Metastatic castration-resistant prostate cancer (mCRPC) has been considered primarily the domain of novel hormone and taxane therapy. Increasingly, however, other treatment approaches are being tested with sometimes promising results. In particular, interesting data on the use of PARP and AKT inhibitors were presented at this year’s ESMO Congress.
To date, personalized medicine has played a minor role in mCRPC. However, this is likely to change in the near future with further research into targeted therapies. However, not only biomarker testing and patient selection will become more relevant in this disease, but also in the field of immunotherapy.
Help for self-help
The development of cellular cancer therapies is not stopping at mCRPC. The so-called BiTE®(bi-specific T-cell engagers) technology is based on the use of so-called TRBAs (T-cell redirecting bispecific antibodies). On the one hand, these recognize a tumor antigen such as PSMA and, on the other hand, recruit patient-derived T cells for tumor defense by binding to the CD3 domain of the T cell receptor [1]. This approach could represent a biomarker-independent option in the field of immunotherapy after the unfortunately unsuccessful trial of classical checkpoint inhibitor therapies in mCRPC.
A phase I trial [2] is currently ongoing in mCRPC patients whose tumor was refractory to a novel hormonal therapy and at least one taxane therapy and showed progression. Initial results indicate good tolerability, with only one treatment-related discontinuation and two reversible dose-limiting toxicities. PSA reductions were also detected in 63% of patients. Thus, treatment with the drug, which is given as a short IV infusion, has been tolerable. Phase II efficacy studies are now eagerly awaited.
BRCA mutations: Relevance in prostate cancer?
To date, mutations in the tumor suppressor genes BRCA1 and BRCA2 have served primarily as biomarkers for therapy with PARP inhibitors. In the phase III PROfound trial [3], olaparib was used in the second-line treatment of mCRPC and demonstrated an overall survival benefit over sequential enzalutamide or abiraterone therapy. In the presence of a BRCA or ATM mutation, the risk of death was reduced by 31% at a median follow-up of 21 months.
BRCA mutations, however, appear to have predictive value not only for PARPi therapy but also to be prognostically important. For example, recent data from a case-control study demonstrated that a germline BRCA2 mutation significantly decreased cancer-specific survival [4]. Patients without the mutation lived on average a full 7 years longer before dying from the consequences of their tumor disease. Somewhat less pronounced effect was also observed for BRCA1 mutations. In light of these findings, the question arises whether earlier use of PARPi might be appropriate in the subgroup of patients who have a corresponding germline mutation. In any case, knowledge of BRCA status plays a role in long-term care, whether for a realistic assessment of prognosis or even for altered treatment regimens.
Personalized medicine also in the first line
For the first time this year, a targeted therapy was successfully used in the first-line treatment of mCRPC. In the phase III IPATential150 trial [5], the authors tested the coadministration of ipatasertib and abiraterone. Compared with abiraterone therapy alone, significant PFS benefits were seen in those patients who had PTEN loss.
Ipatasertib, which is currently also being evaluated for the treatment of breast carcinoma, is an inhibitor of protein kinase B, also known as AKT (RAC-α-serine/threonine-protein kinase) [6]. This kinase is part of a signaling pathway that plays an important role in the development of therapy resistance in tumors and is activated by loss of the phosphatase PTEN. Thus, by eliminating this signaling pathway, ipatasertib may counteract treatment resistance to abiraterone, for example. In particular, for PTEN loss, which can be detected in about 50% of mCRPC, such dual pathway inhibition showed promising results in the IPATential150 trial.
Gene analyses as the basis for optimal therapy decisions
With the increased availability of alternatives to chemotherapy in mCRPC, their use will need to be weighed even more carefully if there are pronounced negative effects on all domains of quality of life [7]. In the future, early genetic or immunohistochemical analysis may allow adequate therapies for selected groups of patients, for example with BRCA or PTEN mutations, and thus improve their prognosis.
Source: ESMO 2020 Virtual
Literature:
- Strohl WR, Naso M: Bispecific T-Cell Redirection versus Chimeric Antigen Receptor (CAR)-T Cells as Approaches to Kill Cancer Cells. Antibodies (Basel) 2019; 8(3): 41.
- Tran B, et al: Results from a phase I study of AMG 160, a half-life extended (HLE), PSMA-targeted, bispecific T-cell engager (BiTE®) immune therapy for metastatic castration-resistant prostate cancer (mCRPC). Annals of Oncology 2020; 31(suppl_4): 507-549.
- de Bono JS, et al: Final overall survival (OS) analysis of PROfound: olaparib vs physician’s choice of enzalutamide or abiraterone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations. Annals of Oncology 2020; 31(suppl_4): 507-549.
- Lozano Mejorada R, et al: Clinical impact of somatic alterations in prostate cancer patients with and without previously known germline BRCA1/2 mutations: Results from PROREPAIR-A study. Annals of Oncology 2020; 31(suppl_4): 507-549.
- de Bono JS, et al: IPATential150: Phase III study of ipatasertib (ipat) plus abiraterone (abi) vs placebo (pbo) plus abi in metastatic castration-resistant prostate cancer (mCRPC). Annals of Oncology 2020; 31(suppl_4): 1142-215.
- Isakoff SJ, et al: Antitumor activity of ipatasertib combined with chemotherapy: results from a phase Ib study in solid tumors. Ann Oncol. 2020; 31(5): 626-633.
- Deschamps A, et al: The real effects of prostate cancer chemotherapy: results of the EUPROMs prostate patient-driven quality of life study. Annals of Oncology 2020; 31(suppl_4): 507-549.
InFo ONCOLOGY & HEMATOLOGY 2020; 8(5): 30 (published 10/20/20, ahead of print).
