Prostate cancer has lagged behind other solid tumors with regard to molecularly targeted therapy and precision medicine, with no targeted therapies approved specifically in prostate cancer, but that has changed with the recent approval in 2020 of a PARP (poly [ADP-ribose] polymerase) inhibitor for men with metastatic castration resistant prostate cancer with germline or somatic homologous recombination repair mutations. At the 2020 Chemotherapy Foundation Symposium, Maha Hussain, MD, FACP, FASCO, Deputy Director of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, updated listeners on PARP inhibition in prostate cancer.1
“We are rocking and rolling with PARP inhibitors [for prostate cancer]; there are several phase II and III trials evaluating them in different prostate cancer settings as single agents or in combinations,” Dr. Hussain told the audience.
“We are rocking and rolling with PARP inhibitors [for prostate cancer]; there are several phase II and III trials evaluating them in different prostate cancer settings as single agents or in combinations.”— Maha Hussain, MD, FACP, FASCO
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As background, she explained that metastatic castration-resistant prostate cancer is the terminal stage of the disease. Preliminary data showed that PARP inhibitors interact with androgen signaling, and castration-resistant tumor cells exhibit increased PARP1 activity. More than 20% of metastatic castration-resistant prostate tumors harbor DNA repair pathway aberrations, such as BRCA1, BRCA2, ATM, and others. Early data suggested that PARP inhibition with olaparib achieved higher response rates in patients with metastatic castration resistant prostate cancer with homologous recombinant repair (HRR) mutations.
“The totality of these data led to conducting the first biomarker-preselected randomized phase III clinical trial evaluating the role of [the PARP inhibitor] olaparib vs enzalutamide or abiraterone/prednisone in metastatic castration-resistant prostate cancer patients whose tumors have an HRR mutation and who have had disease progression on prior abiraterone or enzalutamide therapy for metastatic castration-resistant therapy,” Dr. Hussain told listeners.
PROfound Trial: Details and Results
The PROfound study enrolled men with metastatic castration-resistant prostate cancer and at least one genetic aberration with a direct or indirect role in HRR.2 Prior to enrollment, patients had to have experienced disease progression on enzalutamide or abiraterone acetate/prednisone. Patients were assigned into two cohorts based on the Foundation One assay: cohort A included 245 patients with BRCA1-, BRCA2-, or ATM-mutated metastatic castration-resistant prostate cancer. Cohort B included 12 other genetic alterations (BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L; n = 145). Both cohorts were randomly assigned 2:1 in an open-label design to receive olaparib at 300 mg twice daily or physician’s choice of either enzalutamide or abiraterone/prednisone (control arm). Crossover to olaparib was allowed at disease progression.
The primary endpoint was image-based progression-free survival in cohort A by independent central review. Secondary endpoints were imaging-based progression-free survival in both cohorts, confirmed radiographic overall response rate in cohort A, and time to pain progression and overall survival in cohort A.
Imaging-based progression-free survival (primary endpoint) was significantly better with olaparib vs physician’s choice in cohort A (median of 7.4 months vs 3.6 months, respectively [P < .001]); and 5.8 months vs 3.5 months (hazard ratio [HR] = 0.4, P < .001) in cohorts A and B.
At 6 months, the time to pain progression based on the worst pain score on the Brief Pain Inventory–Short Form was significantly longer for those treated with olaparib in cohort A (HR = 0.44) and for cohorts A and B (HR = 0.64) treated with olaparib.
A subsequent analysis showed that median overall survival was 19.1 months with olaparib vs 14.7 months with physician’s choice in cohort A (P = .02). The difference between treatment arms was even greater in a crossover-adjusted survival analysis for both cohort A and the overall study population.3
KEY POINTS
- Targeted therapies have been approved in prostate cancer for the first time.
- PARP inhibitors have been found to be effective in treating metastatic castration-resistant prostate cancer in patients with BRCA mutations (olaparib, rucaparib) and non-BRCA mutations (olaparib); olaparib has been shown to improve overall survival.
- PARP inhibitors appear to be effective in a wider range of patients than initially assumed, but the magnitude of benefit varies.
- Ongoing studies are evaluating PARP inhibitors in different disease settings, in combination with other therapies including androgen receptor–directed therapies and checkpoint inhibitors.
The investigators performed a gene-by-gene analysis of overall survival in patients enrolled in the PROfound trial with a single mutation. They found evidence of clinical activity with olaparib in cancers with several non-BRCA genetic alterations as well. They also conducted a post hoc analysis to assess overall survival with olaparib in selected genes based on prior taxane exposure.
“This gene-level analysis is exploratory and post hoc, and it is confounded by multiple factors,” Dr. Hussain cautioned. However “It is clinically important because patients and oncologists ask if patients will respond if they have non-BRCA gene mutations or is it better to start with chemotherapy or PARP inhibitors if they have a qualifying mutation, and certainly the data can inform future clinical trials design. In the BRCA setting, the post hoc exploratory analysis showed a benefit (for olaparib) in patients irrespective of prior taxane chemotherapy, though the magnitude was better in those with no prior taxane therapy. The data suggested that patients with CDK12 have a better chance for response if they have not been treated with a taxane, whereas those with ATM seem to do better if they have received prior taxane,” she added.
Olaparib was well tolerated in the PROfound trial, with no new adverse event signal, and with anemia being the most frequent adverse event.
TRITON2 Study
The TRITON2 trial evaluated another PARP inhibitor, rucaparib. The first report was in 98 patients with metastatic castration-resistant prostate cancer and alterations in BRCA (n = 98).4 In this phase II trial, there were radiographic and PSA responses and a median radiographic progression-free survival of 9 months.
A second report from TRITON2 focused on patients with metastatic castration-resistant prostate cancer with non-BRCA DNA repair (DDR) alterations including CDK12, CHEK2, ATM, and other non-BRCA DDR genes.5 In this group of patients, there was much lower/limited number of radiographic and prostate-specific antigen responses with rucaparib.
Currently, rucaparib has accelerated approval from the U.S. Food and Drug Administration (FDA) only in previously treated BRCA-positive metastatic castration-resistant prostate cancer. However, olaparib is approved for metastatic castration-resistant prostate cancer with deleterious germline or somatic HRR mutations (14-gene panel; the FDA removed the PPP2R2A mutation from the approved HRR panel), as assessed by the Foundation One companion diagnostic test.
Tissue Collection and Next-Generation Sequencing
Tissue was collected in more than 4,000 patients enrolled in the PROfound trial.6 The success rate for next-generation sequencing of these tissue samples was overall 69%.
Several lessons emerged from the next-generation sequencing study. The success rate of next-generation sequencing was higher in newly collected tissue samples than in archival samples (archival samples less than 5 years old had better yield); in more recently collected samples; and in samples from metastatic disease. The method of collection and processing is critical to success, favoring multiple samples from core-needle biopsy and embedding into one formalin-fixed paraffin-embedded block to maximize the likelihood of successful pathology review, and it is critical to avoid strong acid decalcification of bone biopsies. “For newly collected bone samples, we recommend decalcification should not be performed,” stated Dr. Hussain.
Dr. Hussain continued: “Data from a phase II clinical trial7 suggested an unexpected association of HRR mutations with response to androgen receptor–targeted therapy with or without PARP1 in the front-line setting of metastatic castration-resistant prostate cancer—an observation that was supported by subsequent data reported from Johns Hopkins investigators based on HRR germline mutations.” This observation has led to a phase II randomized trial to evaluate whether patients with metastatic castration-resistant prostate cancer with HRR mutations in BRCA1/2 or ATM will respond better to olaparib vs abiraterone/prednisone vs combination olaparib plus abiraterone/prednisone in the front-line metastatic castration-resistant prostate cancer setting. This study is almost three-quarters accrued.
Another randomized placebo-controlled study suggested that olaparib combined with abiraterone/prednisone is associated with better radiographic progression-free survival compared to abiraterone/prednisone alone in metastatic castration-resistant prostate cancer irrespective of HRR genes.8
“These emerging data are intriguing and led to the PROpel trial, a phase III trial evaluating abiraterone plus olaparib as first-line therapy in metastatic castration-resistant prostate cancer,” stated Dr. Hussain.
There are several other phase III and phase II clinical trials evaluating PARP inhibitors in different prostate cancer settings including combination therapy with checkpoint inhibitors and other drugs.
“One thing we have learned is prostate cancer is a complex disease. It is characterized by interpatient and intrapatient heterogeneity, and therapy will need to become more individualized.”— Maha Hussain, MD
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“One thing we have learned is that prostate cancer is a complex cancer,” noted Dr. Hussain. “Metastatic prostate cancer has marked inter- and intrapatient heterogeneity; therefore, therapy development must focus on the totality of disease biology and treatment personalization. PARP is a promising therapeutic target in this disease. PARP inhibitors have ushered in the ‘Era of Precision Medicine in Prostate Cancer.’”
Issues to be considered moving forward include the best timing and sequencing of PARP inhibitors in relation to other treatments, resistance mechanisms, use of PARP inhibitors earlier in the course of disease in selected patients with HRR mutations, long-term side effects, and the optimal duration of therapy.
DISCLOSURE: Dr. Hussain has received honoraria from Astellas Pharma, AstraZeneca/Egypt, AstraZeneca/Singapore, Genentech, MLI PeerView, OncLive, PER LLC, Phillips Gilmore Oncology, Projects in Knowledge, Research to Practice, RTP, Sanofi/Genzyme, and UroToday; has served as a consultant or advisor to AstraZeneca, Bayer, BMS, Daiichi Sankyo, Genentech, and Pfizer; has received institutional research funding from AstraZeneca, Bayer, Genentech, PCCTC, Pfizer, and Arvinas; holds patents or other intellectual property in dual inhibition of MET and VEGF for the treatment of castration-resistant prostate cancer and osteoblastic bone metastases, method of treating cancer, and systems and methods for tissue imaging; has been reimbursed for travel, accommodations, or other expenses by Astellas Pharma, Bayer, Genentech/Roche, and Pfizer.
REFERENCES
1. Hussain M: Optimizing the use of PARP inhibition for prostate cancer. 2020 Chemotherapy Foundation Symposium. Presented November 4, 2020.
2. de Bono J, Mateo J, Fizazi K, et al: Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med 382:2091-2102, 2020.
3. Hussain M, Mateo J, Fizazi K, et al: Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. September 20, 2020 (early release online).
4. 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. November 10, 2020 (early release online).
5. Abida W, Campbell D, Patnaik A, et al: Non-BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in metastatic castration-resistant prostate cancer: Analysis from the phase II TRITON2 study. Clin Cancer Res 26:2487-2496, 2020.
6. Hussain MHA, Mateo J, Sandhu SK, et al: Next-generation sequencing of tumor tissue from >4000 men with metastatic castration-resistant prostate cancer: The PROfound phase III study experience. 2020 Genitourinary Cancers Symposium. Abstract 195. Presented February 13, 2020.
7. Hussain M, Daignault-Newton S, Twardowski PW, et al: Targeting androgen receptor and DNA repair in metastatic castration-resistant prostate cancer: Results from NCI 9012. J Clin Oncol 36:991-999, 2018.
8. Clarke N, Wiechno P, Alekseev B, et al: Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 19:975-986, 2018.
