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Profound Trial (Olaparib) BRCA mutation


MBarry

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Hi guys

Is anyone enrolled in the Profound trial or have any knowledge of this?

The official purpose of the trial is:

The purpose of this study is to evaluate the efficacy and safety of olaparib versus enzalutamide or abiraterone acetate in subjects with metastatic castration-resistant prostate cancer who have failed prior treatment with a new hormonal agent and have homologous recombination repair gene mutations

This trial has been enrolling in Australia over the last 6 months or so.

I have germline BRCA2 mutation which has probably caused my mCRPC disease. I have been through my options with enzalutamide and abiraterone and have had Docetaxel. Currently looking at commencing a platinum based chemotherapy treatment using Carboplatin, normally used in Ovarian cancer. 

Any thoughts/experiences around Profound and/or the BRCA mutation and treatment experiences would be very welcome.

Thanks and best wishes to you all

Martin

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Charles (Chuck) Maack

Hello Martin,

Thought you might be interested in some earlier information (February 2016) regarding a trial with Olaparib/Lynparza in my files:

 

From: advancedprostatecancer@yahoogroups.com [mailto:advancedprostatecancer@yahoogroups.com]
Sent: Friday, February 12, 2016 10:56 AM
To: advancedprostatecancer@yahoogroups.com
Subject: Re: Advanced PCa Malecare Group New drug for a subset of patients with DNA repair gene mutations

 

 

See the paper below.  (Click on the link for the full text.)

 

Olaparib [Lynparza] is a PARP inhibitor.

 

PARP [Poly ADP Ribose Polymerase] is a protein that is used in repairing single strand DNA breaks.

 

BRCA1 & BRCA2 are proteins involved in repairing double strand breaks.

 

If one of the BRCA proteins is defective, as commonly occurs in familial breast cancer, how would inhibiting PARP be useful?  The reason, as I understand it, is that in tumor cells that have defective BRCA, the loss of PARP leads to cells becoming unable to be adequately repaired.  Those cells are not viable, & die.  Meanwhile, unaffected cells can survive the loss of PARP.

 

In the Phase 2 trial ("50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel"):

 

-  16 had a response:

 

"either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml."

 

"11 ... had reductions in the PSA level of 50% or more. The median circulating tumor-cell count at baseline was 37 cells per 7.5 ml of blood (interquartile range, 14 to 110); 14 ... had a confirmed reduction in the circulating tumor-cell count to less than 5 cells per 7.5 ml.

 

-  of 16 men with DNA repair gene mutations, 14 responded, including all 7 with BRCA2 loss.

 

In other words: (i) the benefit was mostly confined to those harboring mutations, & (ii) almost all of those men responded to the drug.

 

How significant might this be?:

 

"defects in DNA repair accounts for approximately 25 to 30% of all sporadic, castration-resistant prostate cancers"

 

 

-Patrick

 

FULL Text:  http://www.nejm.org/doi/full/10.1056/NEJMoa1506859#t=article

 

 

 

http://www.ncbi.nlm.nih.gov/pubmed/26510020

 

N Engl J Med. 2015 Oct 29;373(18):1697-708. doi: 10.1056/NEJMoa1506859.

DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.

Mateo J1Carreira SSandhu SMiranda SMossop HPerez-Lopez RNava Rodrigues DRobinson DOmlin ATunariu NBoysen GPorta NFlohr PGillman AFigueiredo IPaulding CSeed GJain SRalph CProtheroe AHussain SJones RElliott TMcGovern UBianchini DGoodall JZafeiriou ZWilliamson CTFerraldeschi RRiisnaes REbbs BFowler GRoda DYuan WWu YMCao XBrough RPemberton HA'Hern RSwain AKunju LPEeles RAttard GLord CJAshworth ARubin MAKnudsen KEFeng FYChinnaiyan AMHall Ede Bono JS.

Author information

  • 1From the Institute of Cancer Research (J.M., S.C., S.S., S.M., H.M., R.P.-L., D.N.R., A.O., N.T., G.B., N.P., P.F., A.G., I.F., C.P., G.S., D.B., J.G., Z.Z., C.T.W., R.F., R.R., B.E., G.F., D. Roda, W.Y., R.B., H.P., R.A., A.S., R.E., G.A., C.J.L., A.A., E.H., J.S.B.), the Royal Marsden NHS Foundation Trust (J.M., S.S., R.P.-L., A.O., N.T., D.B., Z.Z., R.F., D. Roda, R.E., G.A., J.S.B.), and University College London Hospital (U.M.), London, Queen's University, Belfast (S.J.), University of Leeds, Leeds (C.R.), Churchill Hospital, Oxford (A.P.), University of Liverpool, Liverpool (S.H.), Beatson West of Scotland Cancer Centre, Glasgow (R.J.), and Christie Hospital, Manchester (T.E.) - all in the United Kingdom; the University of Michigan, Ann Arbor (D. Robinson, Y.-M.W., X.C., L.P.K., F.Y.F., A.M.C.); Weill Cornell Medical College, New York (M.A.R.); and Thomas Jefferson University, Philadelphia (K.E.K.).

Abstract

BACKGROUND: 

Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.

METHODS: 

We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies.

RESULTS: 

Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib.

CONCLUSIONS: 

Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.).

 

 

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Thank you Chuck, only small numbers but quite amazing response rates. I was aware of this trial and this was one of the reasons that I have been pushing hard for genetic testing for myself.The PROfound trial would seem to be a wider ranging test of these results.

To anyone else reading this, if you have advanced prostate cancer and a family history of breast/ovarian/prostate cancers particularly but also cancers such as pancreatic and melanoma I would recommend that you discuss genetic testing with your medical advisers.

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alanbarlee

G'day Martin,

 

Chuck has shared some great info about PARP inhibitors.

Here's some more information about TRITON2 - a Phase 2 trial of a new PARP inhibitor - an experimental  therapy to treat metastatic castrate resistant prostate cancer (and breast, ovarian and other cancers) that shows a particular gene repair abnormality (such as BRCA-1 or 2 genesRole of PARP Inhibitors Clarified in Prostate Cancer_files, amongst others). This TRITON2 trial is running in parallel with the 'TRITON3 trial', which would also be worth exploring - particularly in relation to the respective control arms to which you may be randomly assigned, and whether crossover is envisaged if the non-control arms are highly responsive).
 also  attached a recent review article on PARP inhibitors that will add some more background. It’s medical literature, but not excessively technical.
Keep in touch - and best wishes,

Role of PARP Inhibitors Clarified in Prostate Cancer.html

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Patrick Turner
10 hours ago, MBarry said:

if you have advanced prostate cancer and a family history of breast/ovarian/prostate cancers particularly but also cancers such as pancreatic and melanoma I would recommend that you discuss genetic testing with your medical advisers.

You got me worried again. I had a sister die of ovarian C, other sister has survived Bca after double mastectomy. 

As they say, diseases of the sex organs in females makes it likely their brothers will cop it.

I was supposed to be in a trial of Ipertasib early this year, but they got enough patients just before they interviewed me, so they kept me out of it.

Like many gee-whiz incremental advances, it may not be easily available, and its very easy to be among those for whom advances would not do much.  

Patrick Turner

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Hi Patrick, I don't think you should worry, if, for instance, you were to test positive to the BRCA gene mutation, it would not affect your disease, it would just give you more understanding of your condition and potentially open some new treatment opportunities.

If you did decide to get tested, I'm sure you would go through some initial counselling which would discuss the impact of the information on any siblings or offspring.

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Thank you for post Alan, this is an extremely interesting and promising area of research IMO.

A couple of takeaways from your report:

 

"DNA repair alterations are present in approximately 25% to 30% of cases of metastatic CRPC"  Which is quite stunning

and

“I think it’s become increasingly apparent that we need a thorough family history of cancer that might point to patients with DNA repair defects,” said Higano. As genomic testing for directing targeted therapies becomes more integrated into the standard of care for patients with CRPC and PARP inhibitors show more durable responses in clinical trials, these agents will become increasingly available.

 

 

 

 

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Patrick Turner
1 hour ago, MBarry said:

we need a thorough family history of cancer

Hmm, maybe somewhat very difficult. My dad died of melanoma at 60, my mum died at 98 in 2015, no cancer apart form a few skin spots which she had frozen off, all due to the time spent on beaches well before SPF 30 sun-creams. 

So there are not too many ppl left alive to test, but cancer sure took many. But I do know one guy whose father had Pca and his 3 older brothers, so he didn't hesitate about getting an RP when Psa went up a bit. The hard fact seems to be that if your Pca isn't successfully removed by surgery well before it has spread, its likely to kill you after trying every potion in the drug cupboard and being radiated so much you glow in the dark. 

 

There has not been a single word from any medico here or online about the availability and effectiveness of having genomic testing.

 

But one doc here had some success analysing DNA of a 47yo bloke with gall bladder cancer, very rare, and when he looked at results he thought a breast cancer drug would work and it did, ( maybe Keytruda ) and the guy had to pay full cost of the drug even though its free for Bca patients.

There was an article in Canberra Times and photo of this guy, and he got a cure, it seems, he's been 5 years OK now. Costs mentioned were $230 a day, but for how long was not stated, but a year at $230 a day = $84,000 a year, and if the cancer looks like causing an early bye-bye time, you just pay up. This 47yo was married, had a young family, and sure, docs like to fix him if possible. But when they see me, I'm just an old bugger, use by date coming up.....

 

After the newspaper article, I phoned the doc's clinic to ask if there was any chance to be included as a patient. The lady at office immediately asked if I was insured, and I said no, but had my own savings so I didn't see any point of insurance, but she insisted I could not even talk any further if I was not insured. My guess is, many say they have the dough, but then when pay up time comes, they really have no dough, but its easier to get money from the insurance company. But I'd be willing to pay in advance, and nup, no insurance, no damn treatment. None of the fancy treatments are available in the public system. Some private hospitals do have the best equipment and possibly the best medicos, but that's a great uncertainty you can't know about until you deal for awhile with them. I have dealt with private hospitals and endured a few nice big cock ups because the humans are just human, no matter what sort of a nice suit they wear. 

The idea of patching up broken DNA in someone with cancer is somewhat far fetched, and methinks we'd just like our immune system to recognize cancer as enemy cells, but its seems it just don't, so cancer has a picnic at out expense. 

One research doc at ANU Curtin School of Medicine spent years trying to make a vaccine for cancer, but soon after he turned about 70, Parkinson's took him. I went to one of his public lectures about 6 years ago when he was well, but now you hear nothing about what the uni dudes in white coats are doing in their labs. They said hello to me, but really didn't wanna know me or my history and they had nothing at all to offer. A research hospital in Adelaide was equally cold. It seem many medicos are jumping up get attention, and FUNDS, and then, nothing.

Patrick Turner. 

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