Drug Effective in 80% of Men With BRC... - Advanced Prostate...

Advanced Prostate Cancer

20,782 members25,889 posts

Drug Effective in 80% of Men With BRCA-mutant Prostate Cancer

pjoshea13 profile image
2 Replies

This is the media version of the TOPARP-B study of Olaparib [Lynparza], conducted by a team at the Royal Marsden:

technologynetworks.com/canc...

"A pioneering gene-targeted drug already licensed for breast and ovarian cancer can benefit some men with prostate cancer, a major new clinical trial reports.

"Some 80 per cent of men with prostate cancer whose tumours had mutations in the BRCA breast cancer genes responded to olaparib.

"And even though men in the trial had advanced, heavily pre-treated prostate cancer, olaparib delayed progression of the disease in these patients for a median of 8.3 months, with 35 per cent free of progression for more than a year.

"The phase II study, called TOPARP-B, was led by researchers at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, and involved several other institutions in the UK.

"The results were presented at the American Association of Clinical Oncology (ASCO) Annual Meeting and show the benefits of olaparib for men with DNA repair defects in their tumours.

"A phase III trial of the drug is under way and researchers hope the treatment will reach patients within the next two years.

"Delayed cancer progression

"Olaparib targets cancer cells that aren’t able to properly repair their DNA. The researchers wanted to look at how effective the drug was in men with mutations in any genes known to have a role in repairing DNA – including BRCA1 and 2.

"Overall, 47 per cent of men with DNA repair defects in their tumours responded to olaparib, and the drug delayed progression for a median of 5.5 months – 2.7 months longer than previous trial TOPARP-A found in men with advanced prostate cancer who weren’t selected for treatment based on gene mutations.

"The trial received funding from AstraZeneca, Cancer Research UK, the Prostate Cancer Foundation, Stand Up To Cancer, Prostate Cancer UK and the Movember Foundation. It was supported by the NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research (ICR), and the Experimental Cancer Medicine Centre (ECMC) network.

"PALB2 mutations

"The researchers initially screened the tumours of 592 men and found 27 per cent had alterations in one or more genes linked to repairing damaged DNA. After screening and evaluation, they enrolled 98 patients with DNA repair mutations onto the trial.

"BRCA mutations were by far the most common mutation – found in 33 per cent of the tumours with a DNA repair mutation. Other common DNA repair mutations were the genes ATM, CDK12, CHEK2 and PALB2.

"Some 57 per cent of patients with mutations in the PALB2 gene responded to olaparib – the next highest response after those with BRCA1 or BRCA2 mutations.

"The trial results follow a recent announcement by the ICR of a £15 million fundraising drive to complete a new £75 million Centre for Cancer Drug Discovery focusing on overcoming cancer evolution and drug resistance.

"The versatility of olaparib

"Olaparib is the first of a new class of drugs called PARP inhibitors which are underpinned by the work of ICR scientists, who showed that the drugs work best in cancers with weaknesses in repairing their DNA.

"Olaparib was the first cancer drug to reach the market targeted against an inherited genetic fault – initially licensed and approved by NICE for women with ovarian cancer who had inherited BRCA mutations, and now also licensed for breast cancer.

"Studies have also shown it is effective against cells with different DNA repair defects, and not just in inherited mutations but also those in the tumour itself.

"Professor Johann de Bono, Regius Professor of Cancer Research at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden, said:

“Our study is exciting because it shows just how powerful genetic targeting and precision medicine can be. We have shown that by testing for DNA repair mutations we can select those patients with a high chance of responding well and for a long time to the targeted drug olaparib.

“We were delighted to see such strong responses in men with very advanced cancers, where BRCA mutations and other faults in DNA repair genes were present within their tumours. The next phase of the trials is now under way and, if the results look as good as we hope, we should see olaparib starting to reach the clinic for men with prostate cancer in the next couple of years.”

"Exciting new treatments for prostate cancer

"Dr Nuria Porta, Principal Statistician on the TOPARP-B trial in the Clinical Trials and Statistics Unit at The Institute of Cancer Research, London, said:

“Our trial shows that PARP inhibitors could be effective in some men with prostate cancer – potentially widening out their use beyond ovarian and breast cancer.

“We also found that these drugs could be effective in men with several different DNA repair mutations, and in men with genetic faults in their tumours rather than just the smaller group of men with inherited mutations.

“We now very much look forward to the results of the phase III trial, which could pave the way to olaparib becoming the latest in a clutch of exciting new treatments for prostate cancer, and the first for the disease to be gene targeted in this way.”

...

The Abstract was included in the ASCO list posted earlier:

(the post) healthunlocked.com/advanced....

(the list of Abstracts) abstracts.asco.org/239/CatA...

(the Abstract) abstracts.asco.org/239/Abst...

"TOPARP-B: A phase II randomized trial of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib for metastatic castration resistant prostate cancers (mCRPC) with DNA damage repair (DDR) alterations.

Sub-category:

Advanced Disease

Category:

Genitourinary (Prostate) Cancer

Meeting:

2019 ASCO Annual Meeting

Abstract No:

5005

Citation:

J Clin Oncol 37, 2019 (suppl; abstr 5005)

Author(s): Joaquin Mateo, Nuria Porta, Ursula Brigid McGovern, Tony Elliott, Robert J Jones, Isabel Syndikus, Christy Ralph, Suneil Jain, Mohini Anna Varughese, Omi Parikh, Simon J. Crabb, Susana Miranda, George Seed, Claudia Bertan, Aude Espinasse, Peter Chatfield, Diletta Bianchini, Emma Hall, Suzanne Carreira, Johann S. De Bono, on behalf of the TOPARP Investigators Group; The Institute of Cancer Research & The Royal Marsden, London, United Kingdom; Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, United Kingdom; University College Hospital, London, United Kingdom; Christie Hospital NHS Foundation Trust, Manchester, United Kingdom; University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom; Clatterbridge Cancer Centre, Wirral, United Kingdom; St. James's Institute of Oncology, University of Leeds, Leeds, United Kingdom; Queen's University, Belfast, United Kingdom; Musgrove Park Hospital, Taunton, United Kingdom; Royal Preston Hospital, Preston, United Kingdom; Southampton Clinical Trials Unit, University of Southampton, Southampton, United Kingdom; The Institute of Cancer Research, London, United Kingdom; Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, United Kingdom

Abstract Disclosures

Abstract:

Background: We previously reported the antitumor activity of olaparib (400mg BID) against molecularly unselected mCRPC (TOPARP-A; Mateo et al NEJM 2015). We now report TOPARP-B, a phase II trial for patients with mCRPC preselected for putatively pathogenic DDR alterations. Methods: Patients with mCRPC progressing after ≥ 1 taxane chemotherapy underwent targeted sequencing of tumor biopsies and were deemed eligible when alterations (germline or somatic; mono- or bi-allelic) in any DDR gene were detected. Patients were randomized 1:1 under a “pick-the-winner” design to 400mg or 300mg of olaparib BID, aiming to exclude ≤30% response rate (RR) in either arm. The primary endpoint RR was defined as radiological response (RECIST 1.1) and/or PSA50% fall and/or CTC count conversion (Cellsearch; ≥5 to < 5), confirmed after 4-weeks. Analyses of RR per gene alteration subgroup was pre-planned. Secondary endpoints included progression-free survival (PFS), tolerability. Results: Overall, 98 patients (median age 67.6y) were randomized, with 92 patients treated and evaluable for the primary endpoint (70 RECIST-evaluable; 89 PSA50%-evaluable; 55 CTC-evaluable). All had progressed on ADT; 99% were post-docetaxel, 90% post-abiraterone/enzalutamide, 38% post-cabazitaxel. The overall RR was 54% (95%CI 39-69%, meeting threshold for primary endpoint) in the 400mg cohort and 37% (95%CI 23-53%) in the 300mg cohort. With a median follow-up of 17.6 months (mo), the overall median PFS (mPFS) was 5.4 mo. Subgroup analyses per altered gene identified indicated response rates for: BRCA1/2 of 80% (24/30; mPFS 8.1mo); PALB2 57% (4/7; mPFS 5.3mo); ATM 37% (7/19; mPFS 6.1mo); CDK12 25% (5/20; mPFS 2.9mo); others [ATRX, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCM, RAD50, WRN] 20% (4/20; mPFS 2.8mo). The highest PSA50% response rates were observed in the BRCA1/2 (22/30; 73%) and PALB2 (4/6; 67%) subgroups. Conclusions: Olaparib has antitumor activity against heavily pre-treated mCRPC with DDR gene defects, with BRCA1/2 aberrant tumors being most sensitive but with confirmed responses in patients with other DDR alterations. Clinical trial information: NCT01682772"

...

-Patrick

Written by
pjoshea13 profile image
pjoshea13
To view profiles and participate in discussions please or .
Read more about...
2 Replies
Shooter1 profile image
Shooter1

Sometimes I almost wish I had one of those mutations, but my tests show no mutations, so maybe I am better off.

monte1111 profile image
monte1111 in reply to Shooter1

I'm with you there shooter. Haven't got a clue. Had blood test about a month ago, at my suggestion. Sure doctor has results by now. Not at all anxious to find out if I'm a mutant or not. Enjoy.

You may also like...

Anti-proliferative effect of Cannabidiol in Prostate cancer cell PC3

gov/37796968/ Abstract Prostate cancer is the second most frequent cancer diagnosed in men in...

Aggressive BRCA Gene Prostate Cancer

metastasized prostate cancer 2020; spread to the bones so far no organs. He’s a VA patient and they...

FDA Approves First PARP Inhibitor Rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer

com/2019/10/olaparib-slows-progression-in-men-with.html About 6% of patients with advanced prostate...

Leftover prostate cancer drugs

Repurposed drugs for Prostate Cancer

Article from NIH on repurposing drugs for Prostate Cancer https://www.mdpi.com/2146836 Magnus