Prostate Adenocarcinoma: Molecular Pathogenesis and Treatment Advances

Testosterone and androgen receptor (AR) signaling play a central role in the development and progression of prostate cancer. Prostate adenocarcinoma makes up the overwhelming majority of prostate cancer cases — well over 95%, in fact.

With this description of prostate adenocarcinoma, one may think that cutting off testosterone is the ultimate solution, which is the whole idea behind androgen deprivation therapy (ADT), which has been the go-to treatment for decades. Unfortunately, for some patients, their cancer eventually finds a way around that. Through various adaptations, it continues to grow even without its supply of androgen hormones. This is when it turns into something much more insidious and harder to combat: Castration-Resistant Prostate Cancer, or CRPC.

At the heart of this matter is the AR. In healthy prostate cells, ARs respond to testosterone and other androgens, helping to regulate growth and function in healthy prostate cells. However, in prostate adenocarcinoma, that pathway is hijacked. The cancer cells become hooked on AR signaling to fuel their growth. The androgen-AR complex activates the transcription of key oncogenic target genes, such as those encoding the PSA enzyme and cyclin-dependent kinases. This promotes the transition from the G1 to the S phase of the cell cycle, effectively forcing the cells to replicate continuously. While blocking this pathway is usually effective as a first line of defence (Freedland et al., 2025),  over time, the tumor cells may figure out how to keep the AR active — or even find workarounds — so they can keep growing even under low testosterone levels.

But hormones aren’t the only part of the story. There are some key genetic mutations that show up in a lot of cases, and they play a major role in how aggressive the cancer becomes. One of the most common is the TMPRSS2-ERG fusion, which shows up in around half of all cases. It’s a gene rearrangement that flips on cancer-promoting pathways and helps the tumor invade nearby tissue (Song & Chen, 2018). Another vital mutation occurs in the PTEN gene. When PTEN gets deleted or lost, which happens often in more aggressive cancers, a pathway called PI3K-Akt gets activated. This helps the tumor resist cell death and keep thriving (Choudhury et al., 2022). There’s also growing attention around DNA repair genes like BRCA1, BRCA2, and ATM. While mutations at these genes can make the tumor genetically unstable, weirdly enough, they also make it more vulnerable to certain treatments like PARP inhibitors (Mateo et al., 2015).

Besides the critical genetic and hormonal factors, the tumor’s environment is vital too. Prostate tumors tend to surround themselves with immune cells that suppress the immune response altogether instead of attacking the tumor. These include regulatory T cells and myeloid-derived suppressor cells (MDSCs), with the latter’s function being to help the tumor evade detection from the immune system.

A lot of men with early-stage prostate cancer fail to notice symptoms right away. Sometimes, the first clue is just a high PSA level picked up during a routine check. The symptoms, if present, usually pertain to the urinary system. For example, the disease may manifest itself in conditions like difficulty urinating, a decreased force of stream, or hematuria, which refers to blood in urine. These conditions usually happen due to the pressure placed on the urethra by the tumor (Garnick & Schmidt, 2025). As the disease progresses, the complications increase in severity. Bone metastases are especially common and can be very painful, even leading to fractures. When the cancer keeps growing despite ADT, it is considered castration-resistant, with a more complicated treatment plan to follow (Roviello et al., 2022).

The challenge of treating the disease intensifies with the development of castration-resistant prostate cancer (CRPC). This immunosuppressive environment has made immunotherapy frustrating in treating prostate cancer thus far.  Sipuleucel-T, the first FDA-approved cancer vaccine, was a big milestone, despite only modestly improving overall survival (Kantoff et al., 2010). Checkpoint inhibitors, like those targeting PD-1 or PD-L1, have been less than effective on their own, but researchers are now testing them in combination with other treatments, like PARP inhibitors or radiation, in an attempt to obtain improved results (Yi et al., 2022). These novel ideas being developed and tested have the potential to improve immunotherapy’s effectiveness in treating prostate adenocarcinoma (Lu et al., 2025).

There has also been significant progress in treating CRPC. A new generation of AR-targeting drugs has extended survival in men with CRPC. Abiraterone, for example, blocks androgen production, including from organs as far away as the adrenal glands, and has shown clear survival benefits in advanced cases (de Bono et al., 2011). Another promising drug, enzalutamide, blocks the androgen receptor inside the nucleus to stop it from turning on growth-related genes (Hussain et al., 2018). Both have become standard tools in the toolbox to fight CPRC.

For patients with BRCA mutations or other DNA repair problems, PARP inhibitors like Olaparib have opened up a new route. These drugs shut down the cancer cell’s backup repair system, causing it to self-destruct under the weight of its own genetic damage (de Bono et al., 2020). This more targeted approach has shown real promise in significantly improving outcomes for this specific patient subgroup.

There are also options that go beyond drugs entirely. Radium-223 is a radioactive compound that homes in on bone metastases and emits alpha particles that kill tumor cells while sparing healthy tissue (Parker et al., 2013). More recently, Lutetium-177–PSMA therapy has gained attention. It targets a protein found mostly on prostate cancer cells, delivering radiation directly to them with minimal spillover. Early trials have been encouraging (Sartor et al., 2021).

At the end of the day, prostate adenocarcinoma is still a complex and evolving disease. While hormones are a key factor in the disease progression, genetics, immune evasion, and tumor location all shape how it behaves and how best to treat it. And while androgen deprivation is still the backbone of therapy, the treatment landscape has been significantly broadened. Between advanced hormone blockers, precision-targeted therapies, radiation strategies, and immunotherapies, there’s more hope than ever for tailoring treatment to each patient’s situation. That said, castration-resistant cases still pose big challenges, and research continues to push for better answers. With any luck, the next few years may bring some major positive shifts, benefiting the thousands who suffer from CPRC on a daily basis. These advancements aim not just to extend life, but to preserve its quality, allowing men more time with family and a greater sense of normalcy in the face of disease.

References

• Roviello, G., Catalano, M., Ottanelli, C., Giorgione, R., Rossi, V., Gambale, E., Casadei, C., De Giorgi, U., & Antonuzzo, L. (2022). Castration-resistant prostate cancer with bone metastases: Toward the best therapeutic choice. Medical Oncology, 39, Article 145.

• Mateo, J., Carreira, S., Sandhu, S., Miranda, S., Mossop, H., Perez-Lopez, R., ... & de Bono, J. S. (2015). DNA-repair defects and olaparib in metastatic prostate cancer. New England Journal of Medicine, 373(18), 1697–1708.

• Freedland, S. J., Hong, A., El-Chaar, N., et al. (2025). Survival benefit associated with first-line androgen receptor pathway inhibitors for de novo metastatic castration-sensitive prostate cancer. Prostate Cancer and Prostatic Diseases.

• de Bono, J. S., et al. (2011). Abiraterone in metastatic prostate cancer. New England Journal of Medicine, 364(21), 1995-2005.

• Yi, M., Zheng, X., Niu, M., Zhu, S., Ge, H., & Wu, K. (2022). Combination strategies with PD-1/PD-L1 blockade: Current advances and future directions. Molecular Cancer, 21, Article 28.

• Lu, H., Teng, Z., Wang, J., & Zhang, W. (2025). Prostate cancer immunotherapy-based strategies: An updated review emphasizing immune checkpoint inhibitors. Frontiers in Immunology, 16, Article 1583363.

• Sartor, O., de Bono, J., Herrmann, K., et al. (2021). Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. New England Journal of Medicine, 385(12), 1091–1103.

• Hussain, M., et al. (2018). Enzalutamide in nonmetastatic CRPC. New England Journal of Medicine, 378(26), 2465-2474.

• Kantoff, P. W., et al. (2010). Sipuleucel-T immunotherapy for prostate cancer. New England Journal of Medicine, 363(5), 411-422.

• de Bono, J., Mateo, J., Fizazi, K., Saad, F., Shore, N., Sandhu, S., ... & Hussain, M. (2020). Olaparib for metastatic castration-resistant prostate cancer. New England Journal of Medicine, 382(22), 2091–2102.

• Garnick, M. B., & Schmidt, C. W. (2025). What are the symptoms of prostate cancer? Harvard Medical School Annual Report on Prostate Diseases. Harvard Health Publishing.

• Parker, C., et al. (2013). Radium-223 for bone metastatic prostate cancer. New England Journal of Medicine, 369(3), 213-223.

• Song, C., & Chen, H. (2018). Predictive significance of TMPRSS2-ERG fusion in prostate cancer: A meta-analysis. Cancer Cell International, 18, Article 177. Song, C., & Chen, H. (2018). Predictive significance of TMPRSS2-ERG fusion in prostate cancer: A meta-analysis. Cancer Cell International, 18, Article 177. 

• Choudhury, A. D. (2022). PTEN-PI3K pathway alterations in advanced prostate cancer and clinical implications. The Prostate, 82(Suppl 1), S60–S72. 

Image Credit: https://blog.dana-farber.org/insight/2019/04/what-is-carcinoma-of-the-prostate/