Analyst Notes: Are personalised treatment approaches on the horizon for prostate cancer?

Prostate cancer is a heterogeneous disease accounting for almost 10 percent of all new cancers diagnosed in the US in 2017. Generally, prognosis is good owing to the slow development of the cancer; five-year overall survival rates in Western countries range between 85 percent to 95 percent. Early-stages of prostate cancer can often be managed very effectively by surgery, radiotherapy and first-line androgen deprivation therapy (ADT), however, if the disease progresses to the metastatic castration-resistant stage, chemotherapy or next-generation anti-androgens (e.g. Johnson & Johnson's Zytiga [abiraterone], Astellas/Pfizer's Xtandi [enzalutamide]) must be employed. Over the past two years, two promising classes of drugs (PARP inhibitors and PD-1/PD-L1 checkpoint inhibitors) have emerged from the pipeline and are targeting biomarker-selected patient subgroups in metastatic castrate-resistant prostate cancer (mCRPC).

Insights, Analysis & Opinion

Key opinion leaders (KOLs) interviewed by FirstWord for the forthcoming report Prostate Cancer: KOL Insight explained that, in terms of personalised approaches, the only novel therapy approved for mCRPC in recent years was a dendritic-cell based therapeutic vaccine called Provenge (sipuleucel-T; originally developed by Dendreon), which faced a wealth of commercial setbacks when it launched on the market.

PARP inhibitors are a novel class of drugs inhibiting the PARP enzymes involved in DNA repair processes. AstraZeneca's Lynparza (olaparib) and Clovis Oncology's Rubraca (rucaparib) are the first two PARP inhibitors to enter the Phase III pipeline for prostate cancer. Along with the PARP inhibitors, two PD-1/PD-L1 immune checkpoint inhibitors - Roche's Tecentriq (atezolizumab) and Merck & Co.'s Keytruda (pembrolizumab) - have also been positioned as potential treatments for mCRPC. One common point stressed by all KOLs throughout the recent report is that although promising, both of these drug classes need to be evaluated in biomarker-defined patient populations in order to attain the most clinical benefit.

Indeed, both of the PARP inhibitors are being investigated in patients harbouring BRCA1/2, ATM mutations or other DNA mismatch repair (MMR) mutations where they have demonstrated significant benefit in ovarian cancer. Overall, KOLs were very optimistic about the prospects for both PARP inhibitors in prostate cancer and deem their investigation in biomarker-selected groups as appropriate and exciting.

"It is very likely that the PARP inhibitors will be approved. Out of all the new agents being tested, the PARP inhibitors are probably the most likely to be successful because you are going with a good biomarker to select patients and there are multiple drugs in this setting. It is sort of a treatment paradigm that has already been pretty validated in breast and ovarian cancer, so that's probably got the highest likelihood of success." - US Key Opinion Leader

With regard to the PD-1/PD-L1 checkpoint inhibitors, KOLs voiced their appreciation about the clear benefits these treatments have shown in other cancers, especially for Keytruda. Interestingly, similar to recent KOL views on colorectal cancer, the specialists believe that the most efficacy for PD-1/PD-L1s is likely to be achieved in patients with high microsatellite instability (MSI-H) tumours or as part of combination approaches rather than as standalone use. These positive expectations further reinforce the tissue agnostic FDA approval of Keytruda in May 2017 for the treatment of metastatic solid tumours that have been identified as MSI-H or MMR-deficient.

"As single agents, these PD-L1 drugs in prostate cancer are unlikely to have a significant benefit unless it's a subset of prostate cancer that has microsatellite instability or a significant mutational burden. Atezolizumab is being evaluated in a few different settings. I think it is being evaluated in combination with radium and with AR [androgen receptor]-targeting therapies, and so those types of combination studies will be more likely to have success." - US Key Opinion Leader

In summary, the KOLs anticipate that use of predictive biomarkers to help determine the appropriate course of treatment will become the norm in patients with metastatic prostate cancer within the next three to five years. They foresee the PARP inhibitors successfully making it to market and hold cautious optimism that the checkpoint inhibitors will follow suit. In particular, combinations of these novel drug classes with conventional anti-androgen therapies as a backbone will be another key avenue of drug development opportunity in the near future.

For companies operating in the prostate cancer market in Europe and the US, Prostate Cancer: KOL Insight is a must read. The report provides actionable insights and commentary on some of the most critical issues in the prostate cancer market, and provides perspectives on pipeline therapies and how their potential in a rapidly increasing market. The report also discusses how treatment paradigms could change in prostate cancer. For more information, please click here.

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