more new research: BRCA-Negative Ovarian Cancer Responds to Monotherapy With PARP Inhibitor

lindaprocopio

I don't know if many of you like to read new research, but I think it's good if we work to make this Discussion Board an important resource for anyone diagnosed with OVA. It is so great to have one place online that is nurturing and informative, with so much scary inaccurate stuff out there. So here's what I read on OncologyStat (brand-new research) today:

BRCA-Negative Ovarian Cancer Responds to Monotherapy With PARP Inhibitor

The PARP inhibitor olaparib, recently confirmed to achieve 46% response in BRCA-mutated ovarian cancers by Fong et al. using 200 mg bid (JCO May 20), was reported to produce response even in BRCA nonmutated cases by Gelmon et al. in a Canadian study. Although none of 28 nonmutated breast cancer patients responded, 23% of pretreated patients with BRCA-negative ovarian cancers responded to monotherapy at 400 mg bid, with a median PFS of 7 months. These results, and those of bevacizumab, increase the number of effective agents with unique mechanisms of action to attack this disease.

ABSTRACT
CHICAGO (EGMN) — A phase II translational study showed that monotherapy with the experimental PARP inhibitor olaparib can draw responses in women with advanced serous ovarian cancer regardless of whether the disease carried a BRCA mutation.

No women with triple-negative breast cancer responded to olaparib monotherapy in the non-randomized study presented at the annual meeting of the American Society of Clinical Oncology.
ABT-888 and MK-4827, two other experimental agents inhibiting poly (ADP-ribose) polymerase (PARP), also showed activity in two small phase I trials described in the same clinical science symposium.

"It is unequivocal that this is a critically important class of new drugs for the treatment of BRCA1 and BRCA2 mutant tumors," said discussant Dr. James H. Doroshow of the National Cancer Institute, Bethesda, Md. "As we saw today...there is exciting efficacy for single-agent PARP inhibitors in non-BRCA mutant serous ovarian cancer. Is this a disease of impaired DNA repair? I think this is a very important therapeutic focus for the future," he said.

PARP is an enzyme involved in DNA repair, particularly single strand break repair, said moderator Dr. Hilary Calvert of University College London. At least 17 PARP isoforms, and nine PARP inhibitors are currently in development. The inhibitors have several potential roles in cancer treatment, including to potentiate specific cytotoxic drugs and radiation therapy; to promote the death of cancer cells through a process being called "synthetic lethality," and for use in combination with drugs such as carboplatin, which are known to be active in tumors with hormone receptor defects, such as ovarian tumors.

Dr. Calvert also described some problems of PARP inhibitors, notably that specific potentiation of the drugs is not consistently seen in vivo. In addition, they carry the potential of enhanced toxicity when used in combination with other drugs. Patients may develop resistance to the inhibitors, and the inhibitors may promote genotoxicity, he said.

Dr. Karen Gelmon of the BC Cancer Agency in Vancouver presented the olaparib study of 26 patients with triple-negative breast cancer and 64 with high grade serous ovarian cancer. All patients were treated with olaparib 400 mg twice daily on a continuous basis in 4-week cycles. The objective response rate RECIST criteria was the primary end point.
Among ovarian cancer patients, it was 41.2% in 17 women found to be BRCA mutation carriers and 23% in 53 women determined to be BRCA negative. None of the breast cancer patients had an objective response by RECIST.

Median progression-free survival reached 219 days in the ovarian cohort and 54 days in the breast cohort. Olaparib was found to be effective and well tolerated in both ovarian and breast cancer populations, with side-effect profiles similar to previous trials.
The ovarian cancer cohort was older with a median age of 58 years vs. 47 years for the breast cancer cohort. The median number of prior chemotherapies in both groups was 3 (range 1-10). "Most patients had good performance status," said Dr. Gelmon.

In concluding remarks Dr. Gelmon said this was the first single-agent trial demonstrating encouraging activity of olaparib in high grade non-BRCA serous ovarian cancer.
"And this adds important translational science, for patients enriched for homologous recombination deficient tumors," she added. The investigators archived tissue samples from all patients before and after therapy and plan to do comprehensive analyses to detect BRCA mutations or promoter hypermethylation of BRCA1.

Dr. Antoinette Tan of the Cancer Institute of New Jersey in New Brunswick presented preliminary results of a phase I trial of ABT-888 in combination with cyclophosphamide. The 30-patient study was designed to determine the maximum tolerated dose of the drugs, evaluate pharmacokinetics, and assess PARP inhibition in peripheral blood mononuclear cells. Inclusion criteria was solid tumors or non-Hodgkin's lymphoma; ECOG performance status of 0-2; adequate hematologic, hepatic and renal function; and measurable or evaluable disease by RECIST analysis.

Dr. Tan concluded that ABT-888 at 200 mg PO every 12 hours given day 1 to day 4 could be safely combined with 750 mg/m2 IV cyclophosphamide given on day 3 every 21 days. The maximum tolerated dose of the drugs was not determined, but ABT-888 was not found to alter the pharmacokinetics of cyclophosphamide. In the patient population, 75% of patients had greater than 50% PARP inhibition in peripheral blood mononuclear cells at 4 hours post-dosing of ABT-888 on day 3.

Dr. Shahneen K. Sandhu of the Royal Marsden NHS Foundation Trust in Sutton, United Kingdom presented a first-in-human trial of the PARP inhibitor MK-4827 in 59 patients with advanced BRCA-deficient and sporadic ovarian cancers.

The drug was well tolerated, and continuous oral administration at 300 mg was found to be the maximum tolerated dose. Dosing was proportional to pharmacokinetic profile. Proof of mechanism confirmed PARP inhibition from doses greater than or equal to 80 mg.

Dr. Sandhu said that compelling anti-tumor activity was observed in heavily pre-treated BRCA1 and BRCA2 mutation carriers, and preliminary anti-tumor activity was seen in sporadic cancers.
In his concluding remarks, discussant Dr. Doroshow reiterated that PARP inhibitors have shown important activity as a class in BRCA 1 and 2 mutant tumors in the clinic, and are showing efficacy as single agents in non-BRCA mutant serous ovarian cancer. He said that an important focus for the future was whether ovarian cancer was perhaps a disease of impaired repair.
Interest in PARP inhibition was perhaps best reflected by the question an attendee at the packed session put to Dr. Gelmon.

"My problem is, as a practicing oncologist, I see these great, wonderful results, in a very difficult population of patients with ovarian cancer," he said. "I want to know when I can get my hands on some. There are patients dying today because of this lack of access."
"I think you'll have to ask the companies," she replied.

Dr. Doroshow, Dr. Tan, and Dr. Sandhu disclosed no relevant financial relationships. Dr. Calvert reported receiving inventor's rewards for AG-014699, research funding from Pfizer, and consultancy from Pfizer, BiPar, Inotek, and Biomarin. Dr. Gelmon disclosed consultant or advisory role to AstraZeneca, and research funding from AstraZeneca. The trial of ABT-888 was sponsored by the National Cancer Institute and the Cancer Institute of New Jersey.

nancy591

thanks
I like reading research! Thanks for sharing, Linda. I think Lisa13's Mom was thinking about doing a PARP trial and she is BRCA neg. Havent' heard from Lisa in awhile.

gdpawel

PARP inhibitors and BRAC mutants
As our understanding of cancer biology continues to advance, this disease has come to be understood as many different diseases. As seen in this trial, mutations work with other proteins. Genes do not operate alone within the cell but in an intricate network of interactions.

The cell is a system, an integrated, intereacting network of genes, proteins and other cellular constituents that produce functions. One needs to analyze the systems’ response to drug treatments, not just one or a few targets (pathways).

In cell function analysis, the excellent results with PARP inhibitors and BRAC mutants have been followed by striking response and survival data combining PARP inhibitors with carbo-platinum and gemcitabine. PARP inhibitors by inhibiting DNA damage response can enhance the effects of ionizing radiation, mustard alkylators, topoisomerase inhibitors, platins, and intercalating agents.

At Rational Therapeutics, Inc., in Long Beach, California, they’ve explored the biology of PARP inhbitors in breast and other cancers. In these investigations, the lab applies the functional profiling platform to understand how PARP inhibitors enhance the effects of drugs and drug combinations.

To date, they have observed good activity for the PARP inhibitors as single agents in BRAC1 positive patients, and in some triple negative patients. More interesting, will be the results combining the PARP inhibitors with mustard alkylators, platins, and drug combinations to optimize PARP inhibitor combinations.

This work is ongoing in triple negative and BRAC positive patients as well as other tumor types where the PARP inhibitors may prove useful in the future.

lindaprocopio

gdpawel said:

PARP inhibitors and BRAC mutants
As our understanding of cancer biology continues to advance, this disease has come to be understood as many different diseases. As seen in this trial, mutations work with other proteins. Genes do not operate alone within the cell but in an intricate network of interactions.

The cell is a system, an integrated, intereacting network of genes, proteins and other cellular constituents that produce functions. One needs to analyze the systems’ response to drug treatments, not just one or a few targets (pathways).

In cell function analysis, the excellent results with PARP inhibitors and BRAC mutants have been followed by striking response and survival data combining PARP inhibitors with carbo-platinum and gemcitabine. PARP inhibitors by inhibiting DNA damage response can enhance the effects of ionizing radiation, mustard alkylators, topoisomerase inhibitors, platins, and intercalating agents.

At Rational Therapeutics, Inc., in Long Beach, California, they’ve explored the biology of PARP inhbitors in breast and other cancers. In these investigations, the lab applies the functional profiling platform to understand how PARP inhibitors enhance the effects of drugs and drug combinations.

To date, they have observed good activity for the PARP inhibitors as single agents in BRAC1 positive patients, and in some triple negative patients. More interesting, will be the results combining the PARP inhibitors with mustard alkylators, platins, and drug combinations to optimize PARP inhibitor combinations.

This work is ongoing in triple negative and BRAC positive patients as well as other tumor types where the PARP inhibitors may prove useful in the future.

I'm triple negative papillary serous uterine cancer.
I'd LOVE to get in a PARP trial. My insurance won't cover any side affects related to any clinical trials, so I haven't pursued them although I know it may be my best hope. But my insurance clearly stated that if I had to be hospitalized as a result of any experimental (i.e., not FDA approved) therapies, they would not cover that cost. No treatments to date have sent me to the hospital, but I just couldn't take that financial risk.

gdpawel

lindaprocopio said:

I'm triple negative papillary serous uterine cancer.
I'd LOVE to get in a PARP trial. My insurance won't cover any side affects related to any clinical trials, so I haven't pursued them although I know it may be my best hope. But my insurance clearly stated that if I had to be hospitalized as a result of any experimental (i.e., not FDA approved) therapies, they would not cover that cost. No treatments to date have sent me to the hospital, but I just couldn't take that financial risk.

Private Insurance and Clinical Trials
Wow! The private insurance companies are really putting the squeeze on cancer patients!

Clinical trials are highly empirical, testing drugs on general populations and look for a clinical response and a treatment effect that is not likely to be a chance result. However, the side effect of this is inflexibility, some patients may unnecessarily be exposed to inferior experimental therapies.

A problem with the empirical approach is it yields information about how large populations are likely to respond to a treatment. Doctors don't treat populations, they treat individual patients. Because of this, doctors give treatments knowing full well that only a certain percentage of patients will receive a benefit from any given medicine. The empirical approach doesn't tell doctors how to personalize their care to individual patients.

Laboratory screening of "live" samples from a patient's tumor can help select the appropriate treatment to administer, avoiding ineffective drugs and sparing patients the side effects normally associated with these agents. If can provide predictive information to help physicians choose between chemotherapy drugs, eliminate potentially ineffective drugs from treatment regimens and assist in the formulation of an optimal therapy choice for each patient.

Identifying patients with resistant neoplams may not only spare them toxicity but may prolong their lives, by sparing them from the life shortening effects of ineffective chemotherapy.

Lisa13Q

Thank you so much for posting this
I had all but lost hope for my mother after her last CT scan. She is now taking PARPs and I believe this is her last best hope. I have been walking around rather depressed and trying to deal with that. These results really help. In fact, I copied and e-mailed my sister and mother. I am not going to get too optimistic, but....maybe a little.....I catch a plane tomorrow am to spend the month with Mom, flying her back and forth from NY to FL, while she takes the drugs. I have to say, her blood counts are holding up, but she does feel rotten. The studies say, the side effects are minimal. That is not the case for my mother. But she is 77. Anyway, thanks so much. And, yes Nance, I have not posted so much lately as I have been struggling with a little depression and sibling issues.....The past 18 months have seemed to catch up to me...thanks for noticing.

nancy591

Lisa13Q said:

Thank you so much for posting this
I had all but lost hope for my mother after her last CT scan. She is now taking PARPs and I believe this is her last best hope. I have been walking around rather depressed and trying to deal with that. These results really help. In fact, I copied and e-mailed my sister and mother. I am not going to get too optimistic, but....maybe a little.....I catch a plane tomorrow am to spend the month with Mom, flying her back and forth from NY to FL, while she takes the drugs. I have to say, her blood counts are holding up, but she does feel rotten. The studies say, the side effects are minimal. That is not the case for my mother. But she is 77. Anyway, thanks so much. And, yes Nance, I have not posted so much lately as I have been struggling with a little depression and sibling issues.....The past 18 months have seemed to catch up to me...thanks for noticing.

post
Lisa, that post from me is from June!!! But, I have been thinking about you and your family. I'm struggling a bit here myself.

nanapam

nancy591 said:

post
Lisa, that post from me is from June!!! But, I have been thinking about you and your family. I'm struggling a bit here myself.

post
I also like to read about the latest research. I am BRCA negative, low grade, and low CA-125, so following my disease will be really tricky! I will find out in a few days if my cancer is hormone-receptive, but I really do NOT want to take Femara or tamoxifen.

pattysoo

nanapam said:

post
I also like to read about the latest research. I am BRCA negative, low grade, and low CA-125, so following my disease will be really tricky! I will find out in a few days if my cancer is hormone-receptive, but I really do NOT want to take Femara or tamoxifen.

Thanks for posting this research. Nanpam, I have a similar dx to you. I'm taking Femara b/c the dr. at MD Anderson said it's been shown to work well to prolong remission even in BRCA negative cases! The drug makes my bones and joints hurt. Let me know what you come up with for maintenance.