Ovarian cancer: Is there hope for women? J Obstet Gynaecol Res. 2009 Jun;35(3):393-404.
• Gupta D, Lis CG, Vashi PG, Lammersfeld CA. Impact of improved nutritional status on survival in ovarian cancer. Support Care Cancer. 2009 May 31. [Epub ahead of print]
• Turgut O, Tandogan I, Yilmaz MB, Gul I, Gurlek A. CA125 levels among patients with advanced heart failure: An emerging independent predictor for survival. Int. J Cardiol. 2009 May 13. [Epub ahead of print]
• Interim phase 2 results for PARP inhibitor BSI-201 at San Antonio Breast Cancer Symposium. Cancer Biol Ther. 2009 Jan;8(1):2-3.

Help your patients understand:

• For consumer-oriented information about the studies in this article, please refer your patients to ASCO’s patient website.