Radium-223 chloride: a potential new treatment for castration-resistant prostate cancer patients with metastatic bone disease

Figures & data

Table 1 Overall survival benefit in recent Phase III trials in mCRPC

Agent (trial, year)	Disease state	Comparator	Hazard ratio	Median OS, months (P-value)	FDA approval
Sipuleucel-T (IMPACT, 2010)^Citation12	Chemonaive mCRPC; asymptomatic or minimally symptomatic	Placebo	0.775	25.8 vs 21.7 (0.032)	Yes
Docetaxel + prednisone (TAX-327, 2004)^Citation5	Chemonaive mCRPC	Mitoxantrone + prednisone	0.76	18.9 vs 16.5 (0.009)	Yes
Cabazitaxel + prednisone (TROPIC, 2010)^Citation13	Post-docetaxel mCRPC	Mitoxantrone + prednisone	0.70	15.1 vs 12.7 (<0.0001)	Yes
Abiraterone + prednisone (COU-AA-301, 2010)^Citation14	Post-docetaxel mCRPC	Placebo + prednisone	0.65	14.8 vs 10.9 (<0.001)	Yes
MDV3100 (AFFIRM, 2012)^Citation17	Post-docetaxel mCRPC	Placebo	0.631	18.4 vs 13.6 (0.0001)	Yes
Radium-223 (ALSYMPCA, 2012)^Citation35	Bone-metastatic mCRPC; symptomatic	Placebo + BSC	0.695	14.0 vs 11.2 (0.00185)	Pending

Abbreviations: mCRPC, metastatic castrate-resistant prostate cancer; OS, overall survival; BSC, best standard of care.

Table 2 Pain responses in randomized studies of survival prolonging therapies in mCRPC

Agent	n (% with pain)	Pain scale*	Pain response (P-value)	Duration (months)
Docetaxel + prednisone^Citation5	1006 (45%)	PPI	35% vs 22% (0.01)	3.5 vs 4.8 (NS)
Cabazitaxel + prednisone^Citation13	755 (45%)	PPI	9.2% vs 7.7% (0.63)	NR
Abiraterone + prednisone^Citation14,Citation20	1195 (44%)	BPI	44% vs 27% (0.0002)	8 vs 5 (P = 0.0056)†

Notes:

† 25th percentile.

* Of note, many of these trials used differing pain scales and variable incorporation of composite analgesic scores; thus, cross-trial comparisons are not possible.

Abbreviations: mCRPC, metastatic castrate-resistant prostate cancer; PPI, Present Pain Intensity; NS, not significant; NR, not reached; BPI, Brief Pain Inventory.

Table 3 Properties of selected radiopharmaceuticals for treatment of bone metastases in mCRPC

Radionuclide	Particle	Primary excretion	Physical half-life (days)	Particle energy in MeV	Tissue range (mm)	Bone surface to red bone marrow dose ratio
Radium-223 (Alpharadin^®)^Citation38	Alpha	Small bowel	11.4	5.56	<0.1	10.3
Samarium-153 (Quadramet^®)^Citation76*	Beta	Kidney	1.9	0.81	3	4.4†
Strontium-89 (Metastron^®)^Citation77*	Beta	Kidney	50.5	1.46	8	1.6†

Notes:

* Values in these rows taken from prescribing information^75,76 insert unless otherwise noted.

† Calculated based on values in product’s prescribing information.

Abbreviations: mCRPC, metastatic castrate-resistant prostate cancer; MeV, mega-electronvolts.

Figure 1 Mechanism of action for the targeting of osseous metastases by ²²³Ra. Reprinted with permission from Algeta ASA, from 2012 ASCO GU Symposium presentation.

Abbreviation:²²³Ra, radium-223.

Table 4 Skeletal-related event (SRE) delay in recent Phase III trials of bone-targeted therapies in bone-metastatic mCRPC

Agent (trial, year)	Mechanism of action	Disease state	Comparator	Hazard ratio	Time to 1st SRE, months (P-value)
Zoledronic acid (Zometa 039, 2002)^Citation15	Bisphosphonate – osteoclast inhibitor	BM mCRPC, asymptomatic	Placebo	0.80	13.8 vs 10.6 (0.02)
Denosumab (2010)^Citation16	RANK-L antibody – osteoclast inhibitor	BM mCRPC, asymptomatic	Zoledronic acid	0.82	20.7 vs 17.1 (0.008)
Radium-223 (ALSYMPCA)^Citation35	Radiopharmaceutical – calcium mimic	BM mCRPC, symptomatic	Placebo + BSC*	0.61	13.6 vs 8.4 (0.00046)

Note:

* BSC included secondary hormonal therapies, external beam radiotherapy, and bisphosphonates (41%), but not cytotoxic chemotherapy or radiopharmaceuticals.

Abbreviations: BM, bone-metastatic; mCRPC, metastatic castrate-resistant prostate cancer; BSC, best supportive care.

Table 5 Radiopharmaceuticals in selected randomized trials in men with prostate cancer

Trial, dose	Comparator	Overall survival	Pain palliation	Key side effects	Comments
Strontium-89
Canadian 400 MBq × 1 adjunct to RT (n = 126)^Citation25	Placebo	No difference	No difference	Increased hematologic toxicity with ^89Sr	Differences in pain progression, PSA, ALP, QoL favoring ^89Sr
British 200 MBq × 1 (n = 284)^Citation26	EBRT (F or HB)	No difference*	No difference†	↓WBC and ↓PLT by 30%–40% with ^89Sr	RT to new site less frequent with ^89Sr (P < 0.01)
EORTC 150 MBq × 1 (n = 203)^Citation27	Local field RT	RT superior vs ^89Sr‡	No difference§	No difference between groups	No difference in PFS or TTP; PSA responses in 10%–13%
Samarium-153
Serafini et al 0.5 or 1.0 mCi/kg × 1 (n = 118; 68% PC)^Citation28	Placebo	No difference	Only with 1.0 mCi/kg dose¶	Mean WBC and PLT nadirs 3100/μL and 118,000/μL with 1.0 mCi/kg\\	72% and 43% pain relief at 4 and 12 weeks with 1.0 mCi/kg
Sartor et al 1.0 mCi/kg × 1 (n = 152)^Citation29	Placebo	No difference	Significant reduction within 1–2 weeks lasting to 4 weeks**	Mean WBC and PLT nadirs 3800/μL and 127,000/μL with ^153Sm††	Significant reductions in opioid use at 3 and 4 weeks with ^153Sm; retreatment feasible^Citation29
Radium-223
ALSYMPCA 50 kBq/kg × 6 (n = 809)^Citation35	Placebo	14.0 vs 11.2 months (P = 0.00185)	Not reported	Diarrhea, vomiting; grade ≥ 3 ANC (2%) and PLT (4%)	Significant delay in SREs^Citation58 and improvements in PSA and ALP

Notes:

* 33 vs 28 weeks for ⁸⁹Sr vs RT (P = 0.1);

† sustained relief in two-thirds at 12 weeks, all 3 treatments provided similarly effective pain relief;

‡ 11 vs 7 months for RT vs ⁸⁹Sr (P = 0.0457);

§ subjective response in about one third, no difference in subjective pain response between groups, compared with placebo, significant pain reductions at 1.0 mCi/kg, but not 0.5 mCi/kg, at 1 and 4 weeks;

¶ compared with placebo, significant pain reductions at 1.0 mCi/kg, but not 0.5 mCi/kg, at 1 and 4 weeks;

\\ no grade 4 hematologic toxicity observed, complete recovery of myelosuppresion by 8 weeks;

** placebo-treated patients could cross over to receive ¹⁵³Sm after 4 weeks;

†† counts generally recovered by 8 weeks.

Abbreviations: MBq, megabecquerel; RT, radiotherapy; PSA, prostate-specific antigen; ALP, alkaline phosphatase; QoL, quality of life; EBRT, external beam radiotherapy; F, focal; HB, hemibody; ⁸⁹Sr, strontium-89; EORTC, European Organization for Research and Treatment of Cancer; PFS, progression-free survival; TTP, time to progression; mCi, millicurie; PC, prostate cancer; ANC, absolute neutrophil count; PLT, platelets; SRE, skeletal-related event.

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