(UroToday.com) The American Urological Association (AUA) annual meeting’s evolving landscape of advanced prostate cancer treatment session included a talk by Dr. Deborah Kaye discussing the role of immunotherapy and PARP inhibitors. Dr. Kaye started by highlighting that there are currently numerous options for systemic treatment of metastatic castration-resistant prostate cancer (mCRPC). As follows is a summary of the mCRPC first and second line options:
However, even with a plethora of options, there are still patients resistant to treatment. Thus, novel mechanisms are needed to target resistance, given that resistance mechanisms are thought to spread through metastasis-to-metastasis seeding. Additionally, similar resistance patterns are observed in tumors with close geographic proximity, suggesting interclonal cooperatively.
New approvals in the mCRPC setting have focused on the PARP inhibitors. DNA repair gene alterations are common in metastatic prostate cancer, given that among mCRPC patients 23% harbor DNA repair alterations, with the frequency of DNA repair alterations increasing with disease progression. Among men with metastatic prostate cancer, 11.8% have a germline alteration in 16 DNA damage repair genes, with age and family history not influencing mutation frequency.1
Dr. Kaye then discussed several key trials in the landscape of PARP inhibitors in mCRPC patients. The TOPARP trial was an investigator-initiated, open-label, multi-stage phase 2 study with an adaptive design focused on predictive biomarker identification. Part A was a test set of all comers, and TOPARP-A demonstrated that treatment with the PARP inhibitor olaparib was associated with improvements in radiographic progression-free survival and overall survival, specifically among patients with extensively pre-treated mCRPC who had DNA-repair defects:2 16 of 49 patients (33%) had a response to olaparib, with 12 patients remaining on treatment for >6 months.
The PROfound study was a phase III trial of men with mCRPC who had progressed on previous abiraterone acetate or enzalutamide.3 The investigators used the FoundationOne CDx assay to identify alterations in one of 15 pre-specified genes involved in homologous recombination repair (BRCA 1/2, ATM, BRIP1, BARD1, CDK12, CHEK 1/2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L). Cohort A included patients with alterations in BRCA1, BRCA2, or ATM while Cohort B had alterations in any of the other 12 included genes. In both cohorts, patients were randomized 2:1 to olaparib vs. abiraterone or enzalutamide. The primary analysis was based on imaging-based progression free survival (soft-tissue according to RESIST 1.1 and bony according to PCCTWG3 criteria) among patients in Cohort A. There was a significantly improved progression-free survival in patients with mutations of BRCA1, BRCA2, or ATM (HR 0.34, 95% CI 0.25 to 0.47):
Similar results were seen in the combined cohort (HR 0.49, 95% CI 0.38 to 0.63). Adverse events were common in both patients on olaparib (any = 95%, grade ≥ 3 = 51%) and in the control group (any = 88%, grade ≥ 3 = 38%). An updated analysis also showed a survival benefit for olaparib with a median OS of 19.1 months compared to 14.7 months in the control arm in Cohort A (HR 0.69, 95% CI 0.50-0.97):4
The TRITON2 trial5 assessed rucaparib 600 mg BID in patients with mCRPC associated homologous recombination repair gene alterations. For the patients with BRCA1/2 alteration, there was a 43.5% confirmed overall response rate and 54.8% confirmed PSA response rate while patients harboring an ATM and CDK12 alteration did not receive significant benefit. As follows is the best change from baseline for the sum of the target lesions and PSA in evaluable patients:
Patients receiving rucaparib in TRITON2 generally tolerated treatment well, with grade >=3 adverse events notable for anemia (25.2%), thrombocytopenia (9.6%), and asthenia/fatigue (8.7%).
Based on the aforementioned clinical trials assessing PARP inhibitors in mCRPC patients, the FDA provided accelerated approval on May 15, 2020, for rucaparib for the treatment of patients with deleterious BRCA1/2 (germline and/or somatic)-associated mCRPC who have been treated with an androgen receptor-directed therapy and taxane-based chemotherapy. On August 26, 2020, the FDA also approved the FoundationOne Liquid CDx as a companion diagnostic for rucaparib. With regards to olaparib, on May 19, 2020, the FDA approved olaparib for the treatment of patients with pathogenic germline or somatic HRR gene-mutated mCRPC who have progressed following prior treatment with enzalutamide or abiraterone.
Several ongoing studies are noteworthy including the phase 3, double-blind, placebo-controlled PROpel study that is testing PARP inhibitor plus abiraterone as a first-line treatment in genetically unselected mCRPC patients. There are a planned 720 patients to be randomized in a 1:1 fashion. Additionally, the TALAPRO-2 trial is assessing talazoparib plus enzalutamide in mCRPC, comparing rPFS in men treated with talazoparib plus enzalutamide versus enzalutamide plus placebo. The estimated enrolment for this trial is 1,037 patients, with part 1 being an open-label non-randomized safety and PK run-in study to confirm the starting dose, and part 2 being a randomized double-blind placebo-controlled, multinational study. As follows is the study design for TALAPRO-2:
Dr. Kaye then talked briefly about several immunotherapy options in mCRPC patients. Sipuleucel-T is an autologous vaccine processed following peripheral dendritic cell collection via leukapheresis. This is then incubated with GCS-F and PAP protein, followed by reinfusion into the patient (after a 36-44 hour period) in order to generate a PAP-specific CD4+ and CD8+ T cell response. Sipuleucel-T was FDA approved based on the results of the phase III IMPACT clinical trial.6 This trial enrolled 512 patients with mCRPC who had asymptomatic disease/minimally symptomatic with no visceral metastases, randomizing men to three infusions of sipuleucel-T (n=341) or placebo (n=171). The IMPACT trial noted a 4.1-month improvement in OS for those taking sipuleucel-T compared to placebo and a 22% reduction in risk of death. There was no difference between the groups with regards to objective disease progression or PSA response (secondary endpoints). An assessment of safety profile for patients in this study found that the treatment was overall well tolerated with minimal concern for severe adverse events.
A recent analysis from the PROCEED outcomes registry among men with mCRPC treated with sipuleucel-T assessed potential differences in outcomes stratified by race, as well as by baseline PSA value.7 Over a median follow-up of 46 months, overall survival differed between African American (35.3 months) and Caucasian (25.8 months) men with a HR of 0.81 (95% CI 0.68-0.97). In patients with baseline PSA below the median (29.5 ng/mL), the HR was 0.52 (95% CI 0.37-0.72), with a median OS of 54.3 for patients with a PSA below the median versus 33.4 months for a PSA above the median.
Dr. Kaye notes that pembrolizumab is also a potential option for mCRPC patients, receiving FDA approval in a tumor agnostic indication for MSI-high (MSI-H) mutation CRPC patients in 2017. Patient selection is key, with the following estimated germline and somatic mutations for metastatic prostate cancer:
Dr. Kaye concluded her presentation with the following take-home messages:
- PARP inhibitors (rucaparib and olaparib) are FDA approved for the treatment of mCRPC patients with DDR mutations: Rucaparib for BRCA1/2 mutations after an AR targeted agent and taxane, and olaparib for DDR mutations after an AR targeted agent
- Sipuleucel-T remains an option for asymptomatic and minimally symptomatic patients without large visceral disease. Black men and men with PSA <29 may have better responses
- Pembrolizumab is FDA approved for men with MSI high tumors
- The guidelines suggest germline and tumor testing for metastatic disease (DDR mutations and MSI-high status)
Presented by: Deborah R. Kaye, MD, MS, Assistant Professor of Surgery, Division of Urology, Duke University Hospital, Durham, NC
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 American Urological Association, (AUA) Annual Meeting, Fri, Sep 10, 2021 – Mon, Sep 13, 2021.
- 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.
- Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. The New England journal of medicine. 2015;373(18):1697-1708.
- de Bono J, Mateo J, Fizazi K, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 2020 May 28;382(22):2091-2102.
- Hussain M, Mateo J, Fizazi K, et al. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 Dec 10;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 Nov 10;38(32):3763-3772.
- Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010;363(5):411-422.
- Sartor O, Armstrong AJ, Ahaghotu C, et al. Survival of African-American and Caucasian men after sipuleucel-T immunotherapy: Outcomes from the PROCEED registry. Prostate Cancer Prostatic Dis. 2020 Sep;23(3):517-526.