Good and Bad News Reported for Ovarian Cancer Therapy

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Good and Bad News Reported for Ovarian Cancer Therapy

July 1, 2014 by sjwilliamspa

Good and Bad News Reported for Ovarian Cancer Therapy

Reporter, Curator: Stephen J. Williams, Ph.D.

“FDA review red-flags AstraZeneca’s case for ovarian cancer drug olaparib”,

John Carroll reports on a disappointing ruling by the FDA on AstraZeneca’s PARP1 inhibitor olaparib for maintenance therapy in women with cisplatin refractory ovarian cancer with BRCA mutation. Early clinical investigations had pointed to efficacy of PARP inhibitors in ovarian tumors carrying the BRCA mutation. The scientific rationale for using PARP1 inhibitors in BRCA1/2 deficiency was quite clear:

DNA damage can result in

1. double strand breaks (DSB)

DSB can be repaired by efficient homologous recombination (HR) or less efficient non-homologous end joining (NHEJ)

b. BRCA1 involved in RAD51 dependent HR at DSB sites

In BRCA1 deficiency DSB repaired by less efficient NHEJ

2. single strand breaks, damage (SSB)

PARP1 is activated by DNA damage and poly-ADP ribosylates histones and other proteins marking DNA for SSB repair
SSB repair usually base excision (BER) or sometimes nucleotide excision repair (NER)

B. if PARP inhibited then SSB gets converted to DSB

C. in BRCA1/2 deficient background repair is forced to less efficient NHEJ thereby perpetuating some DNA damage pon exposure to DNA damaging agent

A good review explaining the pharmacology behind the rationale of PARP inhibitors in BRCA deficient breast and ovarian cancer is given by Drs. Christina Annunziata and Susan E. Bates in PARP inhibitors in BRCA1/BRCA2 germline mutation carriers with ovarian and breast cancer

(http://f1000.com/prime/reports/b/2/10/) and below a nice figure from their paper:

(from Christina M Annunziata and Susan E Bates. PARP inhibitors in BRCA1/BRCA2 germline mutation carriers with ovarian and breast cancer. F1000 Biol Reports, 2010; 2:10.) Creative Commons

Dr. Sudipta Saha’s post BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair discusses how BRCA1 affects the double strand DNA repair process, augments histone modification, as well as affecting expression of DNA repair genes.

Dana Farber’s Dr. Ralph Scully, Ph.D., in Exploiting DNA Repair Targets in Breast Cancer (http://www.dfhcc.harvard.edu/news/news/article/5402/), explains his research investigating why multiple DNA repair pathways may have to be targeted with PARP therapy concurrent with BRCA1 deficiency.

However FDA investigators voiced their skepticism of AstraZeneca’s clinical results, namely

Small number of patients enrolled
BRCA1/2 cohort were identified retrospectively
results skewed by false benefit from “underperforming” control arm
possible inadvertent selection bias
hazard ratio suggesting improvement in progression free survival but higher risk/benefit

The FDA investigators released their report two days before an expert panel would be releasing their own report (reported in the link below from FierceBiotech)

UPDATED: FDA experts spurn AstraZeneca’s pitch for ovarian cancer drug olaparib

in which the expert panel reiterated the findings of the FDA investigators. The expert panel’s job was to find if there was any clinical benefit for continuing consideration of olaparib, basically stating

“This trial has problems,” noted FDA cancer chief Richard Pazdur during the panel discussion. If investigators had “pristine evidence of a 7-month advantage in PFS, we wouldn’t be here.”

The expert panel was concerned for the above reasons as well as the reported handful of lethal cases of myelodysplastic syndrome and acute myeloid leukemia in the study, although the panel noted these patients had advanced disease before entering the trial, raising the possibility that prior drugs may have triggered their deaths.

This was certainly a disappointment as ….

it was at last year’s ASCO (2013) that investigators at Perelman School of Medicine at the University of Pennsylvania and Sheba Medical Center in Tel Hashomer, Israel presented data showing that in 193 cisplatin-refractory ovarian cancer patients carrying a BRCA1/2 mutation, 31% had a partial or complete tumor regression. In addition the study also showed good response in pancreatic and prostate cancer with tolerable side effects.

See here for study details: http://www.uphs.upenn.edu/news/News_Releases/2013/05/domchek/

As John Carrol from FierceBiotech notes, the decision may spark renewed interest by Pfizer of a bid for AstraZeneca as the potential FDA rejection would certainly dampen AstraZeneca’s future growth and profit plans. Last month AstraZeneca’s CEO made the case to shareholders to reject the Pfizer offer by pointing to AstraZeneca’s potential beefed-up pipeline. AstraZeneca had projected olaparib as a potential $2 billion-a-year seller, although some industry analysts see sales at less than half that amount.

A company spokeswoman said the monotherapy use of olaparib for ovarian cancer assessed by the U.S. expert panel this week was only one element of a broad development program.

Please see a table of current oncology clinical trials with PARP1 inhibitors

at end of this post

However, on the same day, FierceBiotechreports some great news (at least in Europe) on the ovarian cancer front:

EU backs Roche’s Avastin for hard-to-treat ovarian cancer

As Arlene Weintraub of FierceBiotech reports:

EU Committee for Medicinal Products for Human Use (CHMP) handed down a positive ruling on Avastin, recommending that the European Commission approve the drug for use in women with ovarian cancer that’s resistant to platinum-based chemotherapy. It’s the first biologic to receive a positive opinion from the CHMP for this hard-to-treat form of the disease.

Please see here for official press release: CHMP recommends EU approval of Roche’s Avastin for platinum-resistant recurrent ovarian cancer

EU had been getting pressure from British doctors to approve Avastin based on clinical trial results although it may be important to note that the EU zone seems to have an ability to recruit more numbers for clinical trials than in US. For instance an EU women’s breast cancer prevention trial had heavy recruitment in what would be considered a short time frame compared to recruitment times for the US.

Below is a table on PARP1 inhibitors in current clinical trials (obtained from NewMedicine’s Oncology KnowledgeBase™). nm|OK is a relational knowledgeBASE covering all major aspects of product development in oncolology. The database comprises 6 modules each dedicated in a specific sector within the oncology field.

PARP1 Inhibitors Currently in Clinical Trials for Ovarian Cancer

Developer and Drug Name	Development Status & Location – Indications
AbbVie Current as of: March 27, 2014 PARP inhibitor: ABT-767	Phase I (begin 5/11, ongoing 2/14) Europe (Netherlands) – solid tumors with BRCA1 or BRCA2 mutations, locally advanced or metastatic • ovarian cancer, advanced or metastatic • fallopian tube cancer, advanced or metastatic • peritoneal cancer, advanced or metastatic
AstraZeneca Affiliate(s): · Myriad GeneticsCurrent as of: June 26, 2014Generic Name: Olaparib Brand Name: Lynparza Other Designation: AZD2281, KU59436, KU-0059436, NSC 747856	Phase I (begin 7/05, closed 9/08) Europe (Netherlands, UK, Poland); phase II (begin 6/07, closed 2/08, completed 5/09) USA, Australia, Europe (Germany, Spain, Sweden, UK), phase II (begin 7/08, closed 2/09) USA, Australia, Europe (Belgium, Germany, Poland, Spain, UK), Israel, phase II (begin 8/08, closed 12/09, completed 3/13) USA, Australia, Canada, Europe (Belgium, France, Germany, Poland, Romania, Spain, Ukraine, UK), Israel, Russia; phase II (begin 2/10, closed 7/10) USA, Australia, Canada, Europe (Belgium, Czech Republic, Germany, Italy, Netherlands, Spain, UK), Japan, Panama, Peru (combination); MAA (accepted 9/13) EU, NDA (filed 2/14) USA – ovarian cancer, advanced or metastatic, BRCA positive • ovarian cancer, recurrent, platinum sensitive • ovarian cancer, advanced, refractory, BRCA1 or BRCA2-associatedPhase I (begin 5/08, ongoing 5/12) USA; phase II (begin 7/08, closed 10/09) Canada – breast cancer, locally advanced, BRCA1/BRCA2-associated or hereditary metastatic or inoperable • ovarian cancer, locally advanced, BRCA1/BRCA2-associated or hereditary metastatic or inoperable • breast cancer, triple-negative, BRCA-positive • ovarian cancer, high-grade serous and/or undifferentiated, BRCA-positive Phase I (begin 10/10, ongoing 1/13) USA (combination) – ovarian cancer, inoperable or metastatic, refractory • breast cancer, inoperable or metastatic, refractory Phase III (begin 8/13) USA, Australia, Brazil, Canada, Europe (France, Italy, Netherlands, Poland, Russia, Spain, UK), Israel, South Korea, phase III (begin 9/13) USA, Australia, Brazil, Canada, Europe (France, Germany, Italy, Netherlands, Poland, Russia, Spain, UK), Israel – ovarian cancer, serous, high grade, BRCA mutated, platinum-sensitive, relapsed, third line, maintenance • ovarian cancer, serous or endometrioid, high grade, BRCA mutated, platinum responsive (PR or CR), maintenance, first line • primary peritoneal cancer, high grade, BRCA mutated, platinum responsive (PR or CR), maintenance • fallopian tube cancer, high grade, BRCA mutated, platinum responsive (PR or
BioMarin Pharmaceutical Current as of: June 14, 2014 PARP inhibitor: BMN-673, BMN673, LT-673	Phase I/II (begin 1/11, ongoing 3/14) USA – solid tumors, advanced, recurrent Phase I (begin 2/13, closed 4/13, completed 5/14) USA – healthy volunteers Phase I/II (begin 11/13) USA – solid tumors, relapsed or refractory, BRCA mutated, second line
BiPar Sciences Current as of: April 16, 2009 Parp inhibitor: BSI-401	Preclin (ongoing 4/09) – solid tumors
Clovis Oncology Affiliate(s): · University of Newcastle Upon Tyne · Cancer Research Campaign Technology · PfizerCurrent as of: June 21, 2014Generic Name: Rucaparib Brand Name: Rucapanc Other Designation: AG140699, AG014699, AG-14,699, AG-14669, AG14699, AG140361, AG-14361, AG-014699, CO-338, PF-01367338	Phase I (begin 03, completed 05) Europe (UK) (combination), phase I (begin 2/10, closed 11/13) Europe (France, UK) (combination) – solid tumors, advanced Phase II (begin 12/07, closed 10/13) Europe (UK) – breast cancer, advanced or metastatic, in patients carrying BRCA1 or BRCA2 mutations • ovarian cancer, advanced or metastatic, in patients carrying BRCA1 or BRCA2 mutations Phase I/II (begin 11/11, ongoing 6/14) USA, Europe (UK) – solid tumors, metastatic, with mutated BRCA • breast cancer, metastatic, HEr2 negative, with mutated BRCA
Sanofi Current as of: June 03, 2013 Generic Name: Iniparib Brand Name: Tivolza Other Designation: BSI-201, NSC 746045, SAR240550	Phase I/Ib (begin 3/06, closed 3/10) USA (combination), phase I (begin 7/10, closed 11/10) USA, phase I (begin 9/10, ongoing 2/11) Japan (combination); phase Ib (begin 1/07, ongoing 1/11) USA (combination) – solid tumors, advanced, refractory Phase II (begin 5/08, closed 1/09) USA – ovarian cancer, advanced, refractory, BRCA-1 or BRCA-2 associated • fallopian tube cancer, advanced, refractory, BRCA-1 or BRCA-2 associated • peritoneal cancer, advanced, refractory, BRCA-1 or BRCA-2 associated
Tesaro Affiliate(s): · MerckCurrent as of: May 18, 2014Generic Name: Niraparib Other Designation: MK-4827, MK4827	Phase I (begin 9/08, closed 2/11) USA, Europe (UK) – solid tumors, locally advanced or metastatic • ovarian cancer, locally advanced or metastatic, BRCA mutant • chronic lymphocytic leukemia (CLL), relapsed or refractory • prolymphocytic leukemia, T cell, relapsed or refractory Phase Ib (begin 11/10, closed 3/11, terminated 10/12) USA (combination) – solid tumors, locally advanced or metastatic • ovarian cancer, serous, high grade, platinum resistant or refractoryPhase III (begin 5/13, ongoing 5/14) USA – ovarian cancer, platinum-sensitive, high grade serous or BRCA mutant, chemotherapy responsive • fallopian tube cancer • primary peritoneal cancer
Teva Pharmaceutical Industries Current as of: May 04, 2013 Designation: CEP-9722	Phase I (begin 5/11, closed 11/12, terminated 10/13) USA, phase I (begin 6/09, closed 7/12, completed 1/12) Europe (France and UK) (combination) – solid tumors, advanced, third line Phase I (begin 5/11, completed 1/13) Europe (France) (combination) – solid tumors, advanced • mantle cell lymphoma (MCL), advanced

Summary of Combination Ovarian Cancer Trials with Avastin (current and closed)

Indication in Development	ovarian cancer, advanced, recurrent, persistent • ovarian cancer, progressive, platinum resistant, second line • fallopian tube cancer, progressive, platinum resistant, second line • primary peritoneal cancer, progressive, platinum resistant, second line
Latest Status	Phase II (begin 4/02, closed 8/04) USA, phase II (begin 11/04, closed 10/05) USA; phase III (begin 10/09) Europe (Belgium, Bosnia and Herzegovina, Denmark, Finland, France, Germany, Greece, Italy, Netherlands, Norway, Portugal, Spain, Sweden), Turkey
Clinical History	Refer to the Combination Trial Module for trials of Avastin in combination with various chemotherapeutic regimens.According to results from the AURELIA clinical trial (protocol ID: MO22224; 2009-011400-33; NCT00976911), the median PFS in women with progressive platinum resistant ovarian, fallopian tube or primary peritoneal cancer treated with Avastin in combination with chemotherapy, was 6.7 months compared to 3.4 months in those treated with chemotherapy alone for an HR of 0.48 (range =0.38–0.60).. In addition, the objective response rate was 30.9% in women treated with Avastin compared to 12.6% in those on chemotherapy (p=0.001). Certain AE (Grade 2 to 5) that occurred more often in the Avastin arm compared to the chemotherapy alone arm were high blood pressure (20% versus 7%) and an excess of protein in the urine (11% versus 1%). Gastrointestinal perforations and fistulas occurred in 2% of women in the Avastin arm compared to no events in the chemotherapy arm (Pujade-Lauraine E, etal, ASCO12, Abs. LBA5002).A multicenter (n=124), randomized, open label, 2-arm, phase III clinical trial (protocol ID: MO22224; 2009-011400-33; NCT00976911; http://clinicaltrials.gov/ct2/results?term=NCT00976911 ), dubbed AURELIA, was initiated in October 2009, in Europe (Belgium, Bosnia and Herzegovina, Denmark, Finland, France, Germany, Greece, Italy, Netherlands, Norway, Portugal, Spain, and Sweden), and Turkey, to evaluate the efficacy and safety of Avastin added to chemotherapy versus chemotherapy alone in patients with epithelial ovarian, fallopian tube or primary peritoneal cancer with disease progression within 6 months of platinum therapy in the first line setting. The trials primary outcome measure is PFS. Secondary outcome measures include objective response rate, biological PFS interval, OS, QoL, and safety and tolerability. According to the protocol, all patients are treated with standard chemotherapy with IV paclitaxel (80 mg/m²) on days 1, 8, 15 and 22 of each 4-week cycle; or IV topotecan at a dose of 4 mg/m² on days 1, 8 and 15 of each 4-week cycle, or 1.25 mg/kg on days 1-5 of each 3-week cycle; or IV liposomal doxorubicin (40 mg/m²) every 4 weeks. Patients (n=179) randomized to arm 2 of the trial are treated with IV Avastin at a dose of 10 mg/kg twice weekly or 15 mg/kg thrice weekly concomitantly with the chemotherapy choice. Treatment continues until disease progression. Subsequently, patients are treated with the standard of care. Patients in arm 1 (n=182), on chemotherapy only may opt to be treated with IV Avastin (15 mg/kg) three times weekly. The trial was set up in cooperation with the Group d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO) and was conducted by the international network of the Gynecologic Cancer Intergroup (GCIG) and the pan-European Network of Gynaecological Oncological Trial Groups (ENGOT), under PI Eric Pujade-Lauraine, MD, Hopitaux Universitaires, Paris Centre, Hôpital Hôtel-Dieu (Paris, France). The trial enrolled 361 patients and was closed as of May 2012..Results were presented from a phase II clinical trial (protocol ID: CDR0000068839; GOG-0170D; NCT00022659) of bevacizumab in patients with persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer that was performed by the Gynecologic Oncology Group to determine the ORR, PFS, and toxicity for this treatment. Patients must have been administered 1-2 prior cytotoxic regimens. Treatment consisted of bevacizumab (15 mg/kg) IV every 3 weeks until disease progression or prohibitive toxicity. Between April 2002 and August 2004, 64 patients were enrolled, of which 2 were excluded for wrong primary and borderline histology and 62 were evaluable (1 previous regimen=23, 2 previous regimens=39). The median disease free interval from completion of primary cytotoxic chemotherapy to first recurrence was 6.5 months. Early results demonstrated that some patients had confirmed objective responses and PFS in some was at least 6 months. Observed Grade 3 or 4 toxicities included allergy (Grade 3=1), cardiovascular (Grade 3=4; Grade 4=1), gastrointestinal (Grade 3=3), hepatic (Grade 3=1), pain (Grade 3=2), and pulmonary (Grade 4=1). As of 11/04, 36 patients were removed from the trial, including 29 for disease progression and 1 for toxicity in 33 cases reported. Preliminary evidence exists for objective responses to bevacizumab (Burger R, et al, ASCO05, Abs. 5009).An open label, single arm, 2-stage, phase II clinical trial (protocol ID: AVF2949g, NCT00097019) of bevacizumab in patients with platinum resistant, advanced (Stage III or IV), ovarian cancer or primary peritoneal cancer for whom subsequent doxorubicin or topotecan therapy also has failed was initiated in November 2004 at multiple locations in the USA to determine the safety and efficacy for this treatment.A multicenter phase II clinical trial was initiated in April 2002 to determine the 6-month PFS of patients with persistent or recurrent ovarian epithelial or primary peritoneal cancer treated with bevacizumab (protocol ID: GOG-0170D, CDR0000068839, NCT00022659). IV bevacizumab is administered over 30-90 minutes on day 1. Treatment is repeated every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter. A total of 22-60 patients will be accrued within 12-30 months. Robert A. Burger, MD, of Chao Family Comprehensive Cancer Center is Trial Chair.This trial was closed in August 2004.

Sources

http://www.fiercebiotech.com/story/fda-review-red-flags-astrazenecas-case-ovarian-cancer-drug-olaparib/2014-06-23

http://www.fiercebiotech.com/story/fda-experts-spurn-astrazenecas-pitch-ovarian-cancer-drug-olaparib/2014-06-25

http://www.fiercepharma.com/story/eu-backs-roches-avastin-hard-treat-ovarian-cancer/2014-06-27

In a followup to this original posting A Report From the Institute of Medicine of the National Academies of Sciences, Engineering, and Medicine entitled

Evolving Approaches in Research and Care for Ovarian Cancers

was generated in a ViewPoint piece in JAMA which discussed their Congressional mandated report on the State of the Science in Ovarian Cancer Research, titled

Ovarian Cancers: Evolving Paradigms in Research and Care

highlights some of the research gaps felt by the committee in the current state of ovarian cancer research including:

consideration in research protocols of the multitude of histologic and morphologic subtypes of ovarian cancer, including the feeling of the committee that high grade serous OVCA originates from the distal end of the fallopian tube (espoused by Dr. Doubeau and Dr. Christopher Crum) versus originating from the ovarian surface epithelium
a call for expanded screening and prevention research with mutimodal screening including CA125 with secondary transvaginal screen
better patient education of the risk/benefit of genetic testing including BRCA1/2 as well as in consideration for PARP inhibitor therapy
treatments should be standardized and disseminated including more research in health outcomes and decision support for personalized therapy

This Perspective article can be found here: jvp160038

Some other posts relating to OVARIAN CANCER on this site include