Duration of ADT needed with salvage radiation

No one wants androgen deprivation therapy (ADT) along with ("adjuvant to") salvage radiation therapy (SRT). We are accumulating evidence about how long one needs to stay on it to prevent the cancer from coming back, but judgment is still necessary.

There are some situations where it is unclear that SRT is needed at all (discussed in this link). This includes: a very long time (>18 months) before biochemical recurrence (BCR), slow doubling time, low Gleason score, elderly, significant comorbidities, no metastases with PSMA PET, and low Decipher score.

0-6 months ADT beneficial

GETUG-16 (article here) found that 6 months of ADT is better than no ADT. Incidence of metastases was improved by 27% among 743 patients.

SPPORT (RTOG 0534) found that 4-6 months was beneficial for everyone and that there was no difference between 4 and 6 months.  It was a very large trial (n=1,762) and used 8-year Freedom from Progression (mostly PSA) as its primary endpoint.

RADICALS-HD found that 6 months was no more beneficial than none! This was a large trial (n=1,500) that ran for 15 years. It used Metastasis Free Survival (MFS) as its primary endpoint. There was an 11% improvement in incidence of metastases which was not statistically significant.

DADSPORT meta-analysis sought to resolve the conflicting findings by combining the results of all 3 trials. It found an 18% improvement in incidence of metastases.

The endpoint and the follow-up are important. For men who are aged 60-70 at the time of prostatectomy, none of the trials had long enough follow-up to detect a difference in overall survival. MFS improvement may be small in the short-run, but metastases may appear later and adversely affect quality of life. Those who want to be definitively cured (i.e., no evidence of disease as evinced by PSA) should have at least short-term ADT.

24 months of ADT beneficial

RTOG 9601 showed that 24 months of adjuvant ADT did not improve survival when postprostatectomy PSA was below 0.7 ng/ml. A recent analysis by Spratt et al. suggested that adjuvant ADT is always necessary when PSA ≥ 1.5 ng/ml, but that risks may outweigh benefits when PSA is lower than 0.6 ng/ml. There were 760 patients with 13 years of follow-up. The primary endpoint was overall survival.

RADICALS-HD showed that 24 months of ADT improved survival over none or 6 months. 10-year MFS improved from 72% to 78%, while incidence of metastases declined by 23%. In the subgroup that had a PSA>0.5, incidence of metastases declined by 33%.

8 months (36 weeks) of ADT with enzalutamide

The EMBARK trial found that by intensifying ADT with enzalutamide (Xtandi) compared to ADT alone, the MFS improved by 58%, and PSA-free survival improved by 97% with 61 months of follow-up.

6 months of ADT with apalutamide and abiraterone

The Formula 509 trial found that by intensifying ADT with both apalutamide (Erleada) and abiraterone (Zytiga) compared to bicalutamide 50 mg/day, MFS improved by 43%, and PSA-free survival improved by 29% with 34 months of follow-up. Among post-op patients with PSA>0.5, MFS improved by 68%.

Positive lymph nodes

When cancerous lymph nodes are detected via pelvic lymph node dissection (PLND) at the time of prostatectomy, there is little doubt that 2-3 years of ADT are needed along with whole pelvic SRT (see this link). A PSMA PET scan may also identify cancerous pelvic nodes. One of the STAMPEDE trials lends credence to this strategy. They found that in men who were newly diagnosed with positive lymph nodes on a CT scan, 3 years of ADT with 2 years of abiraterone, decreased incidence of distant metastases by 47%. While this wasn't post-prostatectomy, it is hard to see why that fact would make a difference.

An NRG Oncology clinical trial is randomizing node-positive recurrent patients who will be getting SRT to 2 years of ADT with or without apalutamide.

AI and Genomics

Artificial intelligence (AI) is proving useful in determining the optimal duration of ADT. AI depends on feeding a lot of data about patients and their outcomes, so it will improve as a tool over the years.

Decipher scores based on the genomics of prostatectomy tissue can help discriminate between those that need more hormone therapy and those that need none.

Similarity to Adjuvant ADT with Primary Radiation

There is no reason why the decision about duration of adjuvant ADT post-prostatectomy should be different from the duration with primary external beam therapy. In general, the higher the risk, the longer the optimal duration. There are no precise cut-offs, so judgment and discussion with your radiation oncology is necessary.

Short-term androgen annihilation in non-metastatic recurrent men after SRT delays progression

 A difficult question for patients who still having rising PSA after prostatectomy and salvage radiation is: Is there any advantage to starting advanced hormone therapy before metastases are visible?

Rahul Aggarwal presented the early results of the PRESTO trial. Patients (n=504) were chosen who had the following characteristics:

• Failed prostatectomy and salvage radiation (85%). Half of those who had salvage radiation, had adjuvant ADT at the time
• PSA>0.5 ng/ml
• PSA doubling time (PSADT) ≤ 9 month
• no metastases on conventional imaging (bone scan/CT/MRI)

Patients were randomly assigned to one year of any of the following treatments:

1. ADT only
2. ADT+apalutamide
3. ADT+abiraterone+apalutamide

With follow-up of 21 months, biochemical progression-free survival (bPFS, PSA stayed under 0.2 ng/ml) was:

• 20 mos. in Group A
• 25 mos. in Group B (48% improvement vs Group A)
• 26 mos. in Group C  (52% improvement vs Group A)
• No significant differences attributable to PSADT
• Group C wasn't significantly different from Group B (Zytiga added little)

Other findings:

• Testosterone recovered in 4-5 months in all groups
• More hypertension with abiraterone

Other trials have looked at adding a limited term of 2nd line hormonal medicines when there is rapid PSADT but before metastases have been discovered on conventional imaging.

• Spetsieris et al. added abiraterone for 8 months. Afterwards, bPFS was 27 mos vs 20 mos. for ADT-only.
• Madan et al. reported substantial PSA control with intermittent use (two 3-month cycles) of enzalutamide alone without ADT. PSA didn't rise for 6-7 months after the first and second cycles.

With detection of metastases with PSMA PET scans, the advantage of early intervention will become clearer. There is also a clearer advantage for men with a higher Decipher score. It is likely that even intermittent use will be advantageous. Recurrent men with rapid PSADT after salvage radiation should consider a short-term intervention with one of the advanced hormonals.

SPPORT trial: whole pelvic salvage radiation + short-term ADT after failed surgery can be a curative option

 In 2018, we saw the early results of the SPPORT randomized clinical trial (see this link). Now Pollack et al. has published the full results. To review:

They randomly assigned 1,792 men with a recurrence after prostatectomy in 2008-2015 at 460 locations in the US, Canada, and Israel to one of 3 therapies:

1. PBRT (prostate-bed radiation only)
2. PBRT + STADT (prostate-bed radiation + short-term ADT)
3. sWPRT + STADT (salvage whole pelvic radiation + short-term ADT)

• ADT consisted of 4-6 months of a combination of an anti-androgen and an LHRH agonist starting 2 months before salvage radiation.
• Radiation dose to the prostate bed was 64.8-70.2 Gy at 1.8 Gy per fraction.
• Radiation dose to the pelvic lymph nodes was 45 Gy at 1.8 Gy per fraction.
• The treated pelvic lymph node area was per RTOG guidelines and did not include the recently recommended expansion. (There is also an expansion of the prostate bed, as discussed here)
• The sample size was powered to detect progression-free survival, but not metastases, prostate cancer mortality, or overall survival. 8 years of follow-up is insufficient for those other endpoints.

The oncological results were:

• 8-year freedom from progression (biochemical or clinical) was 77% for sWPRT+STADT, 72% for PBRT+STADT, and 61% for PBRT (all significantly different, regardless of initial ADT, Gleason score, or stage). They used a nadir+2 definition of biochemical progression because it correlated best with clinical progression.
• At lower PSA (≤ 0.35), Group 3 did no better than Group 2, so widening the treatment area had no effect. Both groups did better than Group1, so ADT had a significant effect.
• At higher PSA (> 0.35), Group 3 was better than Group 2, but the difference was not statistically significant. Both groups did better than Group 1, indicating ADT effectiveness.
• 4 vs 6 months of ADT did not matter. It reduced the occurrence of local and regional metastases.
• Widening the treatment area reduced the long-term rate of local and regional metastases.
• 8-year incidence of metastases was 69 (12%) for PBRT (HR=0.71), 56 (10%) for PBRT+STADT (HR=0.74), and 41 (7%) for sWPRT+STADT (HR=0.52). sWPRT+STADT was significantly better than the other two.

The physician-reported acute toxicity results show some small early adverse effects of ADT and the wider treatment area:

• GI grade 2 or higher: 7% for sWPRT+STADT vs. 4% for PBRT+STADT vs. 2% for PBRT
• GU grade 2 or higher: 12% for sWPRT+STADT vs. 12% for PBRT+STADT vs. 9% for PBRT
• Bone marrow grade 2 or higher: 5% for sWPRT+STADT vs. 2% for PBRT+STADT vs. 2% for PBRT
• Bone marrow grade 3: 2.6% for sWPRT+STADT vs. <1% for PBRT+STADT vs. 1% for PBRT

The physician-reported late toxicity results show that late toxicity was not influenced by ADT or whole pelvic RT:

• GI grade 2 or higher: 9% for sWPRT+STADT vs. 10% for PBRT+STADT vs. 10% for PBRT
• GU grade 2 or higher: 40% for sWPRT+STADT vs. 35% for PBRT+STADT vs. 37% for PBRT
• Bone marrow grade 2 or higher: 4% for sWPRT+STADT vs. 2% for PBRT+STADT vs. 4% for PBRT

This RCT proved that whole pelvic salvage radiation with 4-6 months of ADT is the preferred salvage treatment.

In contrast to a previous trial (RTOG 9601) that told us that ADT can be safely avoided if PSA<0.7, this trial suggests at least 4 months of ADT and whole pelvic treatment. The reason for the difference in recommendations is due to the choice of endpoint. SPPORT is telling us that if we are willing to put up with 4 months of ADT and some extra short-term toxicity from the wider field of radiation, a cure is likely. RTOG 9601 tells us that if your PSA<0.7, you aren't likely to die if you don't get the extra short-term hormone therapy, but you may have to have lifelong ADT eventually. It will always be a managed disease. Patients should acknowledge these trade-offs and discuss with their doctors.

Results may possibly be improved further with:

• Better patient selection using PET scans (PSMA, Axumin, or NaF)
• Extra radiation to the prostate bed
• Boost doses to cancer detected with a PSMA PET scan (if PSA> 0.5 - but do not wait!)
• Selection of patients who would benefit from treatment intensification using a Decipher test
• Hormone therapy intensification in select patients (as in this clinical trial)

Optimal duration of adjuvant ADT depends on the type of radiation used for high-risk patients

No one wants to have androgen deprivation therapy (ADT), even if it is for a limited time. It has been known for a long time that it improves oncological outcomes when given with ("adjuvant to") radiation therapy in patients with high-risk prostate cancer. Several randomized clinical trials (RCTs) have tried to find the best duration to use it, but it is difficult to arrive at reliable optimization points- it would involve varying the duration for a large number of high risk patients. Kishan et al. have taken an innovative approach to solving this problem by combining several RCTs and a multi-institutional observational study. Unlike typical "meta-analyses," they compared similar patients across three studies.

The three studies they used in their analysis were:

1. The high-risk patients in the DART 01.05 GICOR RCT (see this link), which randomized patients to 28 months or 4 months of adjuvant ADT in patients getting high dose external beam radiation (EBRT-only). They found that 28 months is better than 4 months, but is there a duration that is less than 28 months for EBRT-only?
2. The patients in the TROG 03.04 RADAR RCT (see this link), which randomized patients to 18 months or 6 months of adjuvant ADT in patients getting varying doses of EBRT or high dose rate brachy boost therapy (BBT). They found that 18 months is better than 6 months for BBT, but is there a duration that is less than 18 months for BBT?
3. The patients in a multi-institutional (retrospective, non-randomized) study who received varying durations of adjuvant ADT and EBRT-only or brachy boost therapy for their high risk PCa (see this link).

They used distant metastasis-free survival (DMFS) as the endpoint of interest because it has been found to correlate well with eventual overall survival. They went back to the original patient-level data to extract comparable patients when comparing them across studies. This retained many of the advantages of each of the three studies. While this innovative approach does not constitute the highest level of evidence (Level 1), it offers a degree of reliability that goes beyond simple observational studies.

They used two statistical methods to look at the data. In one analysis, they divided the durations into three parts: 

• ≤6mo.
• >6 - 18 mos
• >18 mos

In another analysis (called "cubic splines") they found the best fit for the continuous data. Both analyses led to similar conclusions.

The best estimates for the best minimum adjuvant ADT duration are:

• at least 26.3 months for EBRT-only
• at least 12 months for BBT

But, one might object, didn't Nabid's PCS IV trial show that 18 months is as good as 36 months (see this link)? Kishan points out that only about half of the cohort in that trial who were supposed to get 36 months of ADT actually got that much. And nearly a quarter of the 36-month cohort actually received less than 21 months. The only data we've seen so far has been analyzed by the dose they were intended to get, not by what they actually got. Also, why were the drop-out rates so high? The DART RCT had 95% compliance with the full 28 months, even though the radiation doses given were much higher.

There is a trade-off: BBT can come with severe late-term urinary side effects (among 19% in the ASCENDE-RT RCT), while the late-term urinary side effects are milder for EBRT-only (only 2.5% in DART). Only the patient can decide if he is willing to take on 12 months of ADT with BBT vs over twice as long for EBRT-only, given the higher expected radiation toxicity with BBT.

Which is better: EBRT+2 years of ADT or BBT+1 year of ADT?

Patel et al. looked at the use of the two therapies at many of the top cancer centers. They found there was no significant difference in the occurrence of distant metastases or in prostate cancer-specific survival.

There are several unanswered questions:

• As we have seen (see this link), brief intense use of abiraterone or other advanced hormone therapy may obviate the need for longer ADT.
• Decipher genomic analysis may indicate which patients may be able to get away with less hormone therapy, and which need more. The PREDICT-RT RCT will eventually answer this question.
• Does SBRT monotherapy or HDR brachy monotherapy still require adjuvant ADT? Those therapies can have almost as high a biologically effective dose as BBT but with fewer side effects. This study suggests that 12 months of ADT is beneficial with even the highest dose radiation, but future clinical trials will give a more reliable answer.
• Standard-of-care dictates 2-3 years of adjuvant ADT when enlarged pelvic lymph nodes are found by CT or MRI. What is the optimum duration when cancerous pelvic lymph nodes are only detected with a PSMA PET scan and not by CT? What about when they are too small to be detected by any kind of imaging, and their presence is only suggested by risk characteristics?
• What duration of adjuvant ADT minimizes biochemical recurrence-free survival and the need for any salvage treatment?
• Will these estimates hold up if tested in an RCT?

Whole-pelvic radiation therapy for high-risk patients

The decision about whether or not to treat the entire pelvic lymph node area along with the prostate (called whole pelvic radiation therapy (WPRT)) or to treat just the prostate with a margin around it (called prostate-only radiation therapy (PORT)) has long been a matter of judgment. Now we have proof of its benefit in most high-risk patients.

Murthy et al. reported the results of "POP-RT," a randomized clinical trial conducted among 224 high-risk and very high-risk patients treated at the Tata Memorial Hospital in Mumbai, India between 2011 to 2017. What sets this trial apart from previous trials that had equivocal results (like RTOG 9413 and GETUG-01) are the rigorous patient selection criteria and the now-proven treatments they received.

80% of patients were screened using PSMA PET/CT to rule out those with already-detectable lymph node or distant metastases. The rest were staged using bone scan/CT. Local staging (T1-4) was done with CT, MRI, and physical examination. Patients had to have a probability of microscopic lymph node metastases of greater than 20% using the Roach formula:

Probability of cancer in pelvic lymph nodes = (⅔ x PSA) + (10 x (Gleason score - 6))

This meant that high-risk patients had to have the following risk characteristics:

• If Gleason Score 8-10: Any PSA, T1- T3a N0 M0 
• If Gleason Score 7: PSA > 15, T1-T3a N0 M0 
• If Gleason Score 6: PSA > 30, T1-T3a N0 M0
• Also, any other "Very High Risk" including T3b-T4 N0 M0, with any Gleason Score, any PSA, if their Roach probability was > 20%
• In this group of patients, the median Roach probability was about 40% and the median PSA was 28 ng/ml.

Treatment consisted of dose-escalated IMRT and 2 years of adjuvant androgen deprivation therapy (ADT):

• Prostate dose= 68 Gy in 25 fractions or treatments (equivalent to about 81 Gy in 40 treatments)
• Pelvic lymph node dose = 50 Gy in 25 treatments (note: this is somewhat higher than the 45 Gy in 25 treatments that is usually given)
• Pelvic lymph nodes up to the aortic bifurcation were treated, which conforms to current RTOG specs.
• ADT was started 2 months before IMRT and continued for a total of 2 years
• Note: this trial began before ASCENDE-RT proved the superiority of brachy boost therapy, but used a higher IMRT dose and longer ADT. This high-dose IMRT/long-term ADT treatment was proven effective by the DART 01/03 GICOR trial.

After median follow-up of 68 months, the oncological results were:

• 5-year biochemical failure-free survival was 95% for the WPRT group vs. 81% for the PORT group.
• 5-year disease-free survival, which means they had no PSA progression and no radiographic progression, was 90% for WPRT (15 recurrences) vs 77% for PORT (36 recurrences).
• 5-year metastasis-free survival, which is a good surrogate endpoint for overall survival, was 95% for WPRT vs 88% for PORT
• Younger patients (< 66) derived more benefit from WPRT
• Among those with recurrences, most (52%) of the recurrences in the PORT arm were in pelvic lymph nodes, whereas few (12.5%) were nodal recurrences in the WPRT arm.

Murthy et al. also reported on toxicity and patient-reported quality of life outcomes comparing the two treatments.

• Acute grade 2 or greater GI toxicity was 33% for WPRT vs 25% for  PORT (not statistically different)
• Acute grade 2 or greater GU toxicity was 33% for WPRT vs 24% for PORT (not statistically different)
• Late-term grade 2 or greater GI toxicity was 8.2% for WPRT vs 4.5% for  PORT (not statistically different)
• Late-term grade 2 or greater GU toxicity was 20.0% for WPRT vs 8.9% for PORT (statistically different)
• Very few patients in either arm suffered serious (grade 3) toxicity. There was no grade 4 toxicity.
• While higher rectal radiation doses were not associated with higher bowel toxicity, higher bladder doses were associated with higher urinary toxicity.
• Patient-reported outcomes were not significantly different for urinary, bowel or sexual adverse effects.
• (update 3/24) no significant changes at 75 months.

It is worth noting that cancer in the Indian population is generally more progressed than in the US population at the time of diagnosis. Those with Stage T3b/T4 (seminal vesicle invasion and invasion into surrounding organs) accounted for 47% of this group, whereas it's a rare finding in the US because of more prevalent earlier PSA testing. Another difference is that 27% of patients had a previous TURP, which is high compared to the US. It is possible that the high TURP rate may have contributed to extra urinary toxicity seen in men getting WPRT.

Given the relatively mild side effect profile with no clinically significant difference to patients, WPRT should be the standard of care for high-risk patients at high risk of pelvic lymph node involvement. In 2027, we will have the results of a much larger, multi-institutional randomized trial (RTOG 0924) of WPRT vs PORT. Also, there was no increase in second malignancies due to the expanded coverage in this study.

Rethinking risk stratification for radiation therapy

In 2016, we looked at the Candiolo risk stratification system for radiation therapy. To my knowledge, it has not been prospectively validated or widely adopted. In the intervening 5 years, a number of things have changed:

• Active surveillance has become the treatment of choice for many patients with low-risk PC, and for some with favorable intermediate-risk PCa.
• We have the first large randomized trial (ProtecT) of external beam radiation vs. surgery vs "active monitoring" demonstrating 10-year oncological equivalence for favorable-risk patients.
• Multiparametric MRI is increasingly used to find higher grade cancer. (We won't discuss whether this has been a net benefit, as Vickers et al. doubts).
• Multiparametric MRI has also been used for staging by some doctors. (See this new predictive nomogram for surgery based on MRI staging and size).
• Multiparametric MRI has been used to detect local recurrence.
• Decipher and other genomic tests of biopsy tissue have been used to independently assess risk.
• PSMA PET scans have recently been FDA-approved for unfavorable risk patients to rule out distant metastases.
• PSMA PET and Axumin PET scans have been FDA-approved to determine radiographic recurrence.
• NCCN has added the distinction between favorable and unfavorable intermediate-risk, as described by Zumsteg et al. 
• The use of brachytherapy has declined.
• Several new hormone therapies (abiraterone, enzalutamide, apalutamide, and darolutamide) have been approved for metastatic patients.

Prognostic vs Predictive Risk Stratification

There is a new staging system called "STAR CAP." It shows a patient's prognosis of dying in 5 years or 10 years from prostate cancer (Prostate Cancer-Specific Mortality - PCSM) after availing themselves of whatever standard therapies they choose. This was an enormous undertaking. The researchers looked at the records of 19,684 men with non-metastatic (those with positive pelvic lymph nodes were included) prostate cancer who were treated at 55 sites in the US, Canada, and Europe between January 1992 and December 2013. Treatment may have consisted of radiation of any kind (7,263 patients) or prostatectomy (12,421 patients). They may have also had androgen deprivation therapy and salvage therapy. They may have also had docetaxel (2004) and Provenge (2010) therapy; Xofigo was approved in May 2013, so some few may have had it. Follow-up ended in December 2017. The patients were split equally into "training" and "validation" cohorts. Secondarily, they validated it using 125,575 men in the SEER database. It has also been independently validated in Europe for prostatectomy patients, 

They used 5 risk factors (except for pelvic lymph nodes (N stage))  to assign points (similar to CAPRA and Candiolo), in the following groupings:

• Age: ≤50. 51-70, 71+
• T stage: T1, T2a-b, T2c/T3a, T3b/T4 (based on physical examination, not imaging)
• N stage: N0. N1 (based on CT)- note: only 22 patients were N1 in the training cohort
• Gleason score: 6, 3+4, 4+3, 4+4/3+5,4+5, 5+3/5+4/5+5
• Percent positive cores: ≤50%, 51-75%, 76-100%
• PSA: ≤6, >6-10, >10-20, >20-50, >50-200

It divides patients into 9 risk groups (3 low (IA-C), 3 intermediate (IIA-C), and 3 high (IIIA-C)) based on how likely they are to die of their prostate cancer after all their therapies. Interested patients can use this handy nomogram.

Their system outperforms the AJCC prognostic stage groups (8th edition) or the NCCN system if they were used to predict prostate cancer mortality.

Their system is necessarily limited by the risk factors available in the large databases they used to train and validate their model. That means that there may be risk factors that are not accounted for, including:

• genomic risk
• % pattern 4 in GS 3+4 (this may be important in determining prostatectomy risk and risk of staying on active surveillance. It is often not reported on biopsies.
• Multiparametric MRI for staging and tumor volume
• PSA density and perineural invasion
• Use of 5aris (Proscar or Avodart)
• Use of PSMA PET scans to better select patients for local therapy

The STAR CAP system is also limited by how prostate cancer mortality is ascertained. For example, if a man dies of a blood clot in his lungs, heart, or brain, was that because the cancer increases blood clots, or was that a competing cause of death?

Decision-making

For most patients with localized prostate cancer, their cancer is not likely to be lethal after well-done therapies, at least not for a long time. Patients who are correctly diagnosed with localized PCa and treated for it will usually die of something else - their prognosis is excellent. What patients want to know is which therapy gives them the best chance of a cure and what side effects they can reasonably expect - their predicted outcomes are more important than their prognosis.

I often counsel patients to try to stay in the present moment, and not be concerned with what may or may not happen down the line. The patient is rightly concerned with making the best treatment decision he can make given what he currently knows about his cancer. If his cancer progresses, there are potentially curative salvage therapies for both surgery and radiation. If his cancer progresses after salvage therapy, his cancer can often be managed with a variety of systemic therapies for many years. The list of systemic therapies is growing rapidly. It doesn't help the patient to know the percent of patients who died in the past, given the therapies that were available then (The STAR CAP cohort goes back to 1992!). The patient wants to know his odds of a given therapy working for him now - a predictive model.

A good example of such a predictive model is the Memorial Sloan Kettering (MSK) nomogram for predicting prostatectomy outcomes. It is based on the outcomes of over 10,000 men and is continually updated. Like STAR CAP, CAPRA, and Candiolo, it includes patient age and % positive cores, as risk factors. While it also provides 10-yr and 15-yr prostate cancer survival estimates (also, see this MSK nomogram that uses comorbidities and actuarial survival tables to calculate 10- and 15-yr survival probabilities), it tells the patient what his progression-free survival (PFS) probability is if he is like the average man with his risk characteristics who chooses prostatectomy as his treatment. They define "progression-free survival (PFS)" as a PSA of less than 0.05 ng/ml and no evidence of clinical recurrence. It also shows the probability of adverse pathology after prostatectomy.

I know of no such comparable nomogram for radiation therapies. What is needed is a large predictive model for each of the major types of radiation therapies: external beam radiation, brachytherapy monotherapy, and the combination of external beam radiation and brachytherapy. It also needs to include whether whole pelvic treatment and androgen deprivation therapy (and its duration) are used with it. 

Building such a database is an enormous undertaking. No one institution has enough primary radiotherapy patients to create a reliable sample for all risk strata and for modern best practice. Unlike surgery, which has changed little in its effectiveness over time (even nerve-sparing surgery didn't change that), the effectiveness of radiation therapy changed a lot with dose escalation. Perhaps ASTRO or a multi-institutional consortium can create a registry to hold the data.

While patients making a treatment decision want to compare predictive outcomes across the treatments available to them, there are many reasons why such comparisons are difficult. The only valid way of comparing treatments is via a prospective randomized trial, like ProtecT. As we saw in the MSK nomogram, PFS or biochemical recurrence-free survival (bRFS) depends on the definition of PSA recurrence. MSK uses a PSA of 0.05 ng/ml as their definition of PSA progression after prostatectomy. Radiation therapies define biochemical recurrence as "nadir+2.0 ng/ml." It is impossible to say if these are comparable benchmarks. Perhaps future definitions of local recurrence after radiotherapy will include detection by mpMRI or one of the PSMA radioindicators that are not urinarily excreted that are in trials now.

The patient also needs to understand his likelihood of incurring the side effects associated with each treatment. ProtecT again provides the only direct comparison, but that is limited to prostatectomy, external beam radiation, and active monitoring. We know that side effects may increase with brachy boost therapy,  use of ADT, and whole pelvic treatment.

Case Examples

(1) a 65-year-old man in good health, recently diagnosed with GS 4+3, 7 cores out of 12 were positive, stage T1c (nothing felt by DRE), bone scan/CT negative, and PSA of 7.5 ng/ml. Here's how the various staging systems categorize him:

• STAR CAP: Stage IIB  (IIA-C is intermediate risk) 5-yr PCSM:1.1%   10-yr PCSM:4.4%
• CAPRA Score: 6 - high risk (6-10 is high risk)
• AJCC Prognostic Stage Group: IIC (IIA-C is intermediate risk)
• NCCN: Unfavorable intermediate risk 
• recommended options: RP+PLND, EBRT+ADT (4-6 mos.), Brachy boost therapy ± ADT (4-6 mos.)
• Candiolo score: 162 (intermediate range is 117-193) 
• 5-yr bPFS= 80% 10-yr bPFS=60%
• MSK pre-op nomogram: 10-yr and 15-yr PCSM: 1%
• 5-yr PFS=58% 10-yr PFS=42%
• Organ confined= 34%, EPE=63%, N1=14%, SVI=16%
• Multi-institutional SBRT consortium (Kishan et al.) reported 7-yr bRFS of 85% for unfavorable intermediate-risk (NCCN)
• 10-yr bRFS was reported (Abugharib et al.) to be 92% for brachy boost therapy among unfavorable intermediate-risk (NCCN) with relatively high late-term urinary toxicity
• 5-yr bRFS was reported (Kittel et al.) to be 81% for low dose rate brachytherapy monotherapy among unfavorable intermediate-risk (NCCN)

So brachy boost therapy is far more successful than surgery for unfavorable intermediate-risk patients. SBRT monotherapy may be better than either EBRT or LDR brachytherapy monotherapy because of the higher biologically effective dose.

(2) A 55 y.o. man in good health, GS 3+4 (10% pattern 4), 3/12 positive biopsy cores, perineural invasion, Stage T1c, PSA 4.5 ng/ml

• STAR CAP: Stage IC  (1A-C is low risk) 5-yr PCSM:0.5%   10-yr PCSM:2%
• CAPRA score: 2 (0-2 is low risk)
• AJCC Prognostic Stage Group: IIB (IIA-C is intermediate risk)
• NCCN: favorable intermediate risk
• recommended options: active surveillance, EBRT, brachytherapy monotherapy, RP±PLND
• Candiolo score: 86 (low risk 57-116) 
• 5-yr bPFS= 85% 10-yr bPFS=74%
• MSK pre-op nomogram: 10-yr and 15-yr PCSM: 1%
• 5-yr PFS=90% 10-yr PFS=83%
• Organ confined= 77%, EPE=21%, N1=2%, SVI=2%
• Multi-institutional SBRT consortium (Kishan et al.) reported 7-yr bRFS of 91% for favorable intermediate-risk (NCCN)
• 5-yr bRFS was reported (Kittel et al.) to be 90% for low dose rate brachytherapy monotherapy among favorable intermediate-risk (NCCN)

So, all therapies for favorable intermediate-risk patients have "success" rates in the same range (85%-91% at ~5 years) independent of the chosen therapy. This is consistent with what we saw in the ProtecT trial. However, he isn't a good candidate for active surveillance because of his biopsy-detected perineural invasion (see this link).

(3) A 72 y.o. man with heart stent but otherwise healthy, GS 4+5, 8/12 positive biopsy cores, Stage T3a (felt bulge), PSA 15 ng/ml, neg. bone scan/CT

• STAR CAP: Stage IIIB (IIIA-C is high risk) 5-yr PCSM: 6%   10-yr PCSM:21.2%
• CAPRA score: 8 (6-10 is high risk)
• AJCC Prognostic Stage Group: IIIC (IIIA-C is high risk)
• NCCN: high/very-high risk (2 high risk features)
• recommended options: EBRT+ADT (1.5-3 yrs), brachytherapy boost therapy + ADT (1-3 yrs), RP+PLND
• Candiolo score: 256 (high risk 57-116) 
• 5-yr bPFS= 67% 10-yr bPFS= 43%
• MSK pre-op nomogram: 10-yr PCSM: 4% 15-yr PCSM: 10%
• 5-yr PFS=12% 10-yr PFS=7%
• Organ confined= 1%, EPE=99%, N1=71%, SVI=79%
• Kishan et al. reported that for Gleason 9/10 patients at UCLA and Fox Chase, 10-year bRFS was 70% for brachy boost therapy, 60% for EBRT, and 16% for prostatectomy. While surgery by itself is inferior to radiation therapies for these very high-risk patients. Surgery+ salvage RT has success rates that seem to be closer.

In this case, age and the heart stent probably rule out surgery. His expected lifespan argues against watchful waiting. Brachy boost therapy and 18 months of adjuvant ADT (with cardiologist agreement) is a preferred option. Pelvic lymph nodes should be treated because of the high risk of pelvic lymph node invasion. If possible, a PSMA PET scan should be used to rule out distant metastases.

For patient decision-making, prognostic risk groups like STAR CAP, AJCC, and CAPRA are useless. The NCCN risk groups were based on prostatectomy bRFS. Counts of positive cores already used in the NCCN schema help differentiate very low risk from low risk, favorable intermediate-risk from unfavorable intermediate-risk, and high-risk from very high-risk. It is not clear that age is a risk factor that determines the oncological success of any therapy (although it undoubtedly affects toxicity). As we can see from these prototype cases, we are more needful of a risk stratification system/nomograms for the various radiation therapies similar to the MSK pre-op nomogram.

Brief, intense radiation and hormone therapy for very high risk prostate cancer

(updated)

As we've seen, brachy boost therapy seems to have the best oncological results for men with very high-risk prostate cancer. But brachy boost therapy entails 20-25 external beam radiation treatments plus the invasive placement of radioactive seeds or needles plus at least 18 months of testosterone suppression. While the oncological results are excellent, with about 80% cure rates, there is significant risk of serious late-term urinary retention. In some men, testosterone never fully recovers.

McBride et al. reported the early results of the AASUR trial. The goal of the trial was to find a treatment with equivalent oncological outcomes, but one that is easier on the patient, with less risk of long-term toxicity. They recruited 64 patients at 4 top institutions (Memorial Sloan Kettering, Johns Hopkins, University of Michigan, and Thomas Jefferson University). All patients were "very high risk," defined as:

• any Gleason score (GS) 9 or 10, or
• 4 or more cores of GS 8, or
• 2 high-risk features (stage T3/4, GS 8, or PSA>20)
• No metastases (N0, M0)

Patients were treated with:

• SBRT (7.5-8.0 Gy x 5 treatments)
• 6 months of Lupron, Erleada, and Zytiga

After 30 months of follow-up:

• 90% were free of biochemical failure
• Median PSA at the last follow-up was 0.1
• PSA remained undetectable in 40%
• Testosterone rose to non-castrate levels at a median of 6.5 months after hormone therapy ended, and almost all rose to >150 ng/dl
• 23% experienced transient serious toxicities, mostly hypertension
• Quality of life scores at 1 year held for urinary and rectal domains but declined in sexual and hormone domains.

How do these results compare to other trials of radiation+ADT in high-risk patients?

Lin et al. used whole pelvic IMRT with an SBRT boost to the prostate and 2 years of ADT in 41 high- and very high-risk patients. With 4 years of follow-up, they reported 92% biochemical recurrence-free survival (bRFS).

Hoskin et al. used high dose rate brachytherapy as a monotherapy in 86 high-risk patients. Most (80%) had adjuvant ADT for a median of 6.3 months (range 1-40 months). With 4 years of follow-up, they report 87% biochemical recurrence-free survival (bRFS) among high-risk patients.

Zapatero et al. reported the results of the DART 01.03 GICOR trial of escalated dose IMRT with either short-term (4 months) or long-term (28 months) ADT. There were 185 high-risk patients with about half getting each ADT protocol. About a quarter received simultaneous radiation of their pelvic lymph nodes. With 5 years of follow-up, they report 76% bRFS among high-risk patients who got short-term ADT and 88% bRFS among high-risk patients who got long-term ADT.

(Update) Murthy et al. reported results of a trial where 224 men with ≥ 20% risk of pelvic lymph node metastases were screened with PSMA PET scans and were randomized to get whole pelvic radiation with a boost to the prostate or prostate-only radiation. They all received 2 years of adjuvant ADT. With 5 years of follow-up, they reported 95% bRFS. 

This table summarizes these trials:

	AASUR	SBRT boost (Lin)	HDR-BT (Hoskin)	IMRT DART  GICOR	IMRT DART  GICOR	IMRT POP-RT
follow-up	2.5 yrs	4 yrs	4 yrs	5 yrs	5 yrs	5 yrs
Radiation	SBRT	IMRT+ SBRT boost	HDR-BT  monotherapy	IMRT  (dose escalated)	IMRT  (dose escalated)	WP:50Gy/25fx boost:18Gy/25fx
Coverage  area over  prostate	SV	Whole pelvic	±SV (if MRI+)	• SV • 27%  whole pelvic	• SV • 19%  whole pelvic	Whole pelvic
Adjuvant  hormone  therapy	ADT+Zytiga+Erleada	93% ADT	80% ADT	ADT	ADT	ADT
Duration of  hormone  therapy	6 mos.	2 yrs	6.3 mos.	4 mos.	28 mos.	2 yrs
Risk	VHR	78% HR 22% VHR	HR	HR	HR	≥20% LN risk
bRFS	89%	92%	87%	76%	88%	95%

HR=high risk VHR=very high risk SV=seminal vesicles bRFS=biochemical recurrence-free survival: PSA stayed lower than nadir+2.0 ng/ml

2.5 years of follow-up is too early to draw valid conclusions. We see that most of the trials had higher bRFS even with much longer follow-up; however, only AASUR recruited very high-risk patients exclusively. ICECAP has shown that only metastasis-free survival is a valid surrogate endpoint for overall survival. A trial on high-risk patients will have to run for 8-10 years to collect a sufficient number of metastases to draw valid conclusions, so we can only look at this as an early signal.

Treatment of Pelvic Lymph Nodes

We know that the time to be able to see the first few cancerous pelvic lymph nodes is often several years, so 2.5 years of follow-up tells us little. The newly approved PSMA PET scans will be able to rule out the larger metastases (>5 mm), but will never be able to find metastases smaller than that. Waiting for visibility to make the decision to treat is a bad idea. By the time some lymph nodes are large enough or rapidly growing, the risk of spread outside the pelvic lymph node drainage area increases, and the hope of a cure may vanish.

The PSMA PET/CT is nevertheless worthwhile. While a negative scan does not change the treatment decision, a positive scan may detect occult metastases or pelvic lymph nodes that may benefit from a higher spot dose and more intense or longer hormone therapy.

We rely on validated formulas to tell us the probability that there are microscopic pelvic lymph node metastases. Two of the popular formulas are the Roach Equation (discussed here) and the Yale Formula (discussed here).

There is a risk of overtreatment. Many high-risk patients will never require pelvic lymph node treatment, and we are awaiting evidence (RTOG 0924) that such treatment will improve survival. As we have seen, bRFS is improved.

However, the only risk is that toxicity will be higher when the whole pelvis is treated. Murthy et al. showed that even at higher doses of pelvic lymph node radiation, there was no increase in acute toxicity, late gastrointestinal toxicity, and no deterioration in patient-reported quality of life scores.

Arguably, 25 extra IMRT treatments to the pelvic lymph nodes represent a patient inconvenience over the 5 SBRT prostate-only treatments. In the UCLA and Sunnybrook high-risk SBRT trials (discussed here), the pelvic lymph nodes may be treated (to 25 Gy) within the same 5 treatments. So far, with limited follow-up, cancer control is high and toxicity is low.

Hormone therapy intensification

The DART 01.05 GICOR trial proved that long-term (28 months vs 4 months) ADT improves survival in high-risk patients even when treated with dose-escalated IMRT. Nabid et al. proved that 18 months is often as good as 36 months. AASUR suggests that by including both Zytiga and Erleada, the duration of hormone therapy can be shortened. But the sexual and hormone quality of life did diminish. This raises questions that can only be answered in an expanded randomized clinical trial:

• Are all 3 medications (Zytiga, Erleada, and Lupron) necessary for the benefit? The ACIS trial found that adding Erleada increased radiographic progression-free survival in mCRPC patients. There was no such synergy found in adding Xtandi to Zytiga in this non-randomized trial.
• Do they add much to Lupron alone if whole pelvic radiation is given?
• Does Lupron alone for, say, 9 months, with whole-pelvic SBRT (as in the UCLA trial) afford the same benefit with less toxicity? And would Orgovyx instead of Lupron allow for earlier testosterone recovery?
• Can genomics (Prolaris or Decipher of biopsy tissue) identify patients who might benefit from the combined hormone therapy?

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.

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.

Predicting successful treatment

NaF18 PET predicts Xofigo success (see this link). NaF18 PET is twice as sensitive for finding bone metastases compared to PSMA PET indicators (see this link).

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:

• https://clinicaltrials.gov/ct2/show/NCT04237584
• https://clinicaltrials.gov/ct2/show/NCT02194842
• https://clinicaltrials.gov/ct2/show/NCT03344211
• https://clinicaltrials.gov/ct2/show/NCT03305224
• https://clinicaltrials.gov/ct2/show/NCT04597125
• https://clinicaltrials.gov/ct2/show/NCT05771896 (mHSPC)

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:

• https://clinicaltrials.gov/ct2/show/NCT03574571
• https://clinicaltrials.gov/ct2/show/NCT03737370

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):

• https://clinicaltrials.gov/ct2/show/NCT04071236

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. A trial combining Xofigo with a PARP inhibitor (olaparib) and an immunotherapy (Keytruda) showed no more activity than a second second-generation hormonal, and the toxicity was a lot worse. 

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:

• https://clinicaltrials.gov/ct2/show/NCT04489719
• https://clinicaltrials.gov/ct2/show/NCT03076203
• https://clinicaltrials.gov/ct2/show/NCT03317392
• https://clinicaltrials.gov/ct2/show/NCT04071236

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 compares (darolutamide +ADT) ± Xofigo in newly diagnosed (mHSPC) patients:

• https://clinicaltrials.gov/ct2/show/NCT05771896

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

• https://clinicaltrials.gov/ct2/show/NCT04206319

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:

• https://clinicaltrials.gov/ct2/show/NCT03361735
• https://clinicaltrials.gov/ct2/show/NCT03304418
• https://clinicaltrials.gov/ct2/show/NCT04037358

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:

• https://clinicaltrials.gov/ct2/show/NCT04704505

Th-227-PSMA-antibody

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:

• https://clinicaltrials.gov/ct2/show/NCT03724747

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. and Rahbar 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:

https://clinicaltrials.gov/ct2/show/NCT05383079