Editor's Note: On January 25, 2024, the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO-GU) marked its 20th anniversary in San Francisco, USA. On the occasion of the 20th anniversary of ASCO-GU, "Oncology Frontier" had the privilege of interviewing Dr. Tao Xu from Peking University People's Hospital. Dr. Tao Xu shared insights into the current state of precision treatment for prostate cancer and the changes brought by genetic testing to the clinical diagnosis and treatment.
Oncology Frontier : With the ongoing of molecular research, the treatment of tumors has entered the era of precision medicine. At this ASCO-GU conference, we observed the release of data on several targeted therapies for advanced prostate cancer. Could you introduce the current state of precision treatment for prostate cancer?
Dr. Tao Xu: It’s an honor to be present at such a milestone conference, celebrating the 20th anniversary of the ASCO-GU this year. The first day of the conference saw experts and scholars from around the world in the field of genitourinary tumors sharing and discussing the diagnosis and treatment of prostate cancer, with a focus on precision treatment right from the opening session. I recently read an article in the Journal of Clinical Oncology (JCO) discussing the epidemiological characteristics of various tumors, with prostate cancer being highlighted as the most significant tumor type within the genitourinary system. Moreover, the first day of the ASCO-GU conference emphasized the importance of precision treatment in the diagnosis and treatment of genitourinary tumors. The conference featured two related themes: the personalized choice of immunotherapy for kidney cancer and a post-hoc analysis and interpretation of the PROfound study, underscoring our attention to the hot topic of precision treatment for tumors. However, compared to other tumor types, precision treatment for genitourinary tumors (whether bladder cancer, prostate cancer, or kidney cancer) started relatively late. For prostate cancer, the real clinical introduction of precision treatment began with the PROfound study in 2019, whereas previous chemotherapy and endocrine treatments did not achieve the level of precision treatment.
The PROfound study, since its initial results and subsequent analyses were published in 2019, has truly ushered the era of precision treatment for prostate cancer. Currently, precision treatment for prostate cancer is fundamentally based on the results of the PROfound study, which is stratified based on the status of homologous recombination repair (HRR) gene mutations. The PROfound study showed that, for patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously failed treatment with new hormonal agents (NHAs) and carried BRCA mutations, olaparib significantly extended the median overall survival (mOS) compared to the physician’s choice of NHA (20.1 vs. 14.4 months; HR 0.63) and tripled the radiographic progression-free survival (rPFS) (9.8 vs. 3.0 months; HR 0.22), especially for patients with BRCA2 deletions, where the rPFS reached 16.6 months. Olaparib provided significant survival benefits for patients. Patient stratification based on HRR gene testing has enabled true precision treatment for prostate cancer.
△PROfound study patient rPFS and OS survival curves
During the 2024 ASCO-GU conference, beyond the significant insights into patient rPFS and OS survival curves from the PROfound study, we observed a burgeoning interest in novel stratification methods, genetic testing techniques, and therapeutic approaches in clinical exploration. Notably, the development of new targeted therapies against the PI3K-AKT-mTOR pathway has come into focus, with preliminary research on PI3Ki, AKTi, mTORi, and PTENi capturing our attention. The phase II ProCAID study of the AKT inhibitor Capivasertib, in combination with docetaxel, demonstrated a significant improvement in OS (31.2 vs. 20.3 months; HR 0.54, P=0.01) compared to docetaxel alone. This conference highlighted the ongoing efforts by researchers to delve deeper into patient characteristics through various genetic testing technologies, with the hope that further advancements in research will uncover more personalized diagnostic and therapeutic interventions for prostate cancer.
Oncology Frontier : With the development of molecular typing, targeted therapy for prostate cancer have become a trend in diagnosis and treatment. What role does genetic testing currently play in clinical practice, and what benefits does it bring to the clinical diagnosis and treatment of prostate cancer?
Dr. Tao Xu: Genetic testing and disease molecular typing are foundational to precision medicine. Compared to other cancer types such as lung and breast cancer, the field of urological tumors has lagged in translating genetic testing and precision treatment research. Currently, genetic testing and clinical translation for prostate cancer primarily focus on Homologous Recombination Repair (HRR) gene mutations. Research on other genes is mostly still in the experimental stage, limiting the guidance genetic testing can offer for prostate cancer treatment. The most instructive at this stage remains the detection of BRCA and ATM mutations as evidenced by the PROfound study. Compared to the physician’s choice of novel hormonal agents (NHA), olaparib significantly extends the median overall survival (mOS) and radiographic progression-free survival (rPFS) for mCRPC patients with BRCA mutations, especially those with BRCA2 deletions, where rPFS can reach up to 16.6 months. This allows for stratified treatment of patients, which is crucial for developing personalized treatment plans.
Moreover, genetic testing aids in prognosis assessment. By analyzing DNA and RNA from tumor cells in prostate cancer patients, genetic testing can identify gene mutations and expression patterns closely associated with disease prognosis. Urological experts can use this information to evaluate the risk of disease progression, the likelihood of recurrence, and patient survival expectations, thereby making informed decisions about subsequent clinical treatments, such as choosing between surgery or drug therapy. Besides BRCA1/2, genes and molecular targets related to prostate cancer prognosis include PTEN, TMPRSS2-ERG fusion, high microsatellite instability (MSI-H)/mismatch repair gene deficiencies (dMMR), etc. Testing for these genes and molecular targets offers reference points for immunotherapy or targeted therapy selection for patients at different stages of progression and risk levels.
Furthermore, genetic testing plays a role in assessing hereditary risk, which has more direct clinical significance. Prostate cancer is closely linked to genetic factors, with males carrying BRCA2 mutations facing an approximately 8.6-fold increased risk of prostate cancer, and those with BRCA1 mutations also having a significantly elevated risk, though to a lesser extent. Conducting BRCA1/2 and other genetic tests in populations with familial genetic risk can help identify individuals with hereditary cancer syndromes early, aiding clinicians in devising personalized follow-up and monitoring plans for these individuals and their family members.
Overall, despite the current limited and broad application of genetic testing in the prostate cancer field, ongoing etiological research and the development of new testing technologies are expected to uncover more genetic testing sites. In-depth research based on these new sites will provide more information for clinical diagnosis, treatment, and prevention. With continuous improvements in genetic testing technology, the precision of prostate cancer treatment will further increase, allowing for personalized treatment recommendations based on patients’ molecular typing, thereby offering more treatment opportunities and improved quality of life for patients.
