AUA2023: REFLECTIONS The Role of Poly (Adenosine Diphosphate-ribose) Polymerase Inhibitors in Advanced Prostate Cancer
By: Ashley E. Ross, MD, PhD, Northwestern Feinberg School of Medicine, Chicago, Illinois; Kristen R. Scarpato, MD, MPH, Vanderbilt University Medical Center, Nashville, Tennessee; Nancy B. Davis, MD, Vanderbilt University Medical Center, Nashville, Tennessee | Posted on: 20 Jul 2023
At this year’s AUA, Dr Ashley Ross, urologist at the Northwestern Feinberg School of Medicine, moderated a symposium on poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors (PARPi) with his colleagues, urologist Dr Kristin Scarpato and medical oncologist Dr Nancy Davis, from Vanderbilt University Medical Center. The symposium coincided with the AUA/Society of Urologic Oncology (SUO) amended 2023 advanced prostate cancer guidelines that highlighted genetic testing and the role of PARPi in castration-resistant metastatic disease.
PARPi have been utilized in other malignancies such as breast and ovarian cancer for some time but only recently have been approved and guideline-endorsed as a treatment in selected men with metastatic castration-resistant prostate cancer (mCRPC).1 PARPi are-oral antineoplastics that inhibit PARP proteins that function in DNA repair. Inhibiting these proteins, particularly in cancers where homologous recombination repair is already compromised (ie, those lacking BRCA1 or BRCA2 function), can lead to catastrophic genomic instability and cell death.2 Homologous recombination repair deficiency is present in a significant minority of men with metastatic prostate cancer (roughly 12% at the germline level) and the AUA/SUO guidelines recommend germline genetic testing in all men with advanced prostate cancer and somatic testing in men with mCRPC.3
PARPi tested in late-phase clinical trials in prostate cancer include olaparib, rucaparib, niraparib, and talazoparib, with olaparib and rucaparib currently having Food and Drug Administration approval. PARPi in prostate cancer have been primarily reported on in mCRPC both as single-agent therapeutics (along with androgen deprivation) and in combinatorial regimens with androgen deprivation and androgen receptor signaling inhibitors (ie, abiraterone and enzalutamide). The PROfound and TRITON trials4 investigated PARPi in men with mCRPC who had previously been treated with enzalutamide or abiraterone and with (PROfound, TRITON2)5 or without (PROfound, TRITON3)6 previous chemotherapy. These trials showed significant progression-free survival benefits for men with mCRPC who were biomarker-selected for harboring likely pathogenic or pathogenic mutations in BRCA1 or BRCA2. The updated AUA guidelines suggest that clinicians should offer PARPi to men with mCRPC and deleterious mutations in homologous recombination repair genes following prior therapy with androgen receptor signaling or chemotherapy.
Androgen deprivation therapy can down-regulate cellular DNA repair and there may be added benefit to combining PARPi with androgen signaling agents. In an effort to expand the cohort of men with mCRPC who may benefit from PARPi, investigators have studied combining PARPi with abiraterone or enzalutamide in the MAGNITUDE,7 PROpel, and TALAPRO28 trials. These trials also included men without homologous recombination repair deficiencies.9 The greatest benefit for PARPi combination was found in BRCA-mutated patients. Recently the Oncologic Drugs Advisory Committee to the Food and Drug Administration suggested that PARPi in combination use should be limited to those men with BRCA mutations.
PARPi as a class share certain side effects, particularly anemia and gastrointestinal toxicity, and use can potentially, albeit rarely, lead to myeloproliferative disorders. Understanding PARPi toxicity and which individuals are more or less susceptible remains a needed area of further research. Some other areas of future research highlighted by the panel included understanding the role of PARPi in BRCA-mutated metastatic hormone-sensitive prostate cancer and exploring biomarkers that might better select non-BRCA–mutated men with deleterious gene mutations in DNA repair genes for PARPi therapy.
The symposium concluded with the panel reinforcing key points to the audience. These included that (1) germline (if not performed earlier) and somatic DNA mutation testing should be a standard for patients with mCRPC, (2) over 10% of men with metastatic prostate cancer will have such mutations in their germline and even more in their somatic DNA, and (3) based on their favorable effect on progression-free survival, PARPi are now Food and Drug Administration–approved and AUA/SUO guideline–endorsed as a therapeutic option for men with mCRPC who have received prior therapies and harbor deleterious or likely deleterious homologous recombination repair gene mutations.
- Lowrance W, Dreicer R, Jarrard DF, et al. Updates to advanced prostate cancer: AUA/SUO Guideline (2023). J Urol. 2023;209(6):1082-1090.
- Lord CJ, Ashworth A. PARP inhibitors: synthetic lethality in the clinic. Science. 2017;355(6330):1152-1158.
- Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443-453.
- Hussain M, Mateo J, Fizazi K, et al. Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. 2020;383(24):2345-2357.
- Abida W, Patnaik A, Campbell D, et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol. 2020;38(32):3763-3772.
- Fizazi K, Piulats JM, Reaume MN, et al. Rucaparib or physician’s choice in metastatic prostate cancer. N Engl J Med. 2023;388(8):719-732.
- Chi KN, Rathkopf D, Smith MR, et al. Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. J Clin Oncol. 2023;JCO2201649.
- Agarwal N, Azad A, Carles J, et al. TALAPRO-2: phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clinl Oncol. 2023;41(6_suppl):LBA17.
- Clark NW, Armstrong AJ, Thiery-Vuillemin A, et al. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evid. 2022;1(9).