Improved Response to Olaparib Treatment Among Men With mCRPC Harboring BRCA1/2 vs ATM Mutations

[Balsam01]

BRCA2 and Olaparib

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TAKE-HOME MESSAGE

•This multicenter retrospective study compared outcomes of 23 men with mCRPC, all with BRCA1/2 or ATM mutations, treated with a PARP inhibitor (olaparib). PSA responses were achieved in 76% of men with BRCA mutations versus 0% of men with ATM mutations. Median PFS was 12.3 months and 2.4 months in patients with BRCA and ATM mutations, respectively.

•This is an important study, suggesting that not all mutations in DNA repair genes predict response to PARP inhibitors in patients with mCRPC.

– Pedro C. Barata, MD, MSc

abstract

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BACKGROUND

Poly ADP-ribose polymerase (PARP) inhibitors, such as olaparib, are being explored as a treatment option for metastatic castration-resistant prostate cancer (mCRPC) in men harboring mutations in homologous recombination DNA-repair genes. Whether responses to PARP inhibitors differ according to the affected gene is currently unknown.

OBJECTIVE

To determine whether responses to PARP inhibitors differ between men with BRCA1/2 and those with ATM mutations.

DESIGN, SETTING, AND PARTICIPANTS

This was a multicenter retrospective review of 23 consecutive men with mCRPC and pathogenic germline and/or somatic BRCA1/2 or ATM mutations treated with olaparib at three academic sites in the USA.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS

The proportion of patients achieving a ≥50% decline in prostate-specific antigen (PSA50 response) was compared using Fisher's exact test. Clinical and radiographic progression-free survival (PFS) and overall survival were estimated using Kaplan-Meier analyses and compared using the log-rank test.

RESULTS AND LIMITATIONS

The study included two men with BRCA1 mutations, 15 with BRCA2 mutations, and six with ATM mutations. PSA50 responses to olaparib were achieved in 76% (13/17) of men with BRCA1/2 versus 0% (0/6) of men with ATM mutations (Fisher's exact test; p=0.002). Patients with BRCA1/2 mutations had median PFS of 12.3mo versus 2.4mo for those with ATM mutations (hazard ratio 0.17, 95% confidence interval 0.05-0.57; p=0.004). Limitations include the retrospective design and relatively small sample size.

CONCLUSIONS

Men with mCRPC harboring ATM mutations experienced inferior outcomes to PARP inhibitor therapy compared to those harboring BRCA1/2 mutations. Alternative therapies should be explored for patients with ATM mutations.

PATIENT SUMMARY

Mutations in BRCA1/2 and ATM genes are common in metastatic prostate cancer. In this study we compared outcomes for men with BRCA1/2 mutations to those for men with ATM mutations being treated with olaparib. We found that men with ATM mutations do not respond as well as men with BRCA1/2 mutations.

European Urology Focus

Differential Response to Olaparib Treatment Among Men With Metastatic Castration-Resistant Prostate Cancer Harboring BRCA1 or BRCA2 Versus ATM Mutations

Eur Urol Focus 2019 Feb 21;00(00)00, CH Marshall, AO Sokolova, AL McNatty, HH Cheng, MA Eisenberger, AH Bryce, MT Schweizer, ES Antonarakis

[NPfisherman]

Thanks for posting this Balsam... as they begin coming up with more successful combos, I believe we will see stage 4 become more of a chronic disease, and less of a death sentence..

All the best,

Fish

[Jbooml]

So we continue the search for the inobtanium bullet....lets hope the Protac trials are the first step in that direction.....got a feeling.

[monte1111 in reply to Jbooml]

I See they are just now starting Phase one trials for Protac. Looked like that was supposed to be last year. Guess they are just not in the hurry that we are for new solutions. My Xtandi marathon must some day come to an end. And the Protac may not even work - another story Of Mice and Men.

[Jbooml in reply to monte1111]

I'm pleased with the target but i take it its not the first time the AR has been sighted....nevermind...we must stay positive that this or a more tailored version will hit bulls eye.

[NPfisherman]

Agree with you....and you will see higher success rates I believe as drugs that are sensitizers like NT-219 or RRX-001 are added in to treatment plans... or the drugs that can prevent/inhibit the wild/mutated AR become available ....it is a huge complex puzzle with DNA mutations, intracellular and extracellular environments that are slowly being figured out.... hanging around for the answers is the issue...

Fish

[NPfisherman]

Prayer said for you, my man...

Fish

[Litlerny]

Bummer, dude! I have the ATM mutation.

[Balsam01]

I agree with NPFisherman, my spiritual thoughts are with you.

[podsart]

Good luck

[cfrees1]

I have the ATM mutation as well. This is unfortunate news, but more knowledge is better than no knowledge.

[Stegosaurus37]

I have the ATM mutation and have been in TRITON II (rucaparib) clinical trial. My 4 week PSA showed increase, 6 week small decrease. My 8 week bone and CT scan plus PSA is next Monday. Hope the PARP inhibitor rucaparib works better than olaparib for me.