Prostate cancer has come back: what do castration-sensitive and castration-resistant really mean? | Dr Dilanka De Silva

Many men come to see me after prostate cancer treatment worried about prostate cancer recurrence, often because their PSA has started rising again.

“My PSA is rising again. Does this mean my cancer has come back?”

Sometimes the answer is yes.

But that is only the beginning of the conversation.

What matters next is where the cancer is, whether we can see it on scans, and whether it is still responding to treatments that lower or block testosterone.

Those three things explain why prostate cancer treatment can change so much over time.

Who is this article for?

This article is for men who:

• have previously had prostate surgery or radiotherapy;
• have been told their PSA is rising again;
• have recently been diagnosed with metastatic prostate cancer;
• have heard terms such as hormone-sensitive, castration-sensitive or castration-resistant;
• are receiving androgen-deprivation therapy, or ADT;
• want to understand why their treatment has changed; or
• want to understand what treatments may still be available later.

The question

A gentleman in his early fifties recently came to see me.

Let us call him Michael.

Several years earlier, he had been diagnosed with an aggressive prostate cancer.

His biopsy showed a Gleason score of 4 + 5 = 9, corresponding to ISUP Grade Group 5.

He underwent radical prostatectomy.

After surgery, his PSA became undetectable.

That was exactly what we wanted to see.

For several years, everything remained reassuring.

Then something changed.

His PSA became detectable again.

At first, it was very low.

He felt completely well.

Naturally, he asked:

“Does this mean my prostate cancer has come back?”

The short answer

A rising PSA after prostate cancer treatment can be the first sign that prostate cancer cells remain somewhere in the body.

But a rising PSA does not tell us everything.

It does not necessarily tell us:

• where those cells are;
• whether they can be seen on a scan;
• whether the disease has spread;
• whether the cancer still responds to hormone treatment; or
• which treatment should come next.

That is why understanding the prostate cancer journey is so important.

What does an undetectable PSA after surgery mean?

PSA is produced mainly by prostate cells.

After a radical prostatectomy removes the prostate, we therefore expect the PSA to fall to a very low or undetectable level.

If the PSA later becomes detectable and continues to rise, this may indicate what doctors call biochemical recurrence.

The word ‘biochemical’ means the recurrence is first recognised through the PSA blood test, sometimes before cancer can be seen on imaging.

This does not automatically mean widespread metastatic cancer.

There may initially be only a very small number of cancer cells.

Prostate cancer recurrence: when the PSA starts rising again

Imagine the PSA starts rising after surgery.

The patient feels well.

We may not yet see cancer elsewhere in the body.

This is not the same thing as metastatic prostate cancer.

Depending on the previous treatment, pathology, PSA level, PSA doubling time and imaging findings, there may still be an opportunity to treat the disease with curative intent.

For a man who previously had surgery, one important treatment may be salvage radiotherapy.

What is salvage radiotherapy?

The word “salvage” sounds more frightening than it should.

It simply means radiotherapy given after surgery because there is concern that prostate cancer cells remain in or around the prostate bed or nearby region.

The intention may still be to eradicate the remaining cancer and achieve long-term disease control or cure.

When salvage radiotherapy is appropriate, outcomes are generally better when treatment is given early rather than waiting for the PSA to rise substantially.

Michael underwent salvage treatment and his PSA again fell to a very low level.

For a period, everything remained reassuring.

Then the PSA started rising again

Several months later, the PSA began to increase.

Eventually, it reached several ng/mL.

At that point, further imaging was arranged.

A PSMA PET scan identified prostate cancer deposits beyond the original local treatment area. In Michael’s case, these represented metastatic disease.

What does metastatic prostate cancer mean?

Metastatic simply means that prostate cancer cells have travelled beyond the original prostate region to another part of the body.

Common sites include:

• lymph nodes;
• bones; and
• less commonly, organs such as the liver or lungs.

A metastatic diagnosis is serious.

But it does not mean there are no effective treatments left.

Modern prostate cancer treatment has changed enormously, and many men now live for prolonged periods with metastatic disease.

Understanding the prostate cancer journey

This is the table I would make central to the article:

One important modern nuance is that increasingly sensitive imaging such as PSMA PET can sometimes detect very small metastases that conventional CT or bone scans would previously have missed.

That means the boundaries between some of these older labels are becoming less absolute.

What does “castration-sensitive” actually mean?

The term sounds much more complicated than the concept.

Castration-sensitive prostate cancer means the cancer still responds when testosterone is reduced or its signal is blocked.

You may also hear the term hormone-sensitive prostate cancer.

They largely describe the same biological state.

Prostate cancer cells often depend heavily on androgen signalling.

Androgen-deprivation therapy, or ADT, lowers testosterone to very low levels.

This can be achieved with hormone injections or, less commonly in Australia, by surgical removal of the testicles.

When the cancer responds, the PSA may fall dramatically and metastatic deposits may shrink.

What surprised me about how much treatment has changed

When I first learned about metastatic prostate cancer, androgen deprivation was often the central treatment.

Today, for most men who are fit enough for additional treatment, ADT alone is usually no longer the whole treatment plan. We often add another medicine—and in selected patients chemotherapy—to control the cancer more effectively from the beginning.

Why?

Because multiple large trials have shown that treating the cancer more effectively earlier in its journey can help men live longer.

This is one of the most important changes in modern prostate cancer care.

ADT alone versus modern treatment

A useful example is the TITAN trial.

The trial included 1,052 men with metastatic castration-sensitive prostate cancer.

Men received either:

• ADT plus apalutamide; or
• ADT plus placebo.

At four years, approximately:

• 65 in every 100 men receiving apalutamide plus ADT were alive;
• compared with about 52 in every 100 men receiving ADT without apalutamide.

In statistical terms, this represented about a 35% relative reduction in the risk of death during the study.

That does not mean every individual patient gains exactly the same amount.

But it demonstrates why simply lowering testosterone is no longer considered enough treatment for many fit men with metastatic hormone-sensitive disease.

What are androgen-receptor pathway inhibitors?

These medicines make it harder for prostate cancer cells to use testosterone and related male-hormone signals to grow. Doctors often call these androgen-receptor pathway inhibitors, or ARPIs.

Examples include:

• abiraterone;
• enzalutamide;
• apalutamide; and
• darolutamide.

They do not all work in exactly the same way, and they are not interchangeable in every clinical situation.

The choice depends on factors such as:

• disease volume;
• previous treatment;
• cardiovascular health;
• other medicines;
• liver function;
• seizure risk;
• side-effect profile;
• whether chemotherapy is being used; and
• PBS eligibility.

When is chemotherapy used?

Chemotherapy still has an important role.

The chemotherapy most commonly used early in metastatic hormone-sensitive prostate cancer is docetaxel.

One of the landmark studies was CHAARTED.

In the original analysis, among men with high-volume metastatic disease, median overall survival was approximately:

• 49.2 months with ADT plus docetaxel
• compared with 32.2 months with ADT alone.

That was a difference of around 17 months in median survival in that subgroup.

In this trial, “high-volume” disease meant either cancer involving internal organs or at least four bone metastases, with at least one outside the spine or pelvis.

The trial used six cycles of docetaxel, given every three weeks.

However, I would not translate that into:

“Every patient with metastatic prostate cancer needs six cycles of chemotherapy.”

They do not.

Whether chemotherapy is appropriate depends on the patient’s disease pattern, general health, other available therapies and overall treatment strategy.

What is triplet therapy?

For some men—particularly those with newly diagnosed metastatic disease who are fit enough for chemotherapy—we may consider three treatments together:

• ADT
• an androgen-receptor pathway inhibitor
• docetaxel

This is called triplet therapy.

Two important trials helped establish this approach.

ARASENS

ARASENS included 1,306 men with metastatic hormone-sensitive prostate cancer.

Everyone received ADT and docetaxel.

Half also received darolutamide.

At four years, approximately:

• 63 in every 100 men receiving darolutamide + ADT + docetaxel were alive;
• compared with about 50 in every 100 receiving ADT + docetaxel without darolutamide.

This represented about a 32% relative reduction in the risk of death.

PEACE-1

PEACE-1 also showed that adding abiraterone to ADT and docetaxel improved both progression-free and overall survival in men with de novo metastatic castration-sensitive prostate cancer.

This represented about a 25% relative reduction in the risk of death in that treatment group.

These results are important.

But triplet therapy is not automatically right for every man.

The decision should consider disease volume, whether the metastases were present at the original diagnosis, fitness for chemotherapy, other health conditions and patient priorities.

So what does “castration-resistant” mean?

This is another term that often alarms patients.

It does not mean that hormone treatment has suddenly become completely useless.

It means that the cancer has developed ways to continue growing despite testosterone being suppressed to very low levels.

That is called castration-resistant prostate cancer.

At this point, we usually continue the underlying ADT and add or change another treatment.

Current ASCO guidance recommends continuing androgen deprivation in metastatic castration-resistant disease.

So the journey may look like:

Cancer responds to testosterone suppression
↓
Cancer remains controlled for a period
↓
Cancer eventually begins growing despite very low testosterone
↓
Castration-resistant prostate cancer

This is a change in the biology of the cancer.

It does not mean we have reached the end of treatment.

What treatments are available after prostate cancer becomes castration resistant?

This is where treatment becomes particularly personalised.

Depending on what the patient has already received, options may include:

• chemotherapy such as docetaxel or cabazitaxel;
• other androgen-receptor-targeted treatment in carefully selected situations;
• PARP inhibitors for cancers with appropriate DNA-repair gene alterations;
• lutetium-177 PSMA radioligand therapy for suitable PSMA-positive disease;
• radium-223 for selected men with symptomatic prostate cancer involving the bones;
• immunotherapy in selected biomarker-defined cancers;
• clinical trials; and
• treatments directed at particular painful or threatening metastases.

Current ASCO guidance specifically emphasises that previous treatments used during the hormone-sensitive phase influence what should be used once the disease becomes castration resistant.

This is why treatment sequencing matters so much.

What if my PSA is rising but scans still do not show metastatic cancer?

This is another area where treatment has changed.

Some men develop high-risk biochemical recurrence after surgery or radiotherapy.

The EMBARK study examined selected men with high-risk biochemical recurrence. Importantly, EMBARK was designed using conventional imaging. Today, PSMA PET may detect very small deposits that older CT and bone scans would not have shown, so an individual patient may not fit neatly into exactly the same category.

It included men whose PSA doubling time was 9 months or less.

Patients received:

• enzalutamide plus leuprolide;
• leuprolide alone; or
• enzalutamide alone.

The final survival results are particularly important.

At eight years:

• about 79 in every 100 men receiving enzalutamide plus leuprolide were alive;
• compared with about 70 in every 100 men receiving leuprolide alone.

The combination reduced the relative risk of death by approximately 40%.

This does not mean every man whose PSA rises should immediately start enzalutamide and ADT.

EMBARK studied a carefully selected high-risk population.

PSA doubling time, previous treatment, imaging findings, other health conditions and the patient’s priorities all matter.

One patient can move through several different prostate cancer states

This is the part I think patients find most useful.

A man might begin with:

Localised prostate cancer

↓
Surgery

↓
Undetectable PSA

↓
PSA begins rising

↓
Biochemical recurrence

↓
Salvage radiotherapy

↓
PSA controlled again

↓
PSA rises later

↓
PSMA PET detects metastatic disease

↓
Metastatic hormone-sensitive prostate cancer

↓
ADT + additional systemic treatment

↓
Cancer remains controlled for a period

↓
Eventually progresses despite very low testosterone

↓
Metastatic castration-resistant prostate cancer

This is not what happens to every patient.

Some men never recur.

Some recur but remain non-metastatic for years.

Some metastatic cancers remain controlled for prolonged periods.

The pathway is different for every person.

But understanding these terms makes it much easier to understand why the treatment changes.

What about genetic testing?

Genetics becomes increasingly important as prostate cancer becomes more advanced.

Inherited—or germline—testing looks for cancer-risk gene changes that a person may have been born with, including changes in genes such as BRCA2, BRCA1, ATM and PALB2.

Tumour testing looks for genetic changes that have developed within the cancer itself.

Why?

Because certain DNA-repair changes can make treatments such as PARP inhibitors relevant.

Current guidance supports germline testing for men with metastatic prostate cancer, and tumour genomic testing becomes particularly important when the result may guide systemic treatment.

Genetic findings may also be relevant to children, siblings and other close family members.

What does this mean for patients in Australia?

Australian patients have PBS access to several major prostate cancer treatments in defined clinical settings.

For example, enzalutamide, apalutamide, darolutamide and abiraterone have PBS listings for particular prostate cancer indications, although not every medicine is funded in every disease state or combination.

This distinction matters.

The question should not simply be:

“Is this drug on the PBS?”

It should be:

“Is this drug PBS-funded for my exact stage of prostate cancer and my previous treatment history?”

PBS restrictions change over time and should be checked when treatment is being planned.

What would I usually consider?

When I review a man whose PSA has begun rising again, I do not start by asking:

“Which drug should we use?”

I first try to establish:

• What treatment has he already received?
• Did the PSA previously become undetectable?
• How quickly is the PSA now rising?
• What is the PSA doubling time?
• Is disease visible on PSMA PET or other imaging?
• Is the cancer still hormone sensitive?
• Is testosterone adequately suppressed if he is already receiving ADT?
• How much cancer is present and where?
• What systemic treatments has he already received?
• Has inherited genetic testing been performed?
• Has tumour genomic testing been considered?
• What treatments should we preserve for later?
• What matters most to this particular patient?

Only then does the next treatment decision make sense.

What surprised me most

One of the biggest changes in prostate cancer care over the last decade is that we have stopped thinking only about:

“What do we give when the cancer gets worse?”

Increasingly, we ask:

“Can using the right treatment earlier delay that worsening and help this patient live longer?”

Trials such as CHAARTED, TITAN, ARASENS, PEACE-1 and EMBARK have repeatedly moved effective treatments earlier in the prostate cancer journey.

But more treatment is not automatically better for every patient.

The goal is appropriate treatment intensification.

The right treatment, for the right patient, at the right point in the disease journey.

The one message I want patients to remember

If your PSA starts rising again, it does not mean you have reached the end of your treatment options.

It means we need to understand where you are in the prostate cancer journey.

Is this biochemical recurrence?

Can treatment still be given with curative intent?

Has the cancer become metastatic?

Is it still hormone sensitive?

Has it become castration resistant?

Those answers determine what we do next.

The terminology may change over time because the cancer itself changes over time.

And fortunately, the number of treatments available to us has also changed enormously.

Key takeaways

• A rising PSA is a signal that prostate cancer may have returned, but it does not by itself tell us where the cancer is or what treatment is needed.
• “Hormone-sensitive” means the cancer still responds to lowering or blocking testosterone; “castration-resistant” means it has begun growing despite testosterone already being very low.
• Modern treatment increasingly uses effective therapies earlier. Large trials have shown that adding appropriate systemic treatment to ADT can improve survival for many men with metastatic hormone-sensitive disease.
• The best treatment depends on where you are in the prostate cancer journey. Previous treatment, imaging, PSA behaviour, hormone sensitivity, genetics, overall health and personal goals all help determine what should come next.

Key evidence

1. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737-746. doi:10.1056/NEJMoa1503747
2. Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021;39(20):2294-2303. doi:10.1200/JCO.20.03488
3. Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132-1142. doi:10.1056/NEJMoa2119115
4. Fizazi K, Foulon S, Carles J, et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet. 2022;399(10336):1695-1707. doi:10.1016/S0140-6736(22)00367-1
5. Freedland SJ, de Almeida Luz M, De Giorgi U, et al. Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med. 2023;389(16):1453-1465. doi:10.1056/NEJMoa2303974
6. Shore ND, de Almeida Luz M, De Giorgi U, et al. Improved survival with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med. 2026;394(6):563-575. doi:10.1056/NEJMoa2510310
7. Taplin ME, Riaz IB, Rumble RB, et al. Systemic therapy in patients with metastatic castration-resistant prostate cancer: ASCO living guideline, version 2026.1. J Clin Oncol. 2026;44(6):e1-e14. doi:10.1200/JCO-25-02693
8. European Association of Urology. EAU Guidelines on Prostate Cancer. 2026 edition. Accessed June 26, 2026. https://uroweb.org/guidelines/prostate-cancer

Frequently asked questions (FAQs)

1. Does a rising PSA mean my prostate cancer has definitely spread?

No.

A rising PSA after surgery or radiotherapy may indicate biochemical recurrence before metastatic disease can be identified.

Further assessment depends on PSA behaviour, previous treatment and imaging.

2. What is biochemical recurrence?

Biochemical recurrence means the PSA has risen again after treatment given with curative intent. It is detected through the PSA blood test and does not automatically mean the cancer has spread elsewhere in the body.

3. What does hormone-sensitive prostate cancer mean?

Hormone-sensitive prostate cancer is cancer that still responds to treatments that lower testosterone or block the signals testosterone uses to stimulate prostate cancer growth.

4. Is hormone-sensitive the same as castration-sensitive?

In routine prostate cancer discussions, these terms are generally used to describe the same biological state.

5. What does castration-resistant mean?

It means the cancer has begun growing despite testosterone already being reduced to very low levels.

It does not mean that all treatments have stopped working.

6. Do hormone injections stop when prostate cancer becomes castration resistant?

Usually not.

ADT is generally continued while another treatment is added or changed.

7. Does metastatic prostate cancer always require chemotherapy?

No.

Modern treatment includes several effective hormone-targeted medicines, chemotherapy and other therapies.

The most appropriate combination depends on the individual situation.

8. Does everyone with metastatic hormone-sensitive prostate cancer need triplet therapy?

No.

Triplet therapy can be very effective for selected patients, particularly when chemotherapy is already considered appropriate, but it is not required for every man.

9. What does PSA doubling time mean?

It is an estimate of how quickly the PSA is increasing.

A shorter doubling time may indicate more active disease and can influence whether treatment should begin earlier.

10. Why might I need genetic testing?

Inherited and tumour genetic testing may identify changes that affect future treatment options and can sometimes provide important information for close family members.

About Dr Dilanka De Silva

Dr Dilanka De Silva is a Melbourne-based Medical Oncologist and Cancer Genetics Physician with experience in precision oncology, prostate cancer treatment and complex second opinions.

He completed fellowship training at Memorial Sloan Kettering Cancer Center in New York and reviews Australian and international patients, including patients from Sri Lanka, the Maldives, Indonesia and the Philippines.

Modern prostate cancer care may involve collaboration between medical oncologists, urologists, radiation oncologists, nuclear-medicine specialists, radiologists, pathologists and cancer genetics specialists.

Dr Dilanka De Silva
MBBS, MRCP(UK), MRCP(UK SCE Oncology), FRACP, PhD
Medical Oncologist & Cancer Genetics Physician
Memorial Sloan Kettering Cancer Center Fellow (New York, USA)