PARP Inhibitors in Prostate Cancer - Anitcancer Research - Feb 2021 - Review Article

[cujoe]

In the spirit of our Chief Science Officer here at FPC, Señor Don Pescado, I offer up this short, concise summary article on the current status of the use of PARP inhibitors (Rucaparib, Olaparib, and Niraparib) in mCRPC. These drugs are currently only appropriate for patients with specific gene mutations. (BRCA1/BRCA2 and PTEN.)

From the Review Article:

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PARP Inhibitors and Prostate Cancer

Multiple studies have reported a strong association of frequent deleterious germline mutations in DNA Damage Repair (DDR) genes with advanced PCa, which defines the basis for the use of PARP inhibitors to treat this disease (9). DDR alterations are present in nearly 23% of all metastatic castration-resistant prostate cancer (mCRPC) (19). These mutations often involve the BRCA1/BRCA2 genes, as well as the PTEN gene (20, 21). These genes are involved in DNA damage repair as well as in tumor suppression (22). They are also crucial to the homologous recombination repair (HRR) pathway (23). Due to a reduced ability to repair DNA and regulate cell growth, patients with inherited BRCA2 mutations are five times more likely to be diagnosed with prostate cancer than the general population (24). BRCA mutations are also more frequently associated with prostate cancer of a high grade, high stage, with increased nodal involvement, and metastasis (20). Additionally, 20% of all prostate cancers involve deficient PTEN expression (21). Since BRCA plays a vital role in homologous recombination, researchers believe that BRCA mutant cells depend more heavily on the PARP-associated repair pathway (9). Various experiments have even shown evidence for the upregulation of PARP activity in certain types of cancer cells (10). This has been the rationale behind many recent clinical trials (9).

Since tumor cells with DDR gene mutations rely more heavily on PARP to correct DNA breaks and mismatches, the inhibition of PARP should make these cancerous cells more susceptible to chemotherapy and other treatment options (14). Further, PARP inhibition might even be potent as a single anti-cancer agent. Studies have shown that HRR defective cells are hypersensitive to PARP inhibition alone (25). Recent results have also shown that PARP inhibition in BRCA deficient patients with ovarian cancer led to significantly less cancer progression and mortality (26). These results have encouraged further research into PARP inhibition for PCa therapy.

In May 2020, the Food and Drug Administration (FDA) officially approved the first two PARP inhibitors, Rucaparib and Olaparib, for the treatment of prostate cancer (8). Table I highlights the key developments of the different PARP Inhibitors in the treatment of PCa.

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A discussion of each drug's current regulatory and use status along with a brief discussion of future research directions.

PARP Inhibitors in Prostate Cancer

KABIR GREWAL, KAYANAAT GREWAL and IMAD A. TABBARA

Anticancer Research February 2021, 41 (2) 551-556; DOI: doi.org/10.21873/anticanres...

ar.iiarjournals.org/content...

Importantly, here is an earlier MedPage Today interview with Dr. Michael Schweizer about the use of PARP inhibitors in patients without targeted genetic mutations/defects. Also included are links to the study and "expert commentary about the clinical implications" of the approvals of rucaparib and olaparib in mCRPCa last year. (Note that some of this information has been posted previously.)

Michael Schweizer, MD, on PARP Inhibition in Prostate Cancer With Non-BRCA Mutations— Despite approval, therapy may not be effective in these patients

by Jeff Minerd, Contributing Writer, MedPage Today January 6, 2021

medpagetoday.com/asco/non-p...

Expert commentary is here:

PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer– Some words of caution by Peter E. Lonergan, MD, FRCS (Urol) January 20, 2021

And the full ASCO Journal of Clinical Oncology is here:

ascopubs.org/doi/full/10.12...

To put all this in context, Don Pscado (aka NPfisherman) posted this video with Sumit Subudhi, M.D., Ph.D., that discusses them within the context of other Immunotherapy treatments currently in research and in clinical practice. That post is here:

healthunlocked.com/fight-pr...

Only time will tell if these drugs are widely effective when appropriately used, but their approvals for our patient community supports the need for all patients to have some form of genetic testing done at an appropriate time in their disease history.

So, while we wait for the science on PARP inhibitors to be long-term validated, Get Vaccinated and Stay Safe,

K9 terror

[cesces]

Does anyone have any opinions as to when, and under what circumstances, you might want to not use a parp inhibitor?

[NPfisherman]

I look for researchers to use combos of a CPI with a PARP, other meds with PARPS, and get a little more bang for the buck out of PARPs ... Great article....thanks for posting...

Fish