Emerging Therapeutic Approaches for Prostate Cancer

Approximately one in eight men will be diagnosed with prostate cancer during their lifetime, making it the second-leading cause of cancer-related deaths among men in the United States.^1,2 Early-stage prostate cancer growth is usually androgen-dependent and, therefore, responds well to hormone therapy.

So why do so many men lose their battle with this pervasive cancer? In many cases of late-stage prostate cancer, such as castration-resistant prostate cancers (CRPCs), the disease becomes androgen-independent and is no longer responsive to hormone therapy. Therefore, early detection is crucial for improving survival outcomes. Routine blood tests for prostate-specific antigen (PSA) are used to identify men who may require further diagnostic evaluation.

This post reviews some of the current and emerging treatment strategies CRPCs.

Current and Future Directions for Prostate Cancer Treatment

Currently, the first line of defense against CRPC includes abiraterone, an androgen biosynthesis inhibitor that reduces the production of androgens, and enzalutamide, an androgen receptor (AR) antagonist. However, many cancer cells eventually become resistant to these treatments. 

Therefore, the development of new therapies or combination therapies is essential to improve outcomes for patients with advanced prostate cancer.

Gene Mutations and Variants of Interest

Several gene mutations in prostate cancers have been identified as possible therapeutic targets, including the TMPRSS2-ERG fusion protein, which is present in 50% of prostate cancers. Other frequently observed genetic alterations include mutations in ERG, TMPRSS2, CHD1, FoxA1, SPOP, and BRCA1/2.

Immunohistochemical analysis of paraffin-embedded human prostate adenocarcinoma (two different cases) using ERG (A7L1G) Rabbit mAb #97249.

Additionally, AR variants such as AR-V7 and ARv567 continue to attract interest. These variants tend to arise through aberrant splicing and lack a ligand-binding domain, contributing to androgen-independent growth in prostate cancer cells. This gives the tumor cells the ability for sustained proliferation, one of the hallmarks of cancer. AR-V7 is a key driver of CRPC and is highly expressed in metastatic and CRPCs. As a result, therapeutics aimed at controlling the splicing events that cause different variants to arise are being explored, as well as therapeutics that target specific variants.^3,4

Combinatory Treatment Strategies

One combinatory approach is to target epigenetic machinery along with immunotherapies to address the tumor’s ability to avoid immune destruction, another cancer hallmark.⁵ Treating patients with an immunotherapy alone is usually not effective, since prostate cancers tend to lack T cell infiltration and are therefore considered to be immunologically “cold”. However, EZH2 inhibitors have shown promise in CRPC and neuroendocrine prostate cancers that develop after enzalutamide treatment. EZH2 is a methyltransferase enzyme that regulates chromatin to silence gene function and it is highly expressed in CRPCs. EZH2 inhibitors have been shown to flip the “cold” switch in prostate cancers by reactivating the STING pathway, making them more responsive to immunotherapies.

PARP inhibitors, including olaparib and rucaparib, may play a role in personalized medicine treatments for patients with CRPC, especially for those with mutations in the homologous recombination repair pathway, which is present in approximately 30% of patients. However, the overall efficacy of general PARP inhibition remains to be determined.^6,7

Taxanes, which are standard chemotherapy agents, can be used in combination with androgen-signaling inhibitors like abiraterone or enzalutamide. In one study, treating patients with cabazitaxel and androgen signaling inhibitors, in patients previously treated with docetaxel and AR inhibitors, improved clinical outcomes.^8,9

Promising therapeutic approaches earlier in the discovery stage include the following:

• The degradation of a component of SWI/SNF, a chromatin remodeling complex that promotes access of transcription factors to enhancer elements, increasing expression of FoxA1 and ERG.
• As of February 2022, researchers have also developed a drug, currently entering Phase 1A clinical trials, that restores a long noncoding RNA that suppresses androgen receptor expression.
• Finally, scientists are attacking the mechanisms that confer resistance to AR inhibitor therapies. Prostate cancer cells have increased expression of glucocorticoid receptor, which share similarities with the androgen receptor, to compensate when AR signaling is inhibited.¹⁰ When the glucocorticoid receptor is inhibited, tumors regain their responsiveness to first-line treatment options.

The Future of Prostate Cancer Treatment

The prognosis for castration-resistant prostate cancer remains challenging, but ongoing evaluation of novel combination therapies offers hope for improving patient outcomes. Research to discover effective combination therapies will only give clinicians a larger arsenal to use when fighting castration-resistant prostate cancer, ultimately saving lives.

Select References

1. American Cancer Society – Key Statistics for Prostate Cancer
2. National Cancer Institute – Prostate Cancer
3. Liu LL, Xie N, Sun S, Plymate S, Mostaghel E, Dong X. Mechanisms of the androgen receptor splicing in prostate cancer cells. Oncogene. 2014;33(24):3140-3150. doi:10.1038/onc.2013.284
4. Takayama KI. Splicing Factors Have an Essential Role in Prostate Cancer Progression and Androgen Receptor Signaling. Biomolecules. 2019;9(4):131. Published 2019 Apr 1. doi:10.3390/biom9040131
5. Morel KL, Sheahan AV, Burkhart DL, et al. EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer. Nat Cancer. 2021;2(4):444-456. doi:10.1038/s43018-021-00185-w
6. McFarland TR, Kessel A, Swami U, Agarwal N. Development of PARP inhibitor combinations for castration resistant prostate cancer unselected for homologous recombination repair mutations. Am J Transl Res. 2021;13(7):7427-7439. Published 2021 Jul 15.
7. Antonarakis ES, Gomella LG, Petrylak DP. When and How to Use PARP Inhibitors in Prostate Cancer: A Systematic Review of the Literature with an Update on On-Going Trials. Eur Urol Oncol. 2020;3(5):594-611. doi:10.1016/j.euo.2020.07.005
8. de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N Engl J Med. 2019;381(26):2506-2518. doi:10.1056/NEJMoa1911206
9. Zhang PF, Xie D, Li Q. Cost-effectiveness analysis of cabazitaxel for metastatic castration resistant prostate cancer after docetaxel and androgen-signaling-targeted inhibitor resistance. BMC Cancer. 2021;21(1):35. Published 2021 Jan 7. doi:10.1186/s12885-020-07754-9
10. Shah N, Wang P, Wongvipat J, et al. Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer. Elife. 2017;6:e27861. Published 2017 Sep 11. doi:10.7554/eLife.27861