Sunday, May 23, 2021

Triplet therapy for newly diagnosed metastatic men beats docetaxel+ADT

(Updated)

(Update 4/9/22) Fizazi et al. published the full results of PEACE1 in The Lancet. PEACE1 was a European randomized clinical trial (RCT) conducted from 2013-2018 among 1,173 men who were newly diagnosed with metastases.  All patients got standard of care, which consisted of ADT and docetaxel (after 2015).

They randomized patients to get:

  • prostate radiation or not
  • abiraterone+prednisone or not

After median follow-up of about 3-4 years, they found that prostate radiation:

  • prostate radiation reduced mortality by about a quarter in men who got docetaxel, but it was not statistically significant.
  • prostate radiation cut radiographic progression-free mortality in half.

Adding abiraterone to standard of care (including docetaxel):

  • Increased median survival from 4.4 years to >5.7 years (not reached)
  • Mortality was cut by 25%
    • Cut by 28% in those with high volume metastases
    • Cut by 17% in those with low volume metastases (not statistically significant)
  • Increased radiographic progression-free survival from 2.0 years to 4.5 years
  • Radiographic progression was cut in half
    • Radiographic progression was cut by 53% in those with high volume metastases.
    • Radiographic progression was cut by 42% in those with low volume metastases.
  • Time to castration resistance increased from 1.4 to 3.2 years
    • Castration resistance was cut by 62%
  • Prostate cancer-specific survival increased from 4.7 years to not reached, a 31% decline in prostate cancer mortality
The benefits of receiving the early triplet continued to be evident in patients who later received other therapies, demonstrating a benefit to the triplet over sequential therapy.

There was no increase in the incidence of severe adverse events from receiving docetaxel.


(Update 9/19/21) Karim Fizazi presented the following chart at the ESMO Congress today:


Combining docetaxel and abiraterone in men who were originally diagnosed with high volume metastases increased overall survival significantly over either alone.

(May 23, 2021) The first results of the long-awaited PEACE-1 randomized clinical trial (RCT) are in. They randomized newly diagnosed metastatic men to either prostate radiation or abiraterone or standard-of-care (SOC). SOC included docetaxel for many of the men.

Radiographic progression-free survival increased by 2.5 years (from 2.0 to 4.5 yrs) with the addition of abiraterone to docetaxel. Time to castration resistance increased by 1.7 yrs (from 1.5 to 3.2 yrs). 

The full results will tell us how much the prostate radiation adds, and the effect on overall survival. The analysis by metastatic burden will be important too. Meanwhile, docetaxel+abiraterone+ADT should be considered the new standard of care.

How does this combination therapy compare to previous RCTs for docetaxel or abiraterone?

Because the STAMPEDE RCTs for docetaxel and abiraterone occurred at about the same time, 566 patients were randomized to one or the other. Sydes et al. reported the outcomes after a median of 4 years of follow-up. 
  • Abiraterone reduced PSA more quickly, as reflected in "failure-free survival" (time to PSA increase, clinical progression, or death) and "progression-free survival" (time to first "failure" event, excluding PSA). 
  • Those who received docetaxel first soon caught up. There were no significant differences in "metastasis-free survival," "prostate cancer-specific survival," "overall survival," or "time to the first skeletal-related event (pain or fracture)"
  • Serious toxicity (Grade 3 or greater) was also equal: 50% for docetaxel, 48% for abiraterone.

The STAMPEDE researchers (the STOPCAP group) did a meta-analysis of the STAMPEDE trials that concluded that abiraterone probably had a greater effect than docetaxel, but unlike the analysis above, it was not a direct comparison. They concluded that either should be recommended.

The other RCTs for metastatic hormone-sensitive prostate cancer (mHSPC) included STAMPEDE- abiraterone, LATITUDE- abiraterone, STAMPEDE-docetaxel, CHAARTED-docetaxel.GETUG-AFU-15(docetaxel) did not detect a difference in survival from the early use of docetaxel. 30% had prior treatment. There were differences in the populations studied in each trial that should be understood.

LATITUDE screened for more advanced patients - 80% were "high risk." High risk was defined by having 2 of 3 "high-risk" features, either: Gleason 8-10, or ≥ 3 bone metastases or visceral metastases. About half had performance status of 1 or 2 ("0" is the best performance status).

CHAARTED started by recruiting only patients with a high burden of metastases. But only 73% were de novo, meaning 27% had been previously treated before they entered the trial. They later opened the trial to men with fewer metastases and ended up with a small group (27%) of low burden de novo patients. They defined "high burden" as visceral metastases or ≥ 4 metastases with at least 1 outside the axial skeleton.

The two STAMPEDE trials recruited almost entirely (95%) de novo patients. 56% were "high burden" by the CHAARTED definition. 52% were "high risk" by the LATITUDE definition. 26% had performance status of 1 or 2.

PEACE1 recruited only de novo metastatic patients, with excellent performance status. 57% had high-risk features by the LATITUDE definition.

The following chart shows how long it took for patients to progress on each of the early interventions. Complicating analysis, each trial used a slightly different definition of progression.

Time to "progression" following each early therapy


abiraterone+docetaxel+ADT

docetaxel+ADT

abiraterone+ADT

ADT alone

Trial notes

PEACE1*

4.5 yrs

2.0 yrs



100% de novo, 100% perf. status 0, 57% high volume

STAMPEDE

(abiraterone)



Not reached (> 3.4 yrs)

2.0 yrs

94% de novo,26% perf.status 1 or 2, 55% high volume

LATITUDE*

(abiraterone)



2.8 yrs

1.2 yrs

100% de novo, 45% perf. Status 1 or 2, 80% high volume/high risk

STAMPEDE

(docetaxel)


3.1 yrs


1.7 yrs

95% de novo, 56% high volume

CHAARTED§

(docetaxel)


2.8 yrs


1.7 yrs

73% de novo, 65% high volume

time to radiographic progression or death
time to first symptomatic event or death
§ time to symptoms or radiographic progression

While comparison is complicated, the extension of progression-free survival by 2.5 years by adding abiraterone to docetaxel alone is impressive. Docetaxel adds 1 - 1.5 years to progression-free survival over ADT alone. Abiraterone adds 1 - 1.5 years to progression-free survival over ADT alone.



Triplet Therapy with Nubeqa (darolutamide)

(Update 12/3/2021) Bayer announced that the combination of Nubeqa (darolutamide) and docetaxel + ADT increased survival over docetaxel + ADT alone in the ARASENS trial. This constitutes the second success for "triplet therapy."

(Update 2/15/2022) The first results of the ARASENS trial were presented at the 2022 ASCO Genitourinary Conference. All 1,306 patients treated from 2016-2018 were randomized to receive darolutamide (DARO) or placebo (PBO) on top of docetaxel and ADT. They found that:
  • DARO significantly decreased the risk of death by 32.5%
  • The survival advantage subsisted even though the PBO group received more therapies later
  • The survival advantage was maintained in all subgroups (i.e., disease extent, type of metastases, ALP levels)
  • DARO delayed time to castration resistance by 64%
  • DARO delayed time to pain progression by 21%
  • DARO delayed time to first skeletal event/fracture
  • DARO delayed time to next chemotherapy
  • Treatment-related adverse events were similar and were highest during the time chemo was given (mainly neutropenia)
  • Treatment discontinuation was low and similar in both groups (13.6% for DARO) vs (10.6% for PBO)
(update 8/5/22) The FDA has approved triplet therapy with Nubeqa (darolutamide) and docetaxel for men newly-diagnosed with metastases.

Both the TITAN trial of Erleada (apalutamide) and the ENZAMET trial of Xtandi (enzalutamide) showed no benefit for the advanced hormone therapy when docetaxel had been used previously. Timing is important! When chemo or advanced hormone therapy is used as monotherapy, protective mechanisms (like cellular senescence) kick in soon afterward. It protects the cancer cells from destruction by the other medicine. They have to be used together or wait until the first drug stops working.


(Update 6/6/22) Triplet Therapy with Xtandi (enzalutamide)

An updated, subgroup analysis of the ENZAMET trial among newly diagnosed men with metastases confirms the triplet of ADT+enzalutamide+docetaxel increases survival. 5 year survival was 60% for the triplet vs 52% for ADT+docetaxel. The benefit was especially pronounced in the first 2 years of triplet therapy in men with high volume metastases. There was no benefit to the triplet in recurrent men with metachronous metastases.


Does docetaxel only benefit mHSPC patients with a high-volume of metastases?

This has stirred much controversy. Gravis et al. argue that the overall survival improvement from docetaxel was seen in CHAARTED only among men with high-volume metastases was a real biological effect (i.e., that high-volume PC is a different disease from low-volume PC, that responds differently to chemo). Armstrong argues for a biological difference. They acknowledge, however, that the small sample size of de novo men with low volume metastases (n=154) and their short follow-up (only 16% had died during the 48 months of follow-up) may be underestimating the benefit in the low volume, de novo subgroup. Remember that in CHAARTED, the low-volume subgroup was not recruited initially, so the follow-up is shorter in the group that needs the longer follow-up.

Clarke et al. argue that STAMPEDE is the more definitive trial because its sample size of mHSPC men with low-volume metastases was over twice as great (n=362) and the follow-up was longer (62% of the docetaxel patients had died during 78 months of follow-up). They did not find evidence of heterogeneity - low-volume PC responded just as much to chemo as high-volume PC. While the effect on low volume PC was similar, the statistical confidence in its effect did not meet 95% confidence. They attribute this to insufficient sample size (power). Suzman and Antonarakis agree that chemo should be offered to all mHSPC men, regardless of volume of metastases. It would seem that a meta-analysis combining the low-volume, de novo subgroups from both CHAARTED and STAMPEDE might be sufficiently powered to provide a more definitive answer. Patients wishing to understand why analyses of subgroups are controversial, may be amused by this analysis of STAMPEDE subgroups. The authors found that patients born on a Monday benefited the most from abiraterone, and it was statistically significant. while patients born on a Friday had the least benefit, and it wasn't statistically significant. They further found that men diagnosed on a Monday did not benefit from abiraterone, whereas men diagnosed on other days had a statistically significant benefit. These absurd findings are sometimes known as "p-hacking" or "data dredging." This interview discusses this error and the mistake of drawing biological inferences from statistical significance. Pre-specifying subgroups is one way to avoid such errors, but drawing conclusions from inadequately powered subgroups, while tempting, should be avoided. This controversy is reflected in the conflicting recommendations that constitute the standard of care.

The current NCCN guidelines state: "Docetaxel should not be offered to men with low volume metastatic prostate cancer, since this subgroup was not shown to have improved survival in either the ECOG study or a similar European (GETUG-AFU 15) trial." The current ASCO guidelines state: "Recommendation 1.2. For patients with low-volume metastatic disease (LVD) as defined per CHAARTED who are candidates for chemotherapy, docetaxel plus ADT should not be offered (Type: evidence-based, benefits outweigh harms; Evidence quality: high; Strength of recommendation: strong for patients with LVD)." On the other hand, the current AUA/ASTRO/SUO guidelines state: "15. In patients with mHSPC, clinicians should offer continued ADT in combination with either androgen pathway directed therapy (abiraterone acetate plus prednisone, apalutamide, enzalutamide) or chemotherapy (docetaxel). (Strong Recommendation; Evidence Level: Grade A) Canadian Urological Assn (CUA) guidelines state: "Docetaxel plus ADT may also be an option in patients with mCNPC/mCSPC with good performance status with low-volume disease (Level 2, Weak recommendation)." NICE (UK) guidelines state: "Offer docetaxel chemotherapy to people with newly-diagnosed metastatic prostate cancer who do not have significant comorbidities." European Urological Assn (EAU) guidelines state: "Based on these data, upfront docetaxel combined with ADT should be considered as a standard in men presenting with metastases at first presentation provided they are fit enough to receive the drug [1070]"

I personally believe that the STAMPEDE researchers make a stronger case pending better data from PEACE1.

It is also possible that genomics will allow better selection of patients for early chemotherapy. Hamid et al. examined tissue collected for the CHAARTED trial. They found a subtype called "Luminal B" that was associated with improved survival from chemotherapy. This finding has not yet been validated on an independent trial. Meanwhile, DECIPHER provides the test as part of its GRID analysis.

The major advantages of early chemo vs "saving it for later" are:
  • Longer survival advantage
  • Side effects are milder when patients are less debilitated from years of cancer
  • As many as 10 infusions (usually 6) can be given if it is well tolerated
  • Most patients are not resistant, so docetaxel can be repeated
  • If there is resistance, cabazitaxel can be given


Tuesday, May 18, 2021

New Guidelines for Salvage Radiation Dimensions

It has always been troubling that only about half of all salvage radiation treatments after prostatectomy failure are successful. Usually, only the prostate bed is treated. But sometimes recurrent patients (or those with persistently elevated PSA) receive salvage radiation to the pelvic lymph nodes as well, or subsequently. Radiation oncologists usually follow RTOG (now called NRG Oncology) guidelines on what constitutes the dimensions of the prostate bed and the pelvic lymph nodes.

Prostate Bed Coverage

Often, the cancer has only penetrated into the bed or fossa. This is especially suspected if there are significant positive surgical margins. The 2010 RTOG consensus guidelines were updated in 2020 by the Francophone Group of Urological Radiotherapy (GFRU) based on standard imaging (MRI and CT). Harmon et al. reported on 45 patients within the LOCATE trial who received a positive Axumin PET/CT upon recurrence or persistent PSA after prostatectomy.

  • 30 patients had cancer in the prostate fossa
  • The 2010 RTOG guidelines completely or partially missed cancer in 33% of the patients
  • The 2020 GFRU guidelines completely or partially missed cancer in 10% of the patients
The new GFRU guidelines are clearly superior in terms of oncological outcomes, but toxicity must be considered as well.

Pelvic Lymph Node Coverage

In 2020, NRG Oncology revised its previous 2009 RTOG pelvic lymph node coverage consensus guidelines based on MRI and PET scans. They recommended coverage as high as the aortic bifurcation or common iliac lymph nodes (whichever is higher, depending on patient anatomy), which is about the level of the L4-L5 vertebrae. The expanded coverage area extends down to the pre-sacral nodes at the bottom of vertebra S3. Harmon et al. also validated the expanded NRG Oncology guidelines based on Axumin PET/CT scans. They found:

  • There were 43 sites of cancer in the pelvic lymph nodes
  • The 2009 RTOG guidelines completely or partially missed 32% of the nodal cancers
  • The 2020 NRG Oncology guidelines completely or partially missed none of the nodal cancers

The SPPORT trial found that treating pelvic lymph nodes prophylactically improved outcomes with no increase in late-term genitourinary or gastrointestinal toxicity, and only minor increases in the short-term. This study did not examine the toxicity of the expanded coverage.  Careful contouring of the pelvic lymph node area to exclude bowel, bone, bladder, and muscle seems to prevent excess toxicity at the doses usually used (45-50.4 Gy). In one recent study of high-risk patients, a pelvic lymph node dose as high as 56 Gy was used without extra toxicity. Also there have been no second pelvic malignancies due to the expanded coverage in this study.

 Boosted site doses can also be utilized where PET/CT  or MRI has identified specific tumors. However, treatment should not be delayed until such tumors become apparent on imaging.


Friday, April 30, 2021

First clinical trial of Lu-177-PSMA-617 in recurrent, hormone-sensitive men

While we expect only a few months of extra survival from the VISION trial of Lu-177-PSMA-617 in heavily pretreated, metastatic, castration-resistant men (see this link), we hope to get more out of the radiopharmaceutical if used earlier. Privé et al. reported the results of a pilot trial in 10 recurrent men treated with Lu-177-PSMA-617 at Radboud University in Nijmegen, The Netherlands. They were all:

  • Recurrent after prostatectomy ± salvage radiation (PSA>0.2 ng/ml) 
  • Rapid PSA doubling time (< 6 months)
  • Between 1-10 metastases detectable on a PSMA PET scan or USPIO MRI
  • At least 1 metastasis > 1 cm.
  • Unable to receive SBRT to metastases 
  • No visceral metastases 
  • Have not begun salvage ADT
  • Treated with a low dose (3 GBq) on day 1; second treatment (~6 GBq) after 8 weeks (compared to dose in VISION trial of 7.4 GBq in each of 4-6 cycles)

After 24 weeks of follow-up after Cycle 2:

  • 5 patients had PSA reduced by >50% (1 undetectable)
  • 2 patients had stable PSA
  • 3 patients had PSA progression
  • 6 patients had a radiographic response
  • 4 patients had radiographic progression
  • ADT-deferred survival was 9.5 months (median)
  • Those with lymph node only metastases had the best response
  • Those with any bone metastases had lesser response
After 2nd dose, comparing their 24-week PSA to their 12-week PSA:

  • PSA was continuing to decline in 3 patients
  • PSA was rising again in 6 patients

Side effects were mild (no grade 3) and transient:

  • fatigue in 7; nausea in 3
  • dry mouth (xerostomia) in 2

There are lots more questions than answers:
  • Would a higher dose and more treatments be more effective?
  • Would a higher dose and more treatments be more toxic?
  • Is it like Xofigo in that it's more effective with micrometatases? If so, would a combination with SBRT targeted at the larger metastases be more effective?
  • Since it was more effective on lymph nodes, would it make a good combination with Xofigo for patients who have both lymph node and bone metastases? (See also Th-227-PSMA)
  • Because there seems to be a continued abscopal effect for some patients, would combining it with Provenge be optimal?
  • Would pretreatment with ADT or a new anti-androgen (Xtandi, Erleada or Nubeqa) increase expression of PSMA, and increase radiosensitivity?
  • Can we predict who will benefit?
  • Use in other patient populations remains to be explored: high-risk, newly diagnosed metastatic, castration-resistant but chemo-naive. Optimal sequencing with other therapies remains to be explored.






Wednesday, March 17, 2021

Whole gland TULSA-PRO and HIFU outcomes: Is it time to give up on thermal ablation for prostate cancer?

 We have seen that there are many unanswered questions about focal thermal ablation (see this link), among them are:

  1. Is Index Tumor Theory valid?
  2. Can foci of cancer be precisely targeted using current imaging methods?
  3. Does thermal ablation completely ablate the cancer in the ablation zone?
  4. Will the Heat Sink Effect and biochemical protective mechanisms (e.g., heat shock proteins) always cause sub-lethal killing?
  5. Is toxicity and damage to organs at risk any better than radical (whole gland) radiation?
  6. How do the high "re-do" rates affect toxicity and costs?
  7. How do we track success?
  8. What are the best salvage therapies?
  9. Can it extend the time on active surveillance?
  10. What are the intra-operative risks?
  11. What is the learning curve like for therapists?
  12. Is it worth the cost?
Laurence Klotz et al. conducted a clinical trial of a new kind of high-intensity focused ultrasound (HIFU). He studied whole-gland ablation because current FDA rules only permit ablation for removal of prostate tissue (like a TURP), but not for treatment of prostate cancer. In fact, the FDA specifically rejected HIFU for the treatment of prostate cancer. 

TULSA-PRO utilizes a thermal feedback loop to assure that tissue temperature reaches the desired heating. It is done "in-bore" in an MRI by a team consisting of a urologist and an interventional radiologist, and an anesthesiologist (full anesthesia was required). It was hoped that the MRI precision and assured tissue heating (to 55°C) would afford higher cancer-killing with less toxicity.

115 patients were carefully selected:
  • 15% were low volume GS 3+3 (cancer in ≤2 cores, <50% in any core)
  • 23% were high-volume GS 3+3
  • 60% were GS 3+4
  • 3% were GS> 3+4
  • 94% were T1c or T2a
  • Median PSA=6.3
  • 67% were intermediate risk (predominantly favorable)
  • 33% were low-risk
  • Median prostate volume was 40 cc.
The operative procedure involved:
  • prophylactic antibiotics
  • general anesthesia
  • cystoscopy
  • transurethral US heating wand
  • pelvic tissue at apex avoided to avoid incontinence
  • endorectal cooling device
  • 243 minutes (4 hours), start to finish
  • suprapubic catheter (17 days)

Safety Outcomes/ Adverse Events:

Physician-reported outcomes:
  • Acute (immediate) Grade 2:
    • erectile dysfunction (29%)
    • UTI (25%)
    • bladder spasm (10%)
    • painful urination (10%)
    • urinary retension (8%)
    • pain (7%)
    • incontinence (6%)
    • epidydimitis (5%)
  • Acute (immediate) Grade 3 (severe, requiring intervention):
    • infection (4%)
    • urethral stricture (2%)
    • urinary retention (1.7%)
    • urethral calculus and pain (1%)
    • urinoma (1%)
  • long-lasting Grade 2 adverse events:
    • erectile dysfunction (23%)
    • incontinence (3%)
    • recurrent infections (2%)
Patient-reported outcomes at 12 months vs baseline on EPIC questionnaire (% reporting moderate decline/ % reporting moderate gain):
  • Sexual domain: 32%/ 1%
  • ED on IIEF-15 questionnaire: 35%/6%
  • 75% of previously potent men returned to erections sufficient for penetration with only ED meds.
  • Urinary incontinence:14%/7%
  • Urinary irritation/obstruction: 8%/5%
  • Bowel domain: 5%/2%

Oncologic Outcomes (at 12 months):

  • 35% had residual cancer at biopsy
  • 24% among low volume GS 6
  • 38% among high volume GS 6
  • 37% among GS 3+4
  • Median PSA reduced to 0.5 ng/ml
  • Median prostate volume reduced to 2.8 cc
  • PIRADS ≥3: 30%

There is little 12-month data available for other therapies, but recurrence rates almost always increase with time. There was a 2-year study of SBRT at Georgetown that may be roughly comparable:



TULSA-PRO (1 year)

115 patients

SBRT (2 years)

100 patients

Risk category

Low-risk

Intermediate-risk

High-risk


33%

67%


37%

55%

 8%

Biochemical recurrence-free survival

100%

99% (1 local recurrence in a high-risk patient)

Biopsy-proven local recurrence

35%

1% estimated in the high-risk patient

Nadir PSA

0.5 ng/ml

0.5 ng/ml

Acute urinary toxicity (grade 3)

8%

0%

Acute rectal toxicity (grade 3)

0%

0%

Late-term urinary toxicity (grade 2+)

5%

18% 

(1% Grade 3)

Late-term rectal toxicity (grade 2+)

0%

0%

Potency preservation among previously potent men

75%

79%


Full-gland TULSA-PRO seems to treat PSA without eradicating the cancer (see this link). In about a third of favorable-risk patients, the cancer remained viable in spite of the thermal ablation. We see that compared to whole-gland SBRT, it is less curative, Severe (requiring intervention) acute urinary toxicity is higher with TULSA-PRO, although late-term Grade 2 urinary toxicity is lower (not severe for either therapy). Rectal toxicity is not an issue for either therapy. Potency preservation is good and about equal for both.


15-year study suggests long-term inferiority

Bründl et al. reported 15-year oncological outcomes of 674 patients treated with whole-gland HIFU at one university hospital in Regensberg, Germany. Notably, overall survival and prostate cancer-specific survival were high in all localized risk categories. However, comparing 15-year prostate cancer-specific survival to similar risk men who have undergone prostatectomy at Memorial Sloan Kettering, we see the survival is relatively poor:

15-yr Prostate Cancer-Specific Survival

Risk Group

HIFU

RP*

Low Risk

95%

99%

Intermediate Risk

89%

98%

High Risk

65%

88%

* from the MSK pre-prostatectomy nomogram for a 62 yo man. For low-risk, he had PSA=5, GS 3+3, stage T1c, and 25% positive cores; For intermediate-risk, he had PSA=15, GS 4+3, stage T2c, and 50% positive cores; for high risk, he had PSA=25, GS 4+5, stage T3a and 100% positive cores.

The longest follow-up study there is for SBRT is 12 years. For SBRT, Alan Katz reported rates of "local control" on SBRT - the percent of patients who had recurrences only in the prostate. These could all theoretically be cured with a re-do of SBRT, focal brachytherapy or focal ablation. We can look at long-term local control from SBRT next to the long-term reported rates of salvage therapy after whole-gland HIFU (either re-do of HIFU or other salvage). HIFU does not compare well:

% patients who do not require salvage treatment

Risk Group

HIFU

SBRT

Low Risk

77%

97%

Intermediate Risk

52%

92%

High Risk

28%

88%

It is hard to see why anyone would choose HIFU or TULSA-PRO over SBRT. While focal ablation may incur less toxicity, the local recurrence rate will be much higher. These trials suggest that  HIFU and TULSA-PRO are inferior, although only a direct randomized comparison could prove that definitively.


For an article discussing the use of focal ablation as an active surveillance "extender," see:

What should focal therapy be compared to and how does it compare?

For an article discussing salvage focal ablation after the failure of radiation therapy, see:

Focal salvage ablation for radio-recurrent prostate cancer



Thursday, February 18, 2021

Xofigo 2.0

(updated)

Xofigo (Radium 223 dichloride) is a systemic radiopharmaceutical. Radium is chemically similar to calcium and is taken up by bones in places where bone is actively growing, as in prostate cancer bone metastases. Radium 223 emits powerful alpha radiation that kills the cancer cells in the bone metastases. It has been found to double 2-year survival (see this link), extending survival time and reduce the skeletal-related events by almost a third. It often will not reduce PSA or show bone metastases shrinking in imaging, which some patients find disappointing.

It is FDA-approved for castration-resistant men with painful bone metastases, who do not show evidence of visceral metastases on a CT or MRI  (lymph node metastases are allowed). So far, it is only FDA-approved as a monotherapy, but researchers have wondered whether it may be more effective in combination with other medicines, or used in other situations.

Always use with a bone-preserving agent

Hijab et al. reported the results of the REASSURE trial.  They compared the bone fracture rate of 36 mCRPC patients who took Xofigo to a matched reference cohort of 36 mCRPC who didn't take Xofigo. They were all assessed for fracturesat baseline, 3 times during treatment and every 3 months thereafter with whole-body mpMRI. Very few (2-4 in each cohort) took a bone-strengthening agent. After 16 months of follow-up, they found:

  • 56% had new fractures
  • 3.7 fractures per patient with fractures
  • 13.6 months to first new fracture
  • ⅔ of new fractures were in the spine
  • Only ⅓ were at sites of metastases
  • Half the fractures were asymptomatic (no pain)
  • No association of Xofigo dose with risk of fracture
  • Higher # of bone metastases, high ALP, and previous use of steroids were associated with higher risk of fractures.

In the reference cohort (mostly using Zytiga or Xtandi, no Xofigo), there  was still an increased fracture rate, albeit lower. After 24 months of follow-up, they found:

  • 33% had new fractures
  • 1.3 fractures per patient with fractures
  • Only 38% occurred at sites of metastases

This trial shows that all men taking hormone therapy for mCRPC are at high risk for fracture, but particularly if they use Xofigo, and if they previously used corticosteroids (e.g., with chemotherapy). The effect on bone continues after Xofigo is stopped. These are predominantly "fragility" fractures, not metastasis-related, and can be prevented with bone-strengthening agents like Xgeva or Zometa.


Second-line hormonal therapies

It has long been known that androgen deprivation therapy (ADT) sensitizes prostate cancer cells to radiation therapy. Could a more powerful type of hormonal therapy work even better?

The combination of Zytiga and Xofigo was tried in the ERA 223 trial. The trial was stopped early because there were about 3 times more fractures in the group receiving the combination than in the group receiving a placebo and Zytiga. The combination now carries a black-box warning against the combined use.

It appears that the problem may be at least partly resolved by using a bone-strengthening agent (like Xgeva or Zometa). When they looked at the subgroup who had taken bone-strengthening agents, 15% of those taking Xofigo+Zytiga vs 7% of those taking Zytiga-only experienced a fracture. So, even though Zometa or Xgeva reduced the fracture rates by about half in both arms, the fracture rate was still twice as high among those taking the combination. 

The combination of Xtandi and Xofigo is being tried in the EORTC1333/PEACE 3 trial, which is still recruiting. Because of the problems with the ERA 223 trial, they sent out a safety alert to assure that everyone in both arms was also getting a bone-strengthening agent. Bertrand Tombal (updated at 1 1/2 yrs) reported that skeletal events so far occurred in:
  • 46% of men taking Xofigo and Xtandi without a bone-strengthening agent
  • 3% of men taking Xofigo and Xtandi with a bone-strengthening agent
  • 22% of men taking Xtandi without Xofigo and without a bone-strengthening agent
  • 4% of men taking Xtandi without Xofigo and with a bone-strengthening agent
It is too early to ascertain whether the combination increases radiographic progression-free survival.

Agarwal et al. reported on a small Phase 2 trial where 39 metastatic castration-resistant men were randomized to Xofigo+Xtandi or Xtandi alone. Bone metabolic markers were reduced significantly by the combination, suggesting increased efficacy. A safety analysis found few serious cytopenias and no skeletal events in either arm. A new post-hoc analysis found:
  • PSA progression-free survival was 9 months for Xofigo+Xtandi vs 3 months for Xtand-alone (not significantly different on this small sample size)
  • Time to PSA progression after the next therapy was 19 months for Xofigo+Xtandi vs 8 months for Xtandi-alone (significantly different)
  • Time to next therapy was 16 months for Xofigo+Xtandi vs 3 months .for Xtandi-alone (not significantly different)
  • Overall Survival  was 31 months for Xofigo+Xtandi vs 21 months for Xtandi-alone (not significantly different)
  • There were 3 asymptomatic fractures found in the Xofigo+Xtandi arm.
Presumably, the combination has a deleterious effect on the bone microenvironment or structural integrity. While Zometa has been proven to have no effect on survival as a monotherapy, in a subset of the STAMPEDE trial the combination of Zometa and Celebrex increased survival by 22%. Patients should not combine Xofigo with a second-line hormonal therapy without a bone-strengthening agent, and preferably only in a carefully watched clinical trial. Using them sequentially may be safer. Patients may wish to discuss adding Celebrex as well.

Clinical trials combining Xofigo with second-line hormonals include these:

Chemotherapy

Morris et al. reported the results of a small trial comparing Xofigo + docetaxel to docetaxel alone in 53 castration-resistant men who had ≥ 2 bone metastases. They were given either:
  • Xofigo (55 KBq/kg) every 6 weeks for 5 injections and lower dose docetaxel (60 mg/m2) every 3 weeks for 10 infusions
  • Standard dose docetaxel (75 mg/m2) every 3 weeks for up to 10 infusions
  • The normal schedule for Xofigo is 55 KBq/kg once every 4 weeks for 6 injections
  • The normal schedule for docetaxel is 75 mg/m2 once every 3 weeks for 6 infusions
  • The timing adjustments were made for patient convenience
  • Almost all had tried a second-line hormonal therapy
  • Most were taking a bone-strengthening agent
With 52 weeks of follow-up:
  • Median PSA progression occurred after 6.6 months in the combination arm vs 4.8 months in the docetaxel-only arm
  • PSA declined by ≥ 50% in 61% of the combination arm vs 54% of the docetaxel-only arm
  • Median radiographic or clinical progression occurred after 12 months for the combination vs 9 months for docetaxel only
  • All 10 treatments were given for the combination, whereas there was a median of 9 of 10 treatments in the docetaxel-only arm
  • 12% discontinued treatment in the combination arm vs 23% in the docetaxel-only arm
  • Serious adverse events were suffered by 48% in the combination arm vs 62% in the docetaxel arm
  • Serious blood disorders were noted more often for docetaxel-only
It seems that the more toxic docetaxel dose could be reduced by the combination without any loss of efficacy.

Xofigo was also found to work well after docetaxel. Docetaxel's effectiveness was not diminished by previous Xofigo.

These clinical trials combine docetaxel and Xofigo:

Immunotherapy

There is a synergy between radiation and immunotherapy (see this link). Radiation kills cancer cells and their proteins (antigens) are detected by immune cells that form antibodies to them. 

Marshall et al. reported the results of a small trial that randomized 32 mCRPC patients to Provenge + Xofigo or Provenge alone. After median follow-up of 1.6 years:
  • Median progression-free survival (PFS) was 39 weeks for the combination vs 12 weeks for Provenge alone.
  • The % who had a PSA reduction by more than half was 31% for the combination vs 0% for Provenge alone
  • Median overall survival was higher with the combination: not reached vs 2.6 years
  • The % who had an alkaline phosphatase reduction of more than 30% was 60% for the combination vs 7% for Provenge alone
  • There were no increases in side effects for the combination
Increases in PFS and reductions in PSA and bone ALP are usually not seen for either medication alone, so it is noteworthy that the combination had an enhanced effect.

But immune stimulation will never be long-lasting. Eventually, the immune system will regard the cancer cell as if it were a normal healthy cell of one's own and will stop attacking it. To continue the attack, a different sort of immune encouragement is required. These "checkpoint blockers" are currently represented by drugs that have been FDA-approved for use in other cancers, like Yervoy (ipilimumab) and Keytruda (PD 1 inhibitor).  This trial did not find any clinical benefit in combining Xofigo and Tecentriq (atezolizumab) and the toxicity was high. A trial of the checkpoint inhibitor Keytruda+Xofigo also found no extra benefit to the combination. Hopefully, future Xofigo clinical trials will include a checkpoint blocker as well as an immune stimulant. There are two ongoing clinical trials at UCSF and in Melbourne of Lu-177-PSMA-617 combined with Keytruda. 

This clinical trial includes an arm where patients receive Xofigo + external beam radiation + Bavencio (avelumab):

PARP inhibitors

PARP inhibitors (e.g., olaparib, rucaparib, etc.) have known activity in men who have certain DNA-repair defects, particularly BRCA mutations (either germline or somatic). They boost the deficiency in self-repair, causing the cancer cells to die. They may also be useful in conjunction with radiation. When radiation creates sublethal DNA damage, preventing the DNA-repair machinery from operating, a PARP inhibitor may put the cell over the edge.

van der Doolen et al. reported the results of an exploratory retrospective analysis of 93 castration-resistant patients at Johns Hopkins treated with Xofigo for bone metastases:
  • 28 had DNA-repair defects (DRD+)
  • 65 had no DNA-repair defects (DRD-)
Compared to the men who were DRD-, the DRD+ men had:
  • Twice as high alkaline phosphatase (ALP) response: 80% vs 39%
  • Longer time to ALP progression: 6.9 mos vs 5.8 mos. (not statistically significant)
  • Longer time to next systemic therapy: 8.9 mos. vs 7.3 mos. (not statistically significant)
  • Twice as long overall survival: 36.3 mos. vs 17.0 mos. 
  • Better Xofigo completion rates: 79% vs 47%
  • No difference in PSA response
Xofigo seems to work especially well in men who are DDR+. The combination of PARP inhibitors and Xofigo may be especially effective. There is a trial in Australia of a PARP inhibitor combined with Lu-177-PSMA-617.

These clinical trials examine the effect of DRD+ or PARP inhibitors on Xofigo effectiveness:

Earlier Treatment

A lab study at M.D. Anderson found that Xofigo was excellent at treating micro-metastases, but not as good at treating large bone metastases. This suggests that earlier Xofigo treatment may be preferable and that larger tumors are optimally treated with a combination medical therapy or with a combination with external beam radiation (see below).

In a retrospective study, survival after Xofigo treatment was associated with better performance status, lower PSA at the time of treatment, lower pain scores, less use of advanced hormonals, lower bone scan index, and normal ALP levels.

Hematologic toxicity and bone marrow failure are potential adverse events associated with using Xofigo after extensive bone metastases are already present (see this link and this one). A clinical study showed that high tumor burden predicted skeletal-related events (SREs) and lower overall survival.

Xofigo has only been tested in men with bone-metastatic CRPC, who have bone pain and no visceral metastases. It's use in earlier states of progression have been underexplored. This small study suggested there may be a benefit to Xofigo in some when bone metastases have been found post-prostatectomy, while they were still hormone sensitive. At least, it helped relieve bone pain.

This clinical trial includes Xofigo for biochemically recurrent patients before metastases are visible:

External Beam Radiation

Because Xofigo is especially good at targeting micrometastaic bone metastases, and not so good at targeting the macroscopic bone metastases, it may be optimal to target the visible ones (if there are very few) with SBRT, and the invisible ones with Xofigo.

These clinical trials include Xofigo as well as SBRT to oligometastases:

Radiosensitizers

There are several known radiosensitizers (medicines that increase the cell-killing potential of ionizing radiation). The problem with many radiosensitizers is that they may sensitize healthy cells too, increasing toxicity. Ideally, we want a medicine that only radiosensitizes cancer cells, while not affecting or even being radioprotective of healthy cells. Among the types of medicines being explored for this affect are PARP inhibitors and other DNA-damage repair inhibitors (above), heat shock protein inhibitors, HDAC inhibitors, idronoxil, and a plethora of natural products. Veyonda (idronoxil) has had some promising results when combined with Lu-177-PSMA-617 (see this link). So far, there are no clinical trials pairing radiosensitizers with Xofigo.


Retreatment

While there was no benefit found in increasing the dose per treatment over 55 KBq/kg or extending the number of consecutive treatments beyond 6 (see this link), repeat treatment may be beneficial. Sartor et al. found that repeat cycles are effective and well-tolerated. Multiple treatments are commonly used for Lu-177-PSMA-617.


 BAT

The RESTORE - Cohort C trial of bipolar androgen therapy (BAT) found that testosterone-loading among men who had not had Xtandi or Zytiga only had a benefit among men with lymph node-only metastases. This raises the possibility that Xofigo may be complementary to BAT in men with both lymph node and bone metastases.

This clinical trial will combine Xofigo and BAT in mCRPC patients:

Th-227 decays into Ra-223. While Th-227 readily chelates to the PSMA ligand, Ra-223 does not. So it is possible that as it decays, the Ra-223 detaches and may be picked up by bone tissue, just as Xofigo does. If so, there may be a double treatment effect.

This clinical trial uses Th-227-PSMA-antibody:
For those trying to decide between Lu-177-PSMA and Xofigo, here's a comparison (but not a randomized comparative trial) about the way the two radiopharmaceuticals work.


Use Pluvicto after or together with?

The VISION trial of Pluvicto (Lu177PSMA617) excluded patients that had been previously treated with Xofigo. Therefore, the current FDA approved indication for Pluvicto precludes men who had been previously treated with Xofigo. Ra223 is much better at killing prostate cancer in bone, because it is a more powerful alpha-emitter. Pluvicto kills PSMA-avid cancer in all tissues, so it can "clean up" much of what Xofigo leaves behind. In a small trial, Sartor et al. tried Pluvicto after 6 infusions of Xofigo. They found that the toxicity was reasonable -- blood adverse events in about a third, almost all of whom also received docetaxel. It bears further investigation.

Here's a trial in Melbourne combining both: