(UroToday.com) The 2023 Society of Urologic Oncology (SUO) annual meeting held in Washington, D.C. between November 28th and December 1st, 2023, was host to a prostate cancer course. Dr. Alan Bryce provided an overview of the use and application of serial next generation sequencing (NGS) in the castrate-resistant prostate cancer disease space. The objective of his presentation was to:
- Discuss the general principles of genetic testing in advanced prostate cancer and the rationales behind serial testing
- Review key points regarding the current approval for PARP inhibitors in metastatic castrate-resistant prostate cancer (mCRPC)
Dr. Bryce began his presentation with a case study, as follows:
- January 2013: A 57-year-old man was found to have a screening PSA level of 5.8 ng/ml. A subsequent biopsy demonstrated Grade Group 1 disease.
- April 2014: His PSA level rose to 12.3 ng/ml. The radical prostatectomy pathology demonstrated Grade Group 3 disease with 2/27 lymph nodes involved with metastatic disease. He was staged as pT3aN1MX. His post-op PSA level decreased to <0.1 ng/ml. Given his pathologic nodal involvement, he was started on androgen deprivation therapy (ADT).
- April 2016: He developed biochemical failure with a PSA level of 0.26 ng/ml. Imaging studies demonstrated no evidence of metastatic disease.
- July 2016: He completed salvage radiation therapy to the prostate bed and received 7425 cGy in 30 total fractions.
- April 2017: PSA continued to rise, now at 23 ng/ml. An Axumin® PET/CT showed enlarging retroperitoneal lymphadenopathy.
- May 2017: Started on Sipuleucel T.
- August 2017: Started on abiraterone acetate, with PSA levels now at 66 ng/ml.
- At this point, genetic testing was performed and demonstrated:
- Germline: No pathogenic Variants
- Somatic of prostatectomy tissue: KMT2D p.G4603fs, TMB 0.8 m/MB, MSI-S
- March 2019: PSA 24 ng/ml increased from nadir of 2.6 ng/ml post-abiraterone initiation. Imaging showed new small volume bone metastases. The patient discontinued abiraterone.
- May 2019: The patient was given docetaxel.
- October 2019: Chemotherapy was discontinued after 8 cycles with evidence of stable disease. His PSA was 95.3 ng/ml. Imaging demonstrated evidence of equivocal progression of his bone metastases.
- Cell-free DNA (cfDNA) testing demonstrated a BRCA2 T3033fs mutation
- December 2019: Progression of bone and lymph node metastases. PSA now 163 ng/ml. The patient was initiated on rucaparib.
Overall, his genetic testing demonstrated:
Germline: No pathogenic variants
Somatic:
- Prostatectomy tissue: KMT2D p.G4603fs, TMB 0.8 m/MB, MSI-S
- cfDNA testing: BRCA2 T3033fs
One important takeaway from this case study is the importance of re-testing. This patient initially had negative germline testing, with subsequent somatic testing demonstrating the presence of a somatic (acquired) BRCA2 mutation, facilitating treatment with rucaparib, a PARP inhibitor. Cancers evolve over time and thus when deciding on whether treatment is indicated, we need to know the status of the cancer at the time of treatment. Furthermore, tests can be wrong or incomplete. Additionally, knowledge is expanding daily, and available tools are improving constantly.
It is clear that the mutational landscape of prostate cancer evolves by disease state. The incidence of the following mutations increases as the disease progresses from a localized to mCRPC state:
- BRCA1: 1% to 2%
- BRCA2: 6% to 10%
- ATM: 2% to 11%
- FANCA: 1% to 7%
Additionally, the tumor mutational burden (TMB) and microsatellite instability – high (MSI-H) increase with disease progression.1
The second important point is that tests can be wrong or incomplete. As summarized in the table below, there is significant discordance between the results of plasma (liquid) and tissue testing in the multiple phase 3 trials of PARP inhibitors in the mCRPC testing. Tissue testing may not always be feasible (no archived prostate tissue or no metastatic sites feasible for biopsy sampling). As such, Dr. Bryce argued that we must attempt to perform both liquid and tissue testing where feasible to maximize testing sensitivity.
Another important factor to consider is the impact of tumor age on NGS results. In an ad hoc analysis of PROfound, an evaluation of NGS tissue test outcomes against pre-analytic parameters was performed to identify key factors influencing NGS result generation. A total of 4,858 tissue samples (based on FoundationOneCDx) from 4,047 patients from the phase III PROfound trial were tested and reported. Of the samples submitted, 83% and 17% were from the primary and metastatic tumors, respectively. Of the primary tumor samples, 96% were archival and 4% were newly obtained. Conversely, among the metastatic tumors, 60% were archival and 33% were newly obtained.
NGS results were obtained in 58% of the total samples. NGS results were generated more frequently from newly obtained, compared with archival samples (64% vs. 57%).
Generation of an NGS result declined with increasing sample age. Sample age < 5 years was shown to predict an increased likelihood of acquiring an NGS result.2
While this may appear obvious, it cannot be understated how quickly knowledge is evolving in this disease space. In addition to already published trials, such as PROpel,3 TALAPRO-2,4 MAGNITUDE,5 TRITON2,6 and PROfound,7 among many others, there are numerous ongoing genetically targeted clinical trials in this disease space, as summarized in the table below.
When considering PARP inhibitors in the mCRPC setting, there are several important points of emphasis:
- Clinicians need to understand the clinical scenarios for combination versus monotherapy
- Clinicians need to understand the differences in the predictive significance of the different homologous recombination repair (HRR) genes
- Clinicians should be prepared to manage the toxicities of therapy, with PARP inhibitors requiring monitoring and close attention.
Currently, the NCCN guidelines recommend considering the use of a PARP inhibitor + androgen receptor pathway inhibitor (ARPI; niraparib + abiraterone, olaparib + abiraterone, or talazoparib + enzalutamide) in select circumstances for mCRPC patients who have either received:
- No prior docetaxel or an ARPI
- Prior docetaxel, but no prior ARPI
For patients who received a prior APRI, but no docetaxel, niraparib + abiraterone, olaparib, and talazoparib + enzalutamide may be considered in select circumstances (need to consider HRR and/or BRCA mutational status).
Conversely, among patients who received both prior docetaxel and an ARPI, clinicians may consider olaparib for HRRm patients and rucaparib for those with a BRCA mutation.
What about FDA approvals of PARP inhibitors for mCRPC patients? Currently, olaparib (PROfound) and rucaparib (TRITON2) are approved for single agent use in the following circumstances:
- Olaparib
- For patients with HRR gene-mutated mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone acetate + prednisone
- Rucaparib
- For patients with deleterious BRCA mutations associated mCRPC who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy.
- No updates yet to the indication based on TRITON3 (pre-docetaxel)
- For patients with deleterious BRCA mutations associated mCRPC who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy.
Conversely, the following PARP inhibitor + ARPI combinations are FDA approved:
- Olaparib + abiraterone acetate
- For the treatment of patients with deleterious or suspected deleterious BRCA-mutated mCRPC
- Talazoparib + enzalutamide
- For HRR gene-mutated mCRPC
- Niraparib + abiraterone acetate
- For BRCA-mutated mCRPC
Notably, the FDA makes no specifications about prior treatments, and, currently, there are no approvals for patients with a wildtype HRR mutational status.
Dr. Bryce noted that there are important differences between BRCA2 and BRCA1 mutations. BRCA2 appears to be more responsive to PARP inhibitors, compared to BRCA1. Additionally, BRCA2 deletions yield longer progression-free survival compared to BRCA2 mutations, and this is potentially due to the lack of reversion mutations in such patients.8
Dr. Bryce also highlighted that not all DNA repair defects/mutations predict similar responses to PARP inhibitor therapy. As summarized in the schematic below, it appears that the PSA50 response to PARP inhibitors is highest in patients with PALB2 mutations (70%), followed by BRCA2 (60%) and BRCA1 (24%). Patients with these mutations (PALB2, BRCA1/2) also derive the best objective response and composite response with PARP inhibitor therapy. Conversely, patients with CDK12, CHEK2, and ATM mutations appear to have significantly inferior objective responses to PARP inhibitor therapy. This underlies the importance of the specific HRR mutation when considering PARP inhibitor therapy.
Dr. Bryce next provided an overview of the recently published phase 3 trials of combination PARP inhibitors + an ARPI in the 1st line mCRPC setting. He emphasized the importance of managing potential toxicities with these combinations, the most pertinent of which is anemia, with transfusion rates ranging between 18% and 39% in these trials. Other important considerations with PARP inhibitors include myelosuppression and gastrointestinal toxicity. He did note that PARP interruption (49 – 62%), dose reduction (20 – 53%), and drug discontinuation (15 – 19%) occurred commonly in these trials.
How should we manage/anticipate potential PARP inhibitor toxicities?
- Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) can occur with PARP inhibitors and can have a delayed effect. The probability of occurrence is likely related to the age of the patient, the duration of treatment, and the post treatment survival.
- Bone marrow suppression: At a minimum, clinicians should test complete blood counts weekly for the first month, monthly for the next 11 months, and periodically thereafter for clinically significant changes.
- Do not overlook this. This is the most common reason for dose modification and discontinuation, and the quickest way to land your patient in trouble.
- Be ready to transfuse as needed
- Hypertension and cardiovascular effects: Monitor blood pressure and heart rate at least weekly for the first two months, then monthly for the first year and periodically thereafter
In summary, Dr. Bryce noted that serial/repeat NGS testing is necessary due to tumor evolution, fallibility of tests, and changes in actionable indications over time. PARP inhibitors, either alone or in combination with ARPIs, are key tools in the modern management of mCRPC patients. The efficacy of PARP inhibitors is closely related to the qualifying genomic alteration. The toxicity of PARP inhibitors can be significant and must be respected.
Presented by: Alan Bryce, MD, Professor of Molecular Medicine at Translational Genomics Research Institute, Chief Clinical Officer, City of Hope, Phoenix, AZ
Written by: Rashid K. Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 Society of Urologic Oncology (SUO) annual meeting held in Washington, D.C. between November 28th and December 1st, 2023
References:
- Abida W, Armenia J, Gopalan A, et al. Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making. JCO Precis Oncol. 2017:PO.17.00029.
- Hussain M, Corcoran C, Sibilla C, et al. Tumor Genomic Testing for >4,000 Men with Metastatic Castration-resistant Prostate Cancer in the Phase III Trial PROfound (Olaparib). Clin Cancer Res. 2022;28(8):1518-1530.
- Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al. Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 2022; 1(9).
- Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. 2023;402(10398):291-303.
- Chi KN, Rathkopf DE, Smith MR, et al. Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol 2023; JCO2201649.
- Abida W, Campbell D, Patnaik A, et al. Rucaparib for the Treatment of Metastatic Castration-resistant Prostate Cancer Associated with a DNA Damage Repair Gene Alteration: Final Results from the Phase 2 TRITON2 Study. Eur Urol. 2023;84:321-330.
- De Bono J, Mateo J, Fizazi K, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020;382:2091-2102.
- 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.