History and Clinical Applications of PARP Inhibitor Therapy for Prostate Cancer

Poly (ADP-ribose) polymerase, also known as PARP, is a family of proteins described as early as the 1980s to be involved in repair pathways used to recover DNA from damage.1 In this review, we seek to summarize the biochemical theory underlying the role of in advanced prostate cancer, review major breakthrough evidence that led to the current guidelines advocating for PARP therapy, and explore clinical trials surrounding PARP inhibitors in advanced prostate cancer.

In the United States alone, an estimated 270,000 cases of prostate cancer are diagnosed annually, and approximately 35,000 men will experience mortality resulting from their condition. Most of these cases of mortality can be attributed to advanced disease, specifically metastatic castration-resistant prostate cancer (mCRPC).

To make matters worse, there has been an increase in the number of patients being diagnosed with de novo metastatic disease upon presentation,2 creating a pressing need for further characterization and improved understanding of the disease process.

Despite the increase in cases and continued high mortality rate, however, the good news is that many new therapeutic options in the advanced prostate cancer sphere have yielded improvements in median overall survival (OS) rates above the historical average of 18 to 24 months. 3 The role of PARP inhibitor therapy, as well as other mutation-focused therapies, stands out for emphasis, as an estimated 1 of 4 patients with mCRPC have a germline mutation in BRCA2, BRCA1, ATM, or CHEK2, with BRCA2 being the most frequently noted.4  The evolving use of PARP inhibitor therapy, both independently and in conjunction with other novel therapeutics, may play an important role in further improving outcomes for this vulnerable patient population.

How PARP Inhibitors Work

Several enzyme complexes assist with preventing development of malignancy in cells with damage at the DNA level. The PARP inhibitor family consists of 17 known peptides that play a critical role in DNA damage repair; PARP-1 helps to recruit enzymes in the single-stranded break repair systems.4 These systems—which exist to repair single-strand damage, such as single base deletion, insertions, or mismatches—include mismatch repair enzymes, base excision repair enzymes, and nucleotide excision repair.4

Inhibition of the PARP-1 complex means that single-strand damage cannot be repaired. Cells containing single-strand damage will eventually undergo replication resulting in double-strand DNA damage (also known as double-strand breaks), which requires a different set of DNA repair machinery. Mechanisms for repair of double-strand breaks include homologous recombination repair as well as nonhomologous end joining,4 with the former using the second chromosome as a reference for highly reliable repairs. The process of homologous recombination requires a multitude of important proteins—including ATM, CHK2, BRCA1, PALB2, and BRCA2—and ultimately results in double-strand repair via transfer of the second chromosome data to the damaged segment.4

This basic understanding of the molecular biology of DNA damage repair allows us to comprehend the concept of “synthetic lethality.” Administration of PARP inhibitors (of which the most well-known is olaparib, but including others, such as rucaparib) results in inhibition of single-strand DNA damage repair. When this process is initiated in cells that are deficient in homologous recombination–mediated double-strand DNA repair, the outcome is cell death.4

In addition to preventing single-strand break repair, PARP inhibitors also induce “trapping lethality,” a concept in which the DNA-PARP complex blocks DNA replication4 and requires resolution via homologous recombination repair—which is not available in cells of patients with germline mutations in such genes. This subsequently enhances the targeted cytotoxic effect against cells lacking homologous recombination repair genes (eg, BRCA1, BRCA2, PALB2).4

Olaparib and Rucaparib for Prostate Cancer

The PARP inhibitors that have progressed the furthest in research and clinical application are olaparib and rucaparib. The TOPARP-A trial5 was a phase 2 clinical trial investigating the utility of olaparib in patients with mCRPC with progression after chemotherapy; the primary outcome of the trial was overall response rate (ORR). Of the 50 patients enrolled in the trial, 16 had detectable mutations in genes such as BRCA2, ATM, and BRCA1. The authors reported that these patients had improved rates of median progression-free survival (mPFS; 9.8 vs 2.7 months) and OS (13.8 vs 7.5 months) compared to patients without such mutations. They also reported an ORR of 33%.

In TOPARP-B, another phase 2 clinical trial, investigators used next-generation sequencing to select patients with mCRPC who received prior chemotherapy to examine the dose and therapeutic response relationship. The authors isolated 161 of 592 patients with double-strand DNA repair mutations and randomized them to olaparib 400 mg twice daily or 300 mg twice daily, with complete response rate as the primary outcome. Results slightly favored the higher dose group, but this was not statistically significant; however, patients with BRCA1 and BRCA2 mutations were noted to have the longest mPFS rate.6

The results of the TOPARP-A/-B trials led to the PROfound trial.7 In that phase 3 clinical trial, investigators randomized patients with mCRPC with progression after androgen-targeted therapy (abiraterone or enzalutamide) and with 1 homologous recombination mutation, such as BRCA1/2, to either olaparib (olaparib arm) or alternative androgen-targeted therapy (control arm). A total of 387 patients were enrolled, and patients with BRCA1/2 or ATM mutations were placed into a subgroup (cohort A) separate from those with the other mutations (cohort B). The ORR favored patients in the olaparib arm compared with the control arm (33% vs 2%), and patients in the olaparib arm also had prolonged median imaging-based rate of progression-free survival (PFS; hazard ratio, 0.49).7 Moreover, patients in olaparib group cohort A (BRCA1/2 or ATM mutations) demonstrated a significant improvement in PFS compared with those in cohort B (7.4 vs 3.6 months).

These findings led the US Food and Drug Administration to approve use of olaparib in mCRPC patients with homologous recombination repair mutations with progression after prior enzalutamide or abiraterone treatment.8 Later in 2020, the PROfound investigators reported OS data demonstrating a survival benefit for olaparib use in cohort A compared with cohort B (19.1 vs 14.7 months). In terms of safety, olaparib is generally well-tolerated with grade >3 side effects primarily being anemia, fatigue, and leukopenia.4

Rucaparib has been analyzed in the phase 2 TRITON2 clinical trial of treatment of 115 patients with mCRPC who had a genetic mutation in homologous recombination genes and experienced disease progression on chemotherapy and androgen-targeted therapy. Patients were subdivided into groups with BRCA1/2 or ATM mutations, with or without nodal disease, and patients with other mutations without nodal disease. The authors reported promising results, with prostate-specific antigen responses of >50% in 53.6% of the patients with BRCA mutations and an objective response rate of 40%. The TRITON3 phase 3 clinical trial investigating use of rucaparib for treatment of mCRPC patients with BRCA1/2 and ATM mutations who had no prior chemotherapy exposure is ongoing.9

Conclusions on PARP Inhibitors

Guidelines on when to utilize genetic testing allow clinicians to more accurately characterize mCRPC, as well as the potential benefits eligible patients may gain from PARP inhibitor therapy. The National Comprehensive Cancer Networkâ (NCCNâ) recommends germline genetic testing for all patients with high risk, very high risk, locally advanced, and metastatic prostate cancer.10 Additionally, NCCNâ also recommends testing if patients have a strong family history of prostate cancer, a history of BRCA1/2 mutations, or Lynch syndrome, and in patients with prostate cancer who have Ashkenazi ancestry.

In conclusion, mCRPC is the first known malignancy in which use of PARP-inhibition therapy has demonstrated an OS benefit in patients in a randomized setting. Use of this treatment should be considered for all patients with a documented BRCA1/2 mutation.

Akhil Abraham Saji, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include urology education and machine learning applications in urologic care. He is a founding and current member of the EMPIRE Urology New York AUA section team.

References

  1. Benjamin RC, Gill DM. ADP-ribosylation in mammalian cell ghosts: dependence of poly(ADP-ribose) synthesis on strand breakage in DNA. J Biol Chem. 1980;255(21):10493-10501.
  2. Kelly SP, Anderson WF, Rosenberg PS, Cook MB. Past, current, and future incidence rates and burden of metastatic prostate cancer in the United States. Eur Urol Focus. 2018;4(1):121-127. doi:10.1016/j.euf.2017.10.014
  3. Moreira DM, Howard LE, Sourbeer KN, et al. Predicting Time From Metastasis to Overall Survival in Castration-Resistant Prostate Cancer: Results From SEARCH. Clin Genitourin Cancer. 2017;15(1):60-66.e2. doi:10.1016/j.clgc.2016.08.018
  4. Teyssonneau D, Margot H, Cabart M, et al. Prostate cancer and PARP inhibitors: progress and challenges. J Hematol Oncol. 2021;14(1):51. doi:10.1186/s13045-021-01061-x
  5. Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697-1708. doi:10.1056/NEJMoa1506859
  6. Mateo J, Porta N, Bianchini D, et al. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21(1):162-174. doi:10.1016/S1470-2045(19)30684-9
  7. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091-2102. doi:10.1056/NEJMoa1911440
  8. US Food and Drug Administration. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. May 20, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer
  9. Chowdhury S, Abida W, Arija JA, et al. The TRITON clinical trial programme: Evaluation of the PARP inhibitor rucaparib in patients (Pts) with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination deficiency (HRD). Ann Oncol.2017;28(suppl 5):291; abstract 836TiP. doi:10.1093/annonc/mdx370
  10. Schaeffer E, Srinivas S, Antonarakis ES, et al. NCCN Guidelines Insights: Prostate Cancer, Version 1.2021. J Natl Compr Canc Netw. 2021;19(2):134-143. doi:10.6004/jnccn.2021.0008