Why We Can't "Cure" Cancer

Why We Can't "Cure" Cancer

One Name, Many Diseases: How Genomics Is Rewriting Prostate Cancer Treatment

Why "prostate cancer" is really a family of related illnesses — and what that means for your treatment plan

Informed Prostate Cancer Support Group (IPCSG) Newsletter — Patient Education Series

For most of medical history, prostate cancer was treated as one disease with one playbook: watch it, cut it out, radiate it, or starve it of testosterone. That playbook still matters. But over the last decade, something fundamental has shifted in how oncologists actually think about the disease sitting inside your prostate, or the one that has spread beyond it. The single word "prostate cancer" turns out to be a label covering a family of biologically distinct illnesses, each with its own genetic fingerprint, its own typical behavior, and — increasingly — its own matched treatment. This article walks through what that means in plain language, what tests are now available to find out which version of the disease you have, and what the most recent clinical trials and FDA actions have actually delivered for patients.

It's Not One Disease — It's a Family of Diseases

Pathologists have long graded prostate tumors by how abnormal the cells look under a microscope (the Gleason and Grade Group system). That tells you a lot about how aggressive a tumor looks, but very little about what is driving it at the molecular level, or which drug is most likely to work. Genomic sequencing — reading the actual DNA and RNA inside tumor cells — has shown that tumors with the same Gleason score can be driven by entirely different broken genes and pathways.

Researchers using a gene-expression tool called PAM50, originally developed for breast cancer, have sorted prostate tumors into three molecular subtypes — luminal A, luminal B, and basal — based on patterns of gene activity rather than appearance alone. Tumors in the basal subtype tend to behave more aggressively and respond differently to hormone therapy and chemotherapy than the luminal subtypes, a distinction invisible on a standard pathology report.^[1] A separate 2026 study out of Northwestern University went a step further, training an artificial intelligence model to predict these same molecular subtypes directly from a routine stained tissue slide — the kind every man's biopsy already produces — without needing to send tissue out for separate molecular testing. If validated further, this could make subtype information available to far more patients without added cost or delay.^[2]

Beyond these expression-based subtypes, a comprehensive 2026 review describes the genomic alterations now known to carve advanced prostate cancer into actionable categories, including defects in the DNA-repair machinery (homologous recombination repair, or HRR), mismatch-repair deficiency (MSI-H/dMMR), loss of the tumor-suppressor gene PTEN, BRCA1/BRCA2 mutations, ATM alterations, SPOP mutations, and a more recently recognized pattern of neuroendocrine transformation. The review also notes that roughly 15–20% of treatment-resistant tumors eventually lose the androgen-receptor signaling that hormone therapy depends on entirely, evolving into "double-negative" tumors that no longer look like classic prostate cancer at all under any of the usual molecular markers.^[3,4] This is precisely the kind of evolutionary escape route under treatment pressure that researchers increasingly view as central to why advanced cancer is so hard to eliminate outright — the tumor that returns is genomically not quite the tumor that was first treated.

The bottom line: Two men with the same Gleason score, the same stage, and the same PSA can be carrying meaningfully different diseases at the molecular level — and that difference increasingly determines which drugs will actually work.

Two Kinds of Genetic Testing — and Why the Distinction Matters

Patients often hear "genetic testing" and assume it's one test. In prostate cancer care, there are really two separate categories, and confusing them leads to a lot of patient anxiety and miscommunication with care teams.

Type	What it looks at	Sample	Why it's done
Germline testing	Mutations you were born with, present in every cell of your body and potentially passed to children	Blood or saliva	Identifies inherited risk (e.g., BRCA1/2, ATM, CHEK2, MSH2, HOXB13); informs family members' risk and guides certain treatment eligibility
Somatic (tumor) testing	Mutations that occurred only in the tumor itself, not inherited	Tumor tissue (biopsy or surgical sample) or sometimes blood-based "liquid biopsy"	Identifies treatment-actionable changes (HRR genes, MSI-H/dMMR, PTEN loss) that may not exist anywhere else in the body

Current National Comprehensive Cancer Network (NCCN) and European Association of Urology (EAU) guidelines recommend germline testing for men with metastatic prostate cancer, high-risk or very-high-risk localized disease, a strong family history of breast, ovarian, pancreatic, or prostate cancer, Ashkenazi Jewish ancestry, or intraductal histology on biopsy. Both NCCN and a majority of experts at the 2024–2025 Advanced Prostate Cancer Consensus Conference (APCCC) now recommend that men with metastatic castration-resistant disease receive both germline and somatic testing, since either one alone can miss clinically important mutations.^[5]

One sobering finding worth knowing about: the PROCLAIM trial, a multicenter study of nearly 1,000 prostate cancer patients in community urology practices, found that the rate of pathogenic mutations was nearly as high (6.6%) in patients who did not meet standard NCCN testing criteria as in those who did (8.8%) — suggesting that criteria-based testing may be missing a substantial share of men who carry clinically important mutations, and adding momentum to calls for broader, even universal, germline testing in newly diagnosed patients.^[6]

Genomic Classifiers for Localized Disease

For men with localized (non-metastatic) prostate cancer, a different set of tools — tissue-based genomic classifiers — help estimate how aggressive a given tumor is likely to be, which can guide decisions about whether to add radiation after surgery, or whether active surveillance is reasonable. The Decipher Prostate Test (Veracyte), a 22-gene genomic classifier, currently holds the highest evidence rating (Level 1) in the 2026 NCCN guidelines among the three Medicare-reimbursed risk tests, the others being Myriad Genetics' Prolaris and the Oncotype DX Genomic Prostate Score (now owned by MDxHealth).^[7,8] This evidence comes substantially from post-hoc analyses of large randomized NRG Oncology/RTOG trials, which found that men with low Decipher genomic-classifier scores had meaningfully lower 10-year rates of distant metastasis than those with high scores, suggesting the added benefit of intensifying hormone or radiation therapy is smaller in genomically low-risk tumors.^[7] NCCN guidelines note, appropriately, that in the absence of dedicated prospective trials, these tools should inform — not replace — clinical judgment.

When Genomics Changes the Prescription: PARP Inhibitors

The clearest example of genomics directly steering treatment in prostate cancer involves a class of drugs called PARP inhibitors. These drugs block a DNA-repair enzyme (PARP) that cancer cells with certain DNA-repair defects — most notably BRCA1, BRCA2, and other homologous recombination repair (HRR) gene mutations — depend on to survive. Roughly 25–30% of men with metastatic prostate cancer carry an HRR alteration in their tumor (inherited or acquired), and about 12% carry an inherited DNA-damage-repair mutation.^[9]

Four PARP inhibitors are now FDA-approved in prostate cancer, each tied to a defined genomic trial:

Drug	Combination	Pivotal Trial	Setting
Olaparib (Lynparza)	+ abiraterone/prednisone	PROPEL	mCRPC, approved May 2023
Talazoparib (Talzenna)	+ enzalutamide	TALAPRO-2	mCRPC, approved June 2023
Rucaparib (Rubraca)	monotherapy	TRITON2	BRCA-mutated mCRPC
Niraparib (Akeega)	+ abiraterone/prednisone	MAGNITUDE (mCRPC); AMPLITUDE (mHSPC)	BRCA1/2-mutated mCRPC (2023) and, newly, BRCA2-mutated metastatic hormone-sensitive disease (Dec. 2025)

The newest and arguably most important development came on December 12, 2025, when the FDA approved niraparib plus abiraterone acetate and prednisone for adults with deleterious or suspected deleterious BRCA2-mutated metastatic castration-sensitive prostate cancer (mCSPC) — meaning men earlier in the disease course, before resistance to hormone therapy develops, identified through an FDA-approved companion genomic test.^[10] This approval was based on the phase 3 AMPLITUDE trial (NCT04497844), which enrolled 696 men with HRR-mutated mCSPC. In the pre-specified BRCA2-mutated subgroup of 323 patients, the risk of radiographic progression or death was cut roughly in half (hazard ratio 0.46) compared with placebo plus standard therapy, and at the first interim survival analysis, 22% of men on the niraparib combination had died compared with 34% on placebo.^[10,11] Critically, the trial also showed that men without a BRCA2 mutation derived little to no benefit from adding the PARP inhibitor (hazard ratio 0.88, not statistically significant) — a clean demonstration that this drug's benefit is genuinely concentrated in, and dependent on, a specific genomic signature rather than working broadly across all comers.^[10,11] AMPLITUDE results were first presented at the 2025 ASCO Annual Meeting and published in Nature Medicine in October 2025.^[11]

This is precision oncology functioning exactly as intended: a drug that does real, measurable good for the right genomic subset, and that current evidence says should not be given broadly outside that subset, sparing other patients from unnecessary toxicity and cost for no expected benefit.^[9] Reflecting this, NCCN guidelines have now incorporated PARP-inhibitor-based regimens into the metastatic hormone-sensitive setting for appropriately selected, HRR-mutated patients, based on AMPLITUDE.^[9]

Mismatch-Repair Deficiency and Immunotherapy

A smaller but important subset of prostate cancers — generally estimated at a low single-digit percentage — carry defects in DNA mismatch repair (dMMR) genes (MLH1, MSH2, MSH6, PMS2) or show high microsatellite instability (MSI-H) on testing. This is the same molecular signature associated with Lynch syndrome, more commonly discussed in colorectal and endometrial cancer. These tumors generate unusually high numbers of mutated proteins that the immune system can recognize, which makes them disproportionately responsive to immune checkpoint inhibitors such as pembrolizumab (Keytruda) — a drug otherwise largely ineffective against typical, "immunologically cold" prostate tumors.^[12] Identifying this subgroup requires somatic tumor testing (and ideally germline testing as well, given the Lynch syndrome connection and implications for family members), reinforcing why comprehensive molecular testing, not just standard staging, increasingly belongs in the workup of advanced disease.

PTEN Loss and the PI3K/AKT Pathway

Loss of the tumor-suppressor gene PTEN, found in a substantial minority of advanced prostate tumors, activates a separate growth pathway (PI3K/AKT) that drives resistance to standard hormone therapy. The CAPItello-281 trial tested the AKT inhibitor capivasertib added to standard hormone therapy specifically in men whose tumors showed PTEN loss by immunohistochemistry (≥90% loss). The combination improved radiographic progression-free survival by 7.5 months compared with standard therapy alone, though an overall survival benefit has not yet been demonstrated, and the drug carries real side effects including gastrointestinal toxicity, rash, and hyperglycemia that require careful patient selection.^[9] This is an evolving area — promising, genomically guided, but not yet a slam-dunk standard of care the way the BRCA2/PARP inhibitor story has become.

When the Target Itself Changes: PSMA Theranostics and Genomic Resistance

For men with metastatic castration-resistant prostate cancer (mCRPC), no recent development has generated more hope — including hope for reaching disease hiding in micrometastases beyond the reach of surgery or focal radiation — than PSMA-targeted radioligand therapy ("theranostics"). The approach pairs a diagnostic PET scan with a therapeutic radioactive payload, both built on molecules that latch onto prostate-specific membrane antigen (PSMA), a protein heavily overexpressed on most prostate cancer cells. Lutetium-177 vipivotide tetraxetan (Pluvicto, a beta emitter) became the first FDA-approved PSMA radioligand therapy in 2022, based on the phase 3 VISION trial, which showed that adding it to standard care nearly tripled median imaging-based progression-free survival (8.7 vs. 3.4 months) and extended median overall survival from 11.3 to 15.3 months in heavily pretreated mCRPC patients.^[14] Actinium-225-based agents — which deliver alpha particles, a more potent but shorter-range form of radiation than Pluvicto's beta particles — are the newer generation, currently being tested in trials such as TATCIST (225Ac-PSMA-I&T, Fusion Pharmaceuticals) and other 225Ac-PSMA constructs, including academic and investigator-led trials combining alpha-emitter radioligand therapy with other targeted agents.^[15,16]

But you're right that the results are not universal, and the reasons why are themselves a genomics story.

Why PSMA Therapy Doesn't Work for Everyone

In the VISION trial, roughly 46% of patients had a meaningful PSA response, and real-world cohorts of similar regimens have reported response rates in a comparable range — meaning a substantial share of patients see limited benefit.^[17] Three molecular and biological factors largely explain why:

• PSMA expression heterogeneity. Not every tumor — and not every metastatic site within the same patient — expresses PSMA at the same level. Higher baseline PSMA PET uptake (measured as SUVmean) is consistently associated with better radiographic progression-free survival and overall survival, while tumors with low or "heterogeneous" expression (some lesions PSMA-positive, others not) respond poorly, since radioligand therapy can only deliver radiation to the PSMA-positive disease it can find and bind.^[18,19]
• Neuroendocrine transdifferentiation. Under the sustained pressure of androgen-deprivation and androgen-receptor-pathway therapy, a subset of tumors evolve away from the classic PSMA-expressing adenocarcinoma identity altogether, transforming into a neuroendocrine-like or "double-negative" phenotype that characteristically loses PSMA expression. This is precision oncology's version of the broader evolutionary-resistance pattern seen across cancer treatment generally: a strong selective pressure leaves behind, and indirectly favors, the very subpopulation least vulnerable to that exact pressure. Tumors that have undergone this shift are largely outside the eligibility window for PSMA-targeted therapy and currently have no validated radioligand alternative, though academic groups are now investigating other surface targets — such as the neurotensin receptor NTSR1 — specifically for PSMA-negative, neuroendocrine-transformed disease.^[20]
• Dose delivery and tumor biology. Even with adequate PSMA expression, factors such as tumor volume, the ability to deliver a lethal radiation dose to every metastatic deposit, the surrounding tumor microenvironment, and intrinsic radioresistance of certain tumor clones all influence whether a course of treatment actually kills the cancer cells it reaches.^[17]

Where PSMA Theranostics Is Headed

Several developments from 2025–2026 point toward a more genomically tailored future for this treatment class:

• Moving earlier in the disease course. The PSMAddition trial tested Pluvicto added to standard hormone therapy in PSMA-positive metastatic hormone-sensitive disease — earlier than the heavily pretreated mCRPC population in VISION. New data presented at the American Urological Association's 2026 annual meeting showed a 58% lower risk of PSA progression with the Pluvicto combination compared with standard care alone, with deeper and more durable PSA responses; Novartis filed for expanded approval in the US, China, and Japan, with regulatory decisions expected in the second half of 2026.^[21,22]
• Imaging and dosimetry as predictive biomarkers. Total tumor volume and PSMA expression intensity on PET, and increasingly cycle-by-cycle SPECT imaging done during treatment itself, are being refined as quantitative predictors of who will respond and who will progress — allowing treatment to be adapted in real time rather than continued blindly for a fixed number of cycles.^[18,23]
• Combination strategies. Because alpha-emitter radiation causes direct double-strand DNA breaks, there is growing interest in pairing PSMA-targeted alpha therapy with DNA-damage-response inhibitors such as PARP inhibitors, on the theory that a tumor already struggling to repair radiation-induced DNA damage may be even more vulnerable if its own DNA-repair pathways are simultaneously blocked — directly tying the genomic story of HRR mutations back into the radioligand therapy story.^[15,24]
• Genomic and lineage-plasticity modeling. Experts in the field are now explicitly calling for integrated models that combine imaging, radiation dosimetry, and tumor genomics together, since the same lineage-plasticity programs that drive neuroendocrine transformation also appear to modulate PSMA expression and radiosensitivity — meaning the next generation of patient selection for theranostics may look a lot more like the genomically guided selection already used for PARP inhibitors.^[23]

In short: PSMA theranostics has given real, measurable extra time to many men with mCRPC, including disease that imaging alone could never have targeted with external radiation. But it is not a universal cure, and the reasons it sometimes fails — variable or lost PSMA expression, neuroendocrine transformation, and underlying tumor biology — are exactly the kind of genomic and molecular questions this article has been describing. The field's direction is toward identifying, ahead of time, which men are most likely to benefit, and developing alternative targeted approaches for those whose tumors have evolved past PSMA altogether.

Fighting Evolution With Evolution: Bipolar Androgen Therapy

Every treatment discussed so far works by finding a fixed genomic or molecular feature — a BRCA2 mutation, MSI-H status, PTEN loss, PSMA expression — and exploiting it. But there's a fundamentally different strategy worth understanding, because it attacks the resistance mechanism itself rather than any one mutation: bipolar androgen therapy, or BAT.

Standard androgen deprivation therapy works by starving prostate cancer cells of testosterone. But over time, many tumors adapt: cells that survive the low-testosterone environment often do so by upregulating the androgen receptor (AR) itself, or by producing AR "splice variants" that stay active even without much testosterone around — essentially recalibrating themselves to thrive in the very environment designed to kill them. This is the same survivor-selection process described earlier in this article, just playing out at the level of receptor biology rather than DNA-repair genes.

BAT turns that adaptation into a vulnerability. Rather than holding testosterone permanently low, BAT cycles a patient between supraphysiologic (very high) and near-castrate (very low) testosterone levels, typically by injecting testosterone cypionate every 28 days while continuing standard ADT. Preclinical work has shown that the high-testosterone surge in this cycle can paradoxically harm the very cells that adapted to low testosterone: it downregulates the androgen receptor and its resistant splice variants, slows cell cycle progression, and induces double-strand DNA breaks and genomic rearrangements in tumor cells that had become AR-dependent in a different way.^[25,26] In effect, the same adaptive AR overexpression that let resistant cells survive starvation becomes a liability when testosterone suddenly flares back up — the tumor cell population gets caught flat-footed by oscillating faster, and in the opposite direction, than its resistance mechanism can re-adapt to.

The concept has moved well beyond theory:

• TRANSFORMER trial provided early clinical evidence that BAT can re-sensitize tumors that had become resistant to androgen-receptor pathway inhibitors (ARPIs) to subsequent antiandrogen therapy — essentially resetting the tumor's vulnerability to a drug class it had already escaped.^[25]
• COMBAT trial (phase 2, Johns Hopkins-led, published in Nature Communications) combined BAT with the immune checkpoint inhibitor nivolumab in 45 heavily pretreated mCRPC patients, achieving a 40% confirmed PSA50 response rate and a 24% objective response rate — notable because immune checkpoint inhibitors alone have shown very limited activity in prostate cancer. Patients who responded showed BAT-induced pro-inflammatory gene-expression changes in their tumors, and response correlated with higher baseline PD-1-positive T-cell infiltration, suggesting BAT may "prime" otherwise immunologically cold prostate tumors to respond to immunotherapy.^[27,28]
• ExBAT trial (LACOG 0620), presented at the 2025 ASCO GU symposium, tested an "extreme" version alternating darolutamide with testosterone cypionate in mCRPC patients who had limited benefit from sequential AR-pathway inhibitors alone.^[29]
• WOMBAT trial (ANZUP 2201), also presented at ASCO GU 2025, is testing BAT combined with intermittent darolutamide specifically in earlier, non-metastatic castration-resistant disease (nmCRPC), aiming to delay the development of detectable metastases.^[30]

BAT is not without trade-offs — it requires careful patient selection and monitoring, and its exact mechanism of action is still being worked out, with researchers proposing several overlapping explanations (AR downregulation, direct DNA damage, and immune activation all appear to play a role).^[28] But conceptually, it's one of the more clever examples in current prostate cancer research of treating resistance not as a wall to break through with a bigger hammer, but as a predictable evolutionary trajectory that can itself be exploited — the same insight, turned to the patient's advantage, that explains why chemotherapy and androgen-deprivation therapy eventually stop working in the first place.

A Quick Glossary

Germline mutation

A genetic change present in every cell of the body from birth, potentially heritable.

Somatic mutation

A genetic change acquired only in the tumor, not inherited or passed to children.

HRR (homologous recombination repair)

A group of genes, including BRCA1/2 and ATM, responsible for repairing a particularly dangerous type of DNA damage. Defects in these genes are what make PARP inhibitors effective.

MSI-H / dMMR

Microsatellite instability-high / mismatch repair-deficient — a tumor signature associated with high mutation burden and responsiveness to immunotherapy.

PTEN loss

Loss of a tumor-suppressor gene that normally restrains cell growth; its absence activates the PI3K/AKT growth pathway.

Genomic classifier (e.g., Decipher)

A tissue-based test that scores how aggressively a localized tumor is likely to behave, used to guide treatment intensity decisions.

mHSPC / mCSPC

Metastatic hormone (castration)-sensitive prostate cancer — disease that has spread but still responds to hormone therapy.

mCRPC

Metastatic castration-resistant prostate cancer — disease that has progressed despite hormone therapy.

PSMA (prostate-specific membrane antigen)

A protein overexpressed on the surface of most prostate cancer cells, used as a target for both PET imaging and radioligand ("theranostic") therapy.

Radioligand therapy (RLT) / theranostics

Treatment that pairs a diagnostic scan and a therapeutic radioactive drug built on the same targeting molecule (e.g., PSMA), so imaging confirms the target is present before radiation is delivered to it.

Neuroendocrine transdifferentiation

A process by which a prostate adenocarcinoma evolves, usually after prolonged hormone therapy, into a neuroendocrine-like tumor that typically loses PSMA expression and behaves very differently from typical prostate cancer.

Bipolar androgen therapy (BAT)

A treatment that cycles patients between very high and very low testosterone levels, exploiting the way resistant tumor cells adapt to chronic low testosterone, rather than targeting a fixed gene mutation.

What This Means for You and Your Care Team

• If you have metastatic disease, regional/node-positive disease, high-risk or very-high-risk localized disease, intraductal histology, or a strong family cancer history, ask your oncologist or urologist whether germline genetic testing is appropriate for you — and consider genetic counseling before and after.
• If you have metastatic disease, ask whether tumor (somatic) testing has been done or should be done, since it can reveal HRR mutations, MSI-H/dMMR status, or PTEN loss that exist only in the tumor and could open the door to a PARP inhibitor, immunotherapy, or an AKT-inhibitor trial.
• If you are considering active surveillance or weighing whether to add radiation after surgery, ask whether a genomic classifier test such as Decipher is appropriate for your situation — it is not needed by everyone, and NCCN guidance is explicit that it should be ordered only when the result has the potential to actually change your management plan.
• Genomic findings can change over time as tumors evolve, especially after treatment. A somatic test done years ago at diagnosis may not reflect what your cancer's genome looks like today.

This article is for general education and does not constitute medical advice. Treatment decisions depend on your full clinical picture and should always be made together with your oncology team. IPCSG members are encouraged to bring questions raised by this article to their next clinical appointment.

Sources

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