ADVANCES IN PROSTATE CANCER TREATMENT:
FROM “ALL CANCERS ARE THE SAME” TO INDIVIDUALISED PRECISION ONCOLOGY
Many urologists still approach prostate cancer as one type of tumour: a disease that should be surgically removed, usually by radical prostatectomy, and then treated, if necessary, with radiation or hormone therapy.
But science has moved on.
Tumour genome sequencing now provides detailed information about a patient’s specific prostate cancer — its biological behaviour, its aggressiveness, and its vulnerabilities to specific treatments. This technology analyses the DNA, and sometimes also the RNA, of cancer cells to identify mutations, deletions, rearrangements, and signalling abnormalities that drive tumour growth, treatment resistance, and metastatic spread.
The goal is to move away from the idea that “all prostate cancers should be treated similarly” and toward precision oncology: matching treatment to the biology of the individual tumour.
The advantage is clear: better and more effective treatment for prostate cancer patients, potentially with fewer side effects than many standard therapies. For some patients, this may mean longer survival, even with aggressive prostate cancer, and a better quality of life.
The disadvantage is also clear: treatment options have become immensely complex. Costs, limited availability, and the rapid speed of scientific progress mean that many urologists and clinics struggle to keep up with what is now possible.
At VITUS Privatklinik, we have embraced progress in prostate cancer therapy for many years. We have been pioneers in prostate MRI, abscopal electroporation treatments, and immunotherapy. For us, individualised medicine is not a threat — it is an exciting world of possibilities for our patients.
If you are suffering from prostate cancer and want access to advanced, personalised therapy, talk to us. It is a small effort that might change your life.
How Tumour Genome Sequencing Can Improve Prostate Cancer Treatment
The treatment of prostate cancer has changed substantially in recent years. In the past, treatment decisions were mainly based on tumour stage, PSA level, Gleason score, imaging findings, and whether the cancer was still sensitive to hormone deprivation. These factors remain very important. Today, however, another layer of information is increasingly being added: the molecular analysis of the tumour. This means looking for specific genetic changes inside the cancer cells. This approach is often called tumour genome sequencing or next-generation sequencing.
Genome sequencing does not automatically mean that every patient will immediately receive a perfectly matched “personalised” treatment. However, it can provide valuable information about how a tumour behaves, which therapies may be more likely to work, which treatments may be less effective, and whether participation in a clinical trial may be appropriate. This is especially relevant in advanced, metastatic, or castration-resistant prostate cancer.
DNA repair defects
1: Why BRCA and related genes matter
One of the most important areas in prostate cancer sequencing involves genes responsible for repairing DNA damage. The DNA in our cells is constantly exposed to damage. Normally, cells have repair systems that correct these errors. One particularly important repair mechanism is called homologous recombination repair, often abbreviated as HRR. It is especially important for repairing dangerous double-strand breaks in DNA.
Some prostate cancers carry alterations in genes involved in this repair system. These include BRCA2, BRCA1, ATM, CHEK2, PALB2, and CDK12. Among these, BRCA2 is often the most clinically important. If a tumour cell cannot repair DNA damage properly, it may become genetically unstable, which can contribute to cancer progression. At the same time, this weakness can be exploited therapeutically.
This is where PARP inhibitors come in. PARP is another protein involved in DNA repair. If PARP is blocked in a tumour that already has a defective HRR repair system, the cancer cell may no longer be able to repair accumulated DNA damage and may die. Examples of PARP inhibitors include olaparib and rucaparib. In selected patients with advanced prostate cancer, identifying BRCA1/2 or other HRR alterations can therefore directly influence treatment choice. This is one of the clearest examples of how tumour sequencing can change clinical management.
2. Alterations in the androgen receptor pathway
Prostate cancer is often strongly driven by male sex hormones, known as androgens. Testosterone and related hormones activate the androgen receptor, which can switch on growth programmes inside prostate cancer cells. For this reason, androgen deprivation therapy has been a central part of prostate cancer treatment for many decades.
However, cancer cells can develop ways to continue growing despite very low testosterone levels. Sequencing and related molecular tests may reveal mechanisms behind this resistance. These may include amplification of the androgen receptor gene, androgen receptor mutations, or splice variants such as AR-V7, which are often assessed using blood-based liquid biopsy or transcript-based testing.
These findings may help predict whether treatments such as enzalutamide or abiraterone are likely to work well or whether resistance may develop earlier. In some cases, they may support consideration of alternative strategies, such as taxane chemotherapy. However, these tests usually provide probabilities rather than absolute predictions. They are best interpreted as part of the overall clinical picture.
3. The PI3K–AKT–PTEN pathway: the role of PTEN
Another major pathway in prostate cancer is the PI3K–AKT–PTEN signalling pathway. This pathway helps regulate cell growth, survival, metabolism, and resistance to stress. A key gene in this system is PTEN.
PTEN is a tumour suppressor gene. In simple terms, it acts like a brake on the PI3K–AKT–mTOR growth pathway. When PTEN is lost or inactivated, this brake is removed. As a result, cancer cells may grow more rapidly, survive better, metastasise more easily, and become more resistant to certain treatments.
PTEN loss is relatively common in prostate cancer. It occurs in approximately 20–30% of localised prostate cancers and in up to around 50% of metastatic castration-resistant prostate cancers. “Castration-resistant” means that the cancer continues to progress despite very low testosterone levels.
Tumour sequencing may detect several types of PTEN alteration, including PTEN deletion, PTEN mutation, loss-of-function changes, or copy-number loss. In some cases, PTEN status is also assessed by immunohistochemistry, which checks whether the PTEN protein is still present in tumour tissue. Liquid biopsy may also provide information in selected situations.
The key question is often not simply, “Is PTEN altered?” but rather, “Is the PI3K–AKT pathway sufficiently activated to be therapeutically targeted?”
Why PTEN matters clinically
PTEN loss is associated with more aggressive tumour biology. It is linked to higher Gleason grade, earlier metastasis, poorer prognosis, and resistance to some androgen-signalling therapies. However, PTEN loss may also create a therapeutic vulnerability. Tumours lacking functional PTEN can become more dependent on AKT signalling for survival.
This has led to the development of drugs that inhibit this pathway, especially AKT inhibitors. Important examples include ipatasertib and capivasertib. These drugs aim to block the growth and survival signals that become overactive when PTEN is lost.
Clinical studies have suggested that patients whose tumours show PTEN loss may derive greater benefit from AKT inhibitors than patients without PTEN loss. These approaches have been particularly studied in metastatic castration-resistant prostate cancer, often in combination with abiraterone and ongoing androgen deprivation therapy.
The biological rationale is important: androgen receptor signalling and PI3K–AKT signalling interact with each other. Prostate cancers can sometimes “switch” between different growth programmes. When androgen signalling is blocked, the tumour may rely more heavily on PI3K/AKT survival signalling. Therefore, a dual blockade strategy has become a major area of research: suppress androgen signalling and AKT survival signalling at the same time.
Why PTEN is not yet a simple treatment switch
Despite these promising developments, it is important to be realistic. PTEN loss does not yet function like some targetable mutations in other cancers, such as EGFR mutations in certain lung cancers. In those situations, a single mutation can sometimes point clearly to a highly effective targeted drug. PTEN is more complicated.
A PTEN alteration does not guarantee that a specific drug will work. Responses vary. One reason is that PTEN loss activates a complex signalling network rather than a single isolated switch. Tumours may also evolve alternative escape pathways, and prostate cancer is molecularly heterogeneous.
For this reason, PTEN currently functions more as a prognostic biomarker, a pathway-selection biomarker, and a clinical trial stratification marker than as a guaranteed therapy selector. In other words, PTEN helps identify a biologically important subgroup of prostate cancer, but it does not yet provide a simple one-gene, one-drug answer.
Other sequencing findings that may matter
Tumour sequencing can identify additional changes that may influence treatment. One important example is MSI-high status or mismatch repair deficiency. Tumours with these features may respond to immunotherapy, such as pembrolizumab.
CDK12 alterations may define a distinct prostate cancer subtype that could have particular immunological features. SPOP mutations are associated with a specific form of androgen signalling biology. Combined loss of TP53 and RB1 may indicate a more aggressive subtype, including the possibility of lineage plasticity or neuroendocrine transformation, where the tumour becomes less dependent on typical androgen-driven growth.
Tumour sequencing versus germline sequencing
It is important to distinguish between two different types of genetic testing. Tumour sequencing looks for genetic changes that are present inside the cancer cells. These changes may have developed during tumour evolution and are not necessarily inherited.
Germline sequencing, in contrast, looks for inherited genetic variants that are present in all cells of the body. These findings may be relevant not only for the patient but also for family members.
This distinction is especially important for BRCA1 and BRCA2. If an inherited BRCA2 mutation is found, it may influence the patient’s treatment, but it may also have implications for children, siblings, and other relatives. Genetic counselling and targeted cancer screening may then be appropriate. In advanced prostate cancer, both tumour and germline testing are increasingly recommended.
What this means in practical care
In modern prostate oncology, genome sequencing can help answer several clinically relevant questions. Is there a DNA repair defect that supports treatment with a PARP inhibitor? Is the tumour MSI-high, making immunotherapy a possible option? Is there PTEN loss, suggesting that an AKT-pathway treatment or clinical trial may be relevant? Are there androgen receptor alterations that may explain resistance to hormonal therapies? Are there TP53 and RB1 changes suggesting a particularly aggressive subtype?
Sequencing does not replace traditional medical assessment. Instead, it adds another layer of information. The final treatment decision still depends on the overall situation: tumour stage, symptoms, previous treatments, PSA development, imaging results, tissue findings, general health, and the patient’s personal goals.
The major advance is that prostate cancer is increasingly no longer viewed as a single uniform disease. Instead, it can be divided into molecular subgroups with different vulnerabilities. PTEN is a good example: its loss may indicate more aggressive biology, but it also reveals an important growth pathway that may be therapeutically targeted.
The future is unlikely to depend on one single “miracle drug.” More likely, progress will come from intelligent combinations: androgen blockade, AKT inhibition, PARP inhibition, immunotherapy, radioligand therapy, and other approaches may be combined according to the tumour’s molecular profile. For patients, this means that genome sequencing may help make treatment more individual, more biologically informed, and hopefully more effective over time.
Electroporation-Based Abscopal Therapies, PTEN Loss and PARP Inhibition:
Longer Survival, Fewer Side Effects, Better Quality of Life
Modern prostate cancer research is increasingly focused on understanding the biological weaknesses of each individual tumour. One of the most interesting areas is the interaction between PTEN loss, DNA repair weakness, PARP inhibitors, and local treatments that may stimulate the immune system, such as electroporation-based therapies.
The reason researchers are interested is that these treatments may attack cancer from different directions at the same time. PTEN loss affects tumour growth and survival signalling. PARP inhibitors target weaknesses in DNA repair. Electroporation and other ablative treatments can destroy tumour cells locally and release tumour material that may alert the immune system. The so-called abscopal effect refers to the possibility that a local treatment in one tumour site could trigger an immune response against cancer deposits elsewhere in the body.
In simple terms, the hope is to combine several mechanisms: make the tumour less able to repair itself, less able to survive stress, and more visible to the immune system.
What PTEN loss does to prostate cancer biology
PTEN is a tumour suppressor gene. Its normal role is to act like a brake on a major growth and survival pathway called the PI3K–AKT pathway. When PTEN is lost or inactivated, this brake is removed. The tumour cell may then receive stronger survival signals, making it harder to kill with standard therapies.
PTEN loss does not cause just one change. It can affect several important tumour behaviours at the same time. First, it activates AKT survival signalling, allowing cancer cells to resist stress and continue growing. Second, it may increase genomic instability, meaning that the tumour accumulates more DNA damage and genetic abnormalities. Third, PTEN loss may interfere with some DNA repair processes, including homologous recombination repair, the same broad repair system that is affected in BRCA-mutated cancers.
This is why some researchers describe certain PTEN-deficient tumours as having a partial “BRCA-like” state. That does not mean PTEN loss is the same as a BRCA1 or BRCA2 mutation. BRCA mutations are generally much stronger and more reliable predictors of response to certain DNA repair-targeted drugs. But PTEN loss may, in some tumours, create a degree of DNA repair vulnerability.
There is another important aspect: PTEN loss can also affect the immune environment around the tumour. Some PTEN-deficient cancers appear to create an immunosuppressive microenvironment. This means they may attract immune-suppressing cells, keep cancer-killing T cells away from the tumour, or become less responsive to immune checkpoint therapy. This is one of the central paradoxes of PTEN loss: it may create weaknesses that can be targeted, but at the same time it may help the tumour hide from the immune system.
Why PARP inhibitors may be relevant
PARP inhibitors are drugs that interfere with one of the cell’s DNA repair systems. Examples include olaparib and talazoparib. These medicines are most clearly effective in tumours that already have defects in DNA repair genes such as BRCA1 or BRCA2.
The concept behind this is called synthetic lethality. This means that a cancer cell may survive with one defective repair pathway, and it may also survive if another repair pathway is blocked. But if both repair routes are compromised at the same time, the cancer cell may accumulate so much DNA damage that it dies.
In BRCA-mutated prostate cancer, this concept is already clinically important. In PTEN-deficient tumours, the situation is less certain but scientifically interesting. PTEN loss may increase DNA damage, replication stress, and dependence on alternative repair pathways. Therefore, some PTEN-deficient tumours may be more sensitive to PARP inhibition than tumours with intact repair systems.
However, this should be interpreted carefully. PTEN loss is not currently as reliable a marker for PARP inhibitor response as BRCA1 or BRCA2 mutation. It may contribute to vulnerability, but it does not guarantee that a PARP inhibitor will work.
What electroporation and ablative therapies add
Electroporation-based treatments use short electrical pulses to disturb tumour cell membranes. Depending on the technique, this can directly kill cancer cells, increase the entry of drugs into tumour tissue, or trigger biological stress within the tumour. Examples include irreversible electroporation (IRE, NanoKnife™), electrochemotherapy (ECT), pulsed electric field therapies, and nanosecond pulsed electric fields.
These approaches are being studied because local tumour destruction may do more than simply remove or damage a visible tumour deposit. When tumour cells die, they can release tumour antigens, DNA fragments, inflammatory signals, and so-called danger-associated molecular patterns, often abbreviated as DAMPs. These signals can alert immune cells, especially dendritic cells, which help present tumour antigens to T cells.
This is sometimes described as turning the tumour into an in situ vaccine. “In situ” means “in its original place.” The idea is that instead of injecting a vaccine made in a laboratory, the destroyed tumour itself becomes a source of tumour-specific material that may train the immune system.
The abscopal effect: local treatment, distant response
The abscopal effect is a rare but fascinating phenomenon in cancer therapy. It refers to a situation in which treatment of one tumour site leads to shrinkage or immune attack against tumour sites elsewhere in the body. Historically, this idea has been discussed mainly in relation to radiotherapy. More recently, similar concepts have been explored with other local treatments, including electroporation, cryoablation, focused ultrasound, and thermal ablation.
The biological explanation is immune activation. Local tumour destruction releases antigens and danger signals. These can activate dendritic cells, which then stimulate T cells. If those T cells recognise tumour antigens shared by cancer cells throughout the body, they may travel through the bloodstream and attack metastases at distant sites.
In practice, abscopal responses are not common or predictable. But the concept is important because it suggests that a local therapy might be combined with systemic immune-based treatments to achieve broader disease control.
Why PARP inhibition and electroporation may reinforce each other
The most interesting part of this research area is the possible interaction between DNA damage, immune activation, and tumour cell death.
PARP inhibitors do more than block DNA repair. By increasing DNA damage, they may cause fragments of DNA to accumulate in places where they should not be, including the cytoplasm of the cell. The immune system can interpret misplaced DNA as a danger signal. One important pathway involved in this process is the cGAS–STING pathway.
The cGAS–STING pathway is part of innate immunity, the body’s early warning system. When DNA appears in the cytoplasm, cGAS can detect it and activate STING. This can lead to interferon signalling, inflammation, improved antigen presentation, and stronger T-cell priming.
Electroporation-based tumour destruction may also increase the release of tumour DNA and tumour antigens. Therefore, PARP inhibition and electroporation could theoretically amplify each other: one increases DNA damage and immune signalling, while the other releases tumour material and inflammatory signals into the local environment.
A possible three-way strategy
The proposed combination can be thought of as a sequence of reinforcing events.
First, PTEN loss makes the tumour biologically aggressive but may also increase genomic instability and stress.
Second, PARP inhibition makes DNA repair even more difficult. This may push tumour cells toward death and increase the amount of immunogenic DNA debris.
Third, electroporation or ablation destroys tumour cells locally, releases tumour antigens, and may stimulate dendritic cells.
Fourth, the immune system may become activated strongly enough to attack tumour cells at distant sites. This would be the desired abscopal immune response.
The broader goal is to force tumour cells into a form of death that is not silent, but immunogenic — meaning visible and stimulating to the immune system.
Where AKT inhibitors may fit in
Because PTEN loss activates the PI3K–AKT pathway, another logical treatment layer involves AKT inhibitors, such as ipatasertib and capivasertib. These drugs aim to block the survival signals that become stronger when PTEN is lost.
AKT inhibition may potentially do several things: reduce survival signalling, make tumour cells more sensitive to DNA damage, alter immune suppression, and possibly improve T-cell infiltration into tumours. This creates interest in combinations such as PARP inhibitors plus AKT inhibitors, PARP inhibitors plus immunotherapy, ablation plus immunotherapy, and eventually multi-part strategies that combine PTEN-pathway targeting, DNA repair targeting, and immune-stimulating local treatment.
The idea is not simply to add more drugs, but to block the tumour’s escape routes. If the tumour cannot repair DNA damage, cannot activate survival signalling, and cannot hide from the immune system, it may become more vulnerable.
The major challenge: PTEN loss can also promote immune resistance
The same PTEN loss that may create therapeutic vulnerabilities can also make treatment more difficult. PTEN-deficient tumours may suppress interferon responses, attract myeloid suppressor cells, and prevent effective T-cell entry into the tumour. This means that immune checkpoint inhibitors alone may not be enough in many PTEN-loss tumours.
That is why combination therapy is such an important concept in this field. Electroporation may provide antigen release. PARP inhibition may increase DNA damage and STING-related immune signalling. AKT inhibition may reduce survival signalling and potentially weaken immune suppression. Together, these approaches may help convert an immune-excluded, “cold” tumour into a more inflamed, immune-visible tumour.
What is established and what remains experimental
Several parts of this strategy are already supported individually. PARP inhibitors are established in prostate cancers with certain homologous recombination repair defects, especially BRCA1 and BRCA2 alterations. PTEN loss is recognised as a marker of more aggressive disease and a sign of PI3K–AKT pathway activation. Electroporation and other ablative therapies can destroy tumour tissue and may generate immune activation.
The combined strategy, however, is still at the research frontier. There is strong preclinical rationale for linking PTEN loss, PARP sensitivity, STING activation, and ablation-induced immune responses. Early clinical research is exploring combinations such as PARP inhibitors with checkpoint inhibitors, PARP inhibitors with AKT inhibitors, and ablation with immunotherapy.
But a full triple approach — PTEN-directed therapy, PARP inhibition, and electroporation-mediated abscopal immune stimulation — is not yet a proven standard regimen. At present, it should be considered experimental and best studied in carefully designed clinical trials.
Why this research direction is exciting
The excitement comes from the fact that the biology is complementary. A PARP inhibitor can push the tumour toward DNA damage catastrophe. AKT or PTEN-pathway targeting can reduce survival signalling. Electroporation can release tumour antigens and inflammatory signals. Abscopal immune activation could, in principle, help the immune system attack metastases beyond the locally treated site.
The overall vision is ambitious: to make prostate cancer cells unable to repair themselves, unable to rely on survival pathways, and unable to remain invisible to the immune system. In advanced prostate cancer, where resistance to standard therapies is a major problem, this kind of multi-axis strategy is one of the most interesting areas of translational research.
For patients, the key message is one of cautious optimism. These concepts are scientifically strong and may shape future treatment combinations, especially for biologically aggressive tumours such as those with PTEN loss. But they are not yet routine care. Anyone considering such approaches should discuss them with an experienced oncology team, ideally in the context of a clinical trial where safety, sequencing, dosing, and meaningful outcomes can be properly evaluated.
FAQ
No. Tumour genome sequencing is not necessary for every patient with prostate cancer. In many localized and lower-risk cases, treatment decisions are still mainly based on PSA levels, MRI findings, biopsy results, Gleason score, tumour stage and the patient’s overall situation.
However, molecular profiling can become increasingly relevant in advanced, metastatic or castration-resistant prostate cancer. In these situations, sequencing may help identify biological features such as BRCA alterations, PTEN loss, MSI-high status or androgen receptor changes that could influence therapy considerations or eligibility for certain treatments and clinical trials.
VITUS Privatklinik focuses primarily on advanced imaging, focal electroporation-based therapies and biologically informed prostate cancer treatment concepts.
Comprehensive tumour genome sequencing is not routinely performed in-house at the clinic. However, existing molecular findings, external sequencing reports, liquid biopsy results and relevant biomarkers may be considered as part of the overall treatment evaluation in selected patients.
The goal is not to rely on one single laboratory result, but to evaluate the complete clinical picture of the individual patient.
PTEN is a tumour suppressor gene that normally helps regulate cell growth and survival. When PTEN function is lost, prostate cancer cells may become more aggressive, more resistant to stress and more likely to metastasise.
PTEN loss is relatively common in advanced prostate cancer and is associated with activation of the PI3K–AKT signalling pathway. This pathway has become an important area of research because it may represent a potential therapeutic vulnerability in certain tumours.
Potentially yes. PTEN loss may provide biologically relevant information about tumour behaviour and may influence consideration of certain therapies or clinical trial approaches.
For example, PTEN-deficient tumours may show increased dependence on AKT signalling, which is why AKT inhibitors are being investigated in prostate cancer research. PTEN loss may also interact with DNA repair biology and immune signalling pathways.
However, PTEN is currently not a simple “one mutation, one drug” marker. Its clinical interpretation remains complex and should always be evaluated in the context of the overall disease situation.
PARP inhibitors are drugs that interfere with one of the cell’s DNA repair systems. Examples include olaparib and talazoparib.
These therapies are especially relevant in tumours with defects in DNA repair genes such as BRCA1 or BRCA2. In selected patients with advanced prostate cancer, PARP inhibitors may become an important part of modern precision oncology approaches.
Research is also exploring whether certain PTEN-deficient tumours may show increased sensitivity to PARP inhibition, although this remains an evolving field.
Electroporation-based therapies use short electrical pulses to affect tumour cells. Depending on the technique, this may directly destroy tumour tissue, increase uptake of therapeutic agents or induce biological stress within cancer cells.
Examples include:
- Irreversible electroporation (IRE / NanoKnife™)
- Electrochemotherapy (ECT)
- Pulsed electric field therapies
Unlike many thermal ablative methods, electroporation techniques may preserve surrounding connective tissue structures more effectively and are increasingly being investigated for their possible immunological effects.
Potentially yes. One of the major research interests surrounding focal therapies is the possibility that local tumour destruction may also trigger systemic immune activation.
When tumour cells die, they can release tumour antigens, DNA fragments and inflammatory signals that may help activate immune cells. This concept is sometimes referred to as turning the tumour into an “in situ vaccine.”
The extent to which this translates into meaningful systemic anti-cancer immune responses varies between patients and remains an active area of research.
The abscopal effect describes a rare phenomenon in which treatment of one tumour site appears to contribute to immune responses against tumour deposits elsewhere in the body.
Historically this concept has mainly been discussed in radiotherapy, but it is increasingly being explored in relation to electroporation, cryoablation, focused ultrasound and immunotherapy combinations.
Although true abscopal responses remain uncommon and unpredictable, the concept has become scientifically important because it suggests that local therapies may sometimes interact with systemic immune mechanisms.
Not currently. While some individual components are already established in selected patients — such as PARP inhibitors for certain BRCA-associated tumours — many combination strategies discussed in modern translational oncology remain experimental.
Research is actively investigating combinations involving:
- PARP inhibitors
- AKT inhibitors
- Immunotherapy
- Electroporation and ablative therapies
These approaches are scientifically promising but are still being evaluated in ongoing clinical research.
No. Molecular profiling is best understood as an additional layer of information rather than a replacement for established diagnostic methods.
MRI findings, biopsy results, PSA progression, tumour stage, symptoms, imaging and the patient’s general health remain central to treatment planning. Tumour sequencing may complement these findings by providing additional biological insight into the tumour.