see blogger's note: Medical News: More Good Data for PARP Blocker (Olaparib) in Ovarian Ca - in Meeting Coverage, ASCO from MedPage Today

Blogger's Note: see blog postings 'olaparib' (searchable) of March 27th and March 8th and others; also use NEJM search for more information on ovarian cancer/Olaparib

Medical News: More Good Data for PARP Blocker in Ovarian Ca - in Meeting Coverage, ASCO from MedPage Today

March 27th: Medscape article - Olaparib for Ovarian Cancer, No Longer in Development

Olaparib for Ovarian Cancer, No Longer in Development

(2nd item) New Data Updating Overall Survival Rate in Olaparib Study -- SGO conference

New Data Updating Overall Survival Rate in Olaparib Study -- AUSTIN, Texas, March 27, 2012 /PRNewswire-USNewswire/ --SGO conference

Medical News:Data Confirm PARP Inhibitor (Olaparib) Slows Ovarian Ca - in Meeting Coverage, SGO from MedPage Today

Medical News:Data Confirm PARP Inhibitor Slows Ovarian Ca - in Meeting Coverage, SGO from MedPage Today

Action Points

Note that this randomized, placebo controlled study demonstrates that olaparib, an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor, significantly improved progression-free survival but not overall survival, in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer.

abstract: Evaluation of Iniparib as a PARP Inhibitor (BRCA2....)

Evaluation of Iniparib as a PARP Inhibitor:

Purpose:

Poly(ADP-ribose) polymerase (PARP) inhibitors are undergoing extensive clinical testing for their single-agent activity in homologous recombination (HR)-deficient tumors and ability to enhance the action of certain DNA-damaging agents. Compared with other PARP inhibitors in development, iniparib (4-iodo-3-nitrobenzamide) is notable for its simple structure and the reported ability of its intracellular metabolite 4-iodo-3-nitrosobenzamide to covalently inhibit PARP1 under cell-free conditions. The present preclinical studies were conducted to compare the actions iniparib with the more extensively characterized PARP inhibitors olaparib and veliparib.

Results:

Consistent with earlier reports, olaparib and veliparib selectively induced apoptosis and inhibited colony formation in cells lacking BRCA2 or ATM. Moreover, like earlier generation PARP inhibitors, olaparib and veliparib sensitized cells to the topoisomerase I poisons camptothecin and topotecan. Finally, olaparib and veliparib inhibited formation of pADPr in intact cells. In contrast, iniparib exhibited little or no ability to selectively kill HR-deficient cells, sensitize cells to topoisomerase I poisons, or inhibit pADPr formation in situ. In further experiments, iniparib also failed to sensitize cells to cisplatin, gemcitabine, or paclitaxel.


Conclusions:

While iniparib kills normal and neoplastic cells at high (>40 μmol/L) concentrations, its effects are unlikely to reflect PARP inhibition and should not be used to guide decisions about other PARP inhibitors.  

Clin Cancer Res; 18(6); 1655–62. ©2012 AACR.

March 7th /text and/or podcast: PARP Inhibitors and the Challenges of Developing Ovarian Cancer Therapeutics - Cancer Network Dr's Ledermann/Birrer

Blogger's Note: podcast and/or text available, registration required (free)
                          ~~~~~~~~~~~~~~~~~~

PARP Inhibitors and the Challenges of Developing Ovarian Cancer Therapeutics - Cancer Network

Jonathan Ledermann, Cancer UK, London; Michael Birrer, Harvard Medical School, Dana-Farber Institute

AUDIO:
Right-click to download MP3

PODCAST 

PARP Inhibitors and the Challenges of Developing Ovarian Cancer Therapeutics

Interviewed by Anna Azvolinsky, PhD | March 7, 2012

---

Ovarian cancer is notoriously difficult to treat because it is usually diagnosed at an advanced stage, and because of the high variance in the types of mutations that are found in individual tumors. This creates hurdles for the development of efficacious treatments.
CancerNetwork presents an interview with two prominent ovarian cancer researchers from both sides of the Atlantic. Dr. Jonathan Ledermann is professor of medical oncology at the UCL Cancer Institute in London, England. He treats gynecological cancers and is heavily involved in ovarian cancer clinical trials. Dr. Michael Birrer is a professor of medicine at the Harvard Medical School and is part of the Dana-Farber/Harvard Cancer Center where he also treats gynecological cancers and leads an effort to molecularly characterize gynecological cancers.......

                           ~~~~~~~~~~~~~~~~~~~~~

"CancerNetwork: Despite promising results at ASCO last year, with one of the PARP inhibitors, olaparib, showing positive progression-free survival (PFS) benefit, the phase II trial was stopped in mid December because this PFS benefit was not likely to translate to an overall survival benefit. I would like to get both of your perspectives on this and then what the future holds for other PARP inhibitors in development.



Dr. Ledermann: Mike Birrer will want to comment on this, but can I just correct you on a point of fact. The phase II trial was not stopped. In fact it is still going. There are still patients on treatment, and it has not been unblinded. What the company that manufactures olaparib, which is one of the PARP inhibitors, said in their press release was they were not going to continue development of olaparib in high-grade serous ovarian cancer because, as you said, the interim analysis of survival didn’t show the benefit they wanted to see in relation to the benefit in PFS that I reported at the ASCO conference. But the trial is still continuing and a final analysis will be done probably toward the end of this year."

open access: Nature Reviews: Key Advances in Medicine - Ovarian Cancer/Markman page 15-16

Key Advances in Medicine (book)


Nature Reviews Clinical Oncology  (page 15)S11 ovarian cancer | Mutations and non-inferiority analyses show a way forward Maurie Markman      (page 15-16)






Highly clinically relevant ovarian cancer clinical research in 2011 focused on an increased understanding of the biology of the malignancy, limitations of strategies for early detection and screening, and the provocative reports of alternative primary and second-line management strategies.

"Although there were a number of very interesting
preliminary reports of therapeutic
advances in ovarian cancer in 2011 (for
example, bevacizumab in the first-line and
second-line management of the malignancy,
and olaparib  (Blogger's Note: links to Olaparib (parp inhibitor) - Cancer Research UK)  as maintenance therapy for
high-grade serous cancers), as of the writing
of this commentary these studies have not
appeared in the peer-reviewed oncology literature......."

Key advances
■■ There are currently no evidence-based
data supporting the clinical utility of any
ovarian cancer screening strategy in
non‑high-risk populations1
■■ Provocative data suggest there may be a
clinically meaningful difference between
the presence of a BRCA1 or a BRCA2
mutation in influencing outcome in ovarian
cancer6
■■ Under specific circumstances (for example,
neuropathy) it might be reasonable to
substitute pegylated liposomal doxorubicin
for paclitaxel in the front-line chemotherapy
management of ovarian cancer7

Markman, M. Nat. Rev. Clin. Oncol. 9, 69–70 (2012); published online 20 December 2011; doi:10.1038/nrclinonc.2011.200

                                   ~~~~~~~~~~~~~
"The articles included in Nature Reviews Key Advances in
Medicine were originally published in the February 2012
issues of the eight clinical Nature Reviews journals. The journals’
editors commissioned international experts to write a short
essay highlighting up to five key papers that made the biggest
contribution to their field in 2011."

Comparing Poly (ADP–Ribose) Polymerase Inhibitors With Standard Chemotherapy in BRCA-Mutated, Recurrent Ovarian Cancer: Lessons Learned From a Negative Trial (Olaparib)

"...Thus, although the study by Kaye et al¹¹ does not show a clear advantage of olaparib compared with PLD, it is noteworthy for what it teaches us about the difficulties in performing and interpreting the results of randomized trials that involve this promising class of new agents in patients with recurrent EOC."

AstraZeneca - AstraZeneca updates on olaparib

AstraZeneca updates on olaparib

"AstraZeneca today (December 20th, 2011) announced that its investigational compound olaparib will not progress into Phase III development for the maintenance treatment of serous ovarian cancer."

abstract: 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 : The Lancet Oncology (with/without brca mutation/s)

The Lancet Oncology, Early Online Publication, 22 August 2011

doi:10.1016/S1470-2045(11)70214-5Cite or Link Using DOI

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

 "...

Findings

91 patients were enrolled (65 with ovarian cancer and 26 breast cancer) and 90 were treated between July 8, 2008, and Sept 24, 2009. In the ovarian cancer cohorts, 64 patients received treatment. 63 patients had target lesions and therefore were evaluable for objective response as per RECIST. In these patients, confirmed objective responses were seen in seven (41%; 95% CI 22—64) of 17 patients with BRCA1 or BRCA2 mutations and 11 (24%; 14—38) of 46 without mutations. No confirmed objective responses were reported in patients with breast cancer. The most common adverse events were fatigue (45 [70%] of patients with ovarian cancer, 13 [50%] of patients with breast cancer), nausea (42 [66%] and 16 [62%]), vomiting (25 [39%] and nine [35%]), and decreased appetite (23 [36%] and seven [27%])...."

May 20th Medscape - PARP Inhibitor Improves Outcomes in Ovarian Cancer - olaparib

Open Label Study to Assess Efficacy and Safety of Olaparib in Confirmed Genetic BRCA1 or BRCA2 Mutation Pats - Full Text View - ClinicalTrials.gov

Cancer drug olaparib (PARP inhibitor) shows early promise | Philadelphia Inquirer (BRCA 1/2)

ASCO: Drug May Reactivate Chemo Effect in Ovarian CA - Olaparib (PARP)

"Chemotherapy resulted in an overall response rate of 42% in this heavily pretreated patient population, including a 55% response rate for carboplatin and/or a taxane," said Ang. "If these results are confirmed in a larger patient population, they could remain an option for these patients, even if they have demonstrated prior resistance."