Ac-225 PSMA Therapy — when Lu-177 stops working.

What is Ac-225 PSMA therapy?

Ac-225 PSMA is positioned in our practice as a salvage line — not a first option. The patients who arrive here have typically already received 4 to 6 cycles of Lu-177 PSMA and are progressing despite continued PSMA-PET avidity. A smaller subset are referred for Ac-225 as initial therapy when disease pattern (very bulky, very aggressive, or PSMA-heterogeneous) suggests beta radiation alone may be insufficient.

The therapy has been pioneered by the Heidelberg group (Kratochwil et al.) since 2014 and validated by the Sathekge South African cohorts^2,3 and Indian centres including AIIMS Delhi. At Theranostic Physicians, we administer Ac-225 PSMA-617 on alternate Fridays, with fortnightly cadence and dose individualised at 100 kBq per kilogram body weight.

Alpha vs beta — what changes.

Both Lu-177 and Ac-225 use the identical PSMA-617 ligand and bind the same PSMA receptors on prostate cancer cells. The clinical differences come down to particle physics.

The reason this matters clinically: tumour cells that survive Lu-177 beta therapy — through DNA repair, hypoxic resistance, or simply being outside the 2 mm range of a poorly distributed dose — often remain vulnerable to Ac-225's clustered DNA damage. The short alpha range also reduces some off-target effects (kidneys see less dose) but concentrates damage intensely in tissues with PSMA expression. This includes the salivary glands.

Who is a candidate?

Patient selection for Ac-225 PSMA is more conservative than Lu-177 because the side-effect profile — particularly xerostomia — is materially worse. We discuss the trade-off candidly before offering the therapy. The three scenarios where we recommend Ac-225 at our centre:

• Post-Lu-177 progression with retained PSMA-PET uptake. The most common indication. Patients have completed 4–6 cycles of Lu-177 PSMA, achieved partial response or stable disease, and then progressed. Repeat 68Ga-PSMA-11 PET still shows avid disease — meaning the target is still present, just no longer responding to beta radiation.
• De novo bulky aggressive disease. Selected first-line cases with very high tumour burden, particularly visceral or large nodal disease, where the cell-kill per cycle of Lu-177 alone is unlikely to be sufficient. Often combined with starting Lu-177 first and escalating to Ac-225 at cycle 3 or 4.
• PSMA-heterogeneous or PSMA-low disease. When PSMA-PET shows non-uniform uptake, beta crossfire from Lu-177 may miss PSMA-low pockets. Alpha radiation's intense local damage is sometimes effective even at lower receptor density.

Standard organ-function thresholds apply: creatinine clearance >50 mL/min, haemoglobin >9 g/dL, platelets >100 × 10⁹/L, normal liver function. Salivary function should be assessed at baseline; significantly impaired salivary function pre-therapy is a relative contraindication.

The 3–4 cycle protocol.

Standard Ac-225 PSMA at our centre follows the Heidelberg-Sathekge protocol: 3 to 4 cycles of 100 kBq per kilogram body weight, every 8 weeks, with dose adjustment in later cycles based on tolerability — particularly xerostomia severity.

Total course duration: approximately 6 to 7 months. Each cycle is a same-day outpatient procedure; international patients typically combine each cycle with a 2–3 night stay in Gurugram.

What the data shows.

There is no phase 3 randomised trial for Ac-225 PSMA — the evidence base is built on prospective and retrospective cohorts from Heidelberg, South Africa, Australia and India. The signal is consistent: meaningful PSA decline and disease control in heavily pre-treated patients who have run out of standard options.

Heidelberg — the original series

Kratochwil and colleagues¹ published the first proof-of-concept case series in 2016, demonstrating dramatic radiographic responses in heavily pre-treated mCRPC patients including those refractory to chemotherapy and Lu-177 PSMA. The clinical photographs of complete PSMA-PET disappearance in chemotherapy-refractory patients shifted the field.

Sathekge South African cohort

The Sathekge group^2,3 at Steve Biko Hospital, Pretoria, has published the largest prospective Ac-225 PSMA experience in the world. In Lu-177-refractory mCRPC, PSA50 response rates of approximately 70% were reported, with median overall survival of approximately 18 months — remarkable for a population with no remaining standard-of-care options.

Indian experience

Yadav and colleagues at AIIMS Delhi⁴, and our own centre, have administered Ac-225 PSMA-617 in Indian mCRPC cohorts since 2018. Real-world Indian PSA50 response rates align with Sathekge data (60–75% in Lu-refractory patients). Bone-marrow-replaced disease and very high baseline PSA (>1000 ng/mL) are consistent negative predictors.

Xerostomia — the conversation we must have.

The single most important counselling point before Ac-225 PSMA. 80–90% of patients develop xerostomia (dry mouth), and in approximately 30% it is grade 2 or 3 — meaningful enough to affect speech, swallowing, sleep, and dental health. In a meaningful minority, it is permanent.

This happens because salivary glands physiologically express PSMA — not as much as prostate cancer cells, but enough to bind PSMA-617. Lu-177 beta therapy also deposits some radiation in the salivary glands, but the relative biological effect is mild because beta radiation produces sparse, repairable DNA damage. Alpha radiation from Ac-225 produces clustered, double-strand DNA breaks that salivary acinar cells cannot easily repair. The short alpha range concentrates that damage intensely within the gland.

What we do to mitigate it

• Cold packs to parotid and submandibular glands during infusion and for several hours after, reducing perfusion and tracer delivery to the glands.
• Sialagogue support — sugar-free gum and sialagogue lozenges, encouraging hydration and salivary stimulation.
• Dose reduction to 75 or 50 kBq/kg in later cycles if grade 2 xerostomia develops by cycle 2.
• Dental optimisation before cycle 1 — treating active caries, scaling, and fluoride application reduces post-therapy dental morbidity.

None of this eliminates xerostomia. It tempers severity in many patients. Patients should know this honestly. The trade-off is therapy that can extend life materially, against quality-of-life impact that is real and sometimes lasting.

Cost of Ac-225 PSMA in India.

Indicative cycle pricing. The numbers cover the therapy itself — PSMA-PET imaging, inpatient room category, and concomitant medication are billed separately by FMRI.

For sequencing context, see our Lu-PSMA page — most Ac-225 patients at our centre come through that pathway first.

Beyond xerostomia.

Common (>15% of patients)

• Fatigue — moderate, lasting 1–2 weeks after each cycle. Often more pronounced than with Lu-177.
• Anaemia — transient reductions in haemoglobin; occasionally requires transfusion in heavily pre-treated patients.
• Thrombocytopenia — transient platelet count reduction. Monitored every 3–4 weeks.
• Nausea — mild to moderate. Pre-medication with antiemetics.

Uncommon (1–15%)

• Lymphocytopenia — transient.
• Mild transaminitis — transient hepatic enzyme elevation.
• Acute kidney injury — uncommon at standard dosing; renal dose is lower with Ac-225 than Lu-177 because of the short alpha range.

Rare but serious

• Severe myelosuppression — in <5%. More likely with prior extensive marrow disease, prior radium-223, or post-Lu-177 marrow stress.
• Myelodysplastic syndrome / acute leukaemia — very rare. Reported in extended follow-up of heavily pre-treated patients.

Next available Ac-225 PSMA slots.

Ac-225 PSMA at our centre is scheduled fortnightly on Fridays, alternating with Tb-161 PSMA. Slots are limited by isotope availability — please reserve at least 4 weeks ahead.