Washington, DC (UroToday.com) To conclude the Society of Urologic Oncology (SUO) 2019 advanced prostate cancer session, Dr. Joaquin Mateo provided an overview of PARP inhibitors in prostate cancer. Metastatic prostate cancer remains a lethal disease, however, abiraterone, enzalutamide, and radium-223 have prolonged survival. Currently, the one-size-fits-all approach remains the standard of care in metastatic castration-resistant prostate cancer (mCRPC). As we learn more about mCRPC, Dr. Mateo notes that we identify potential additional targets for tailored treatment.
The PARP inhibitor story in prostate cancer starts with the TOPARP trial, which Dr. Mateo was one of the lead investigators. The TOPARP-A trial demonstrated that patients with mCRPC unresponsive to standard therapy who had DNA-repair defects responded to the PARP inhibitor olaparib.1 Specifically, 16 of 49 patients (33%) had a response to olaparib, with 12 patients remaining on treatment for >6 months.
TOPARP-B, was a phase II trial for patients with mCRPC preselected for putatively pathogenic DNA damage repair alterations.2 Because TOPARP-A used a 400 mg olaparib dose and patients with breast cancer typically use a 300 mg dose, patients in TOPARP-B were randomized 1:1 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, confirmed after 4-weeks. There were 98 patients (median age 67.6 years) randomized, with 92 patients treated and evaluable for the primary endpoint. The overall RR was 54% (95%CI 39-69%), meeting threshold for primary endpoint) in the 400 mg cohort and 39% (95%CI 24-54%) in the 300 mg cohort. Over a median follow-up of 17.6 months, the overall median PFS (mPFS) was 5.4 months. Subgroup analyses per altered gene identified indicated response rates for BRCA1/2 of 83% (mPFS 8.1 months), PALB2 57% (mPFS 5.3 months), ATM 37% (mPFS 6.1 months), CDK12 25% (mPFS 2.9 months), and others [ATRX, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCM, RAD50, WRN] 20% (mPFS 2.8 months). The highest PSA50% response rates were observed in the BRCA1/2 (77%) and PALB2 (67%) subgroups.
The TRITON2 trial is an ongoing phase 2 study evaluating rucaparib 600 mg BID in patients with mCRPC and a deleterious germline or somatic alteration in BRCA1, BRCA2, ATM, CDK12, or other prespecified DDR gene. This study was initially presented at ESMO 2019 in Barcelona, Spain. Eligible patients have progressed on 1–2 lines of androgen receptor–directed therapy and one line of taxane-based chemotherapy for mCRPC. As of February 2019, 190 patients had received rucaparib with a median follow-up of 13.1 months (range 4.1-28.5 months): 98 with a BRCA1/2 alteration, 57 with an ATM alteration, 14 with a CDK12 alteration, 7 with a CHEK2 alteration, and 14 with another DDR gene alteration. Among the patients with a BRCA mutation and measurable disease at baseline, 43.9% had a confirmed ORR, and responses were durable with the majority lasting >24 weeks. ORR was poor for the other patients: 9.5% for ATM, and 0% for both CDK12 and CHEK2. Among patients with BRCA mutations, 52.0% had a confirmed PSA response (>50% decrease), with a median duration of PSA response of 5.5 months.
Dr. Mateo then highlighted the PROfound study, also initially presented at ESMO 2019. PROfound was a phase III trial of olaparib versus enzalutamide or abiraterone for mCRPC with homologous recombination repair gene alterations. Cohort A included patients with alterations in BRCA1, BRCA2 or ATM, while Cohort B patients included any one of 12 other homologous recombination repair alterations (BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or RAD54L). Patients were randomized 2:1 to olaparib (300 mg bid) or physician’s choice of enzalutamide (160 mg/day) or abiraterone (1000 mg/day + prednisone 5 mg BID). The primary endpoint was radiographic progression-free survival (rPFS) in Cohort A.
There were 4,425 men screened for PROfound, leading to 245 randomized to Cohort A, and 142 to Cohort B (of which 65.6% had prior taxane chemotherapy). Olaparib was associated with improved rPFS compared to enzalutamide/abiraterone among patients in Cohort A (HR 0.34, 95% CI 0.25-0.47), which was consistent across the majority of subgroups assessed. A key secondary endpoint was time to pain progression in Cohort A, which also favored olaparib (HR 0.44, 95% CI 0.22-0.91). The interim results for OS demonstrated improved survival among patients in Cohort A (HR 0.64, 95% CI 0.43-0.97).
Implementing PARP inhibitors in clinical practice requires knowledge of side effects associated with a new group of medications. Hematologic toxicity is common: anemia (50%), thrombocytopenia (10-20%), and less commonly neutropenia (<5%). According to Dr. Mateo, there will be 20% of patients that will develop severe anemia, requiring dose interruptions/reductions. Additionally, there will be a subset of patients that develop fatigue, nausea/vomiting, and a small subset of patients that will develop cardiovascular events.
Dr. Mateo concluded with several take-home messages from his high-level review of PARP inhibitors in prostate cancer:
- PARP inhibitors are active in mCRPC with certain mutations, such as BRCA2 loss, validating the concept of this class of treatment
- This will likely represent the first precision treatment (genomically driven selection) treatment for prostate cancer
- Combination therapies may extend the benefit and may expand the target population
- Genomic testing is to be implemented into routine care, ideally as part of the diagnostic process
- There are several challenges to address: stratification to personalization, establishing what test/sample to use, and handling intra-patient heterogeneity
Presented by: Joaquin Mateo, MD, Ph.D., Vall d’Hebron Institut d’Oncologia, Barcelona, Spain
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 20th Annual Meeting of the Society of Urologic Oncology (SUO), December 4 - 6, 2019, Washington, DC
- 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.
- Mateo J, Porta N, McGovern U, et al. 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. J Clin Oncol. 2019;37(15_suppl):5005.