Showing posts with label Zytiga. Show all posts
Showing posts with label Zytiga. Show all posts

Thursday, June 3, 2021

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?



Sunday, May 23, 2021

Triplet therapy for newly diagnosed metastatic men beats docetaxel+ADT

(Updated)

I. Triplet therapy with abiraterone (PEACE1)

(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.



II. Triplet Therapy with Nubeqa (darolutamide) - ARASENS

(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.

(update 2/18/23) Maha Hussain presented some planned subgroup results at the 2023 ASCO GU Conference. They defined two "volume groups" and two "risk groups" of the 1,305 men in the trial.

The volume groups were:
  • High Volume (77% of patients)= Visceral metastases and/or 4 bone metastases with at least one outside of the axial skeleton
  • Low Volume (23% of patients) = Every other newly-diagnosed metastatic man in the trial
The risk groups were:
  • High Risk (70% of patients) = any ≥2 of these risk factors: Gleason score≥8, ≥ 3 bone metastases, visceral metastases.
  • Low Risk (30% of patients) = Every other newly-diagnosed metastatic man in the trial
With about 4 years of follow-up:
  • Overall survival increased significantly in the High Volume (mortality risk reduced by 31%). In the Low Volume subgroup, the difference (by 32%) was not yet statistically significant, but may be with larger sample size or more time (survival curves separated after 3 years).
  • In High Risk (mortality risk reduced by 29%), and Low Risk (by 38%) subgroups, the differences were statistically significant.
  • Time to castration resistance increased significantly in all subgroups.
  • Time to next chemotherapy increased significantly in all subgroups.
  • Adverse events were similar in all subgroups.

III. SENESCENSE WITH SEQUENTIAL USE

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.


IV. (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.


V. 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


Saturday, December 7, 2019

Optimal chemohormonal sequencing for mCRPC MAY be Taxotere->Zytiga->[Pluvicto] ->Jevtana->Xtandi

(1) Taxotere (docetaxel) first

In a retrospective study presented at the Society for Urologic Oncology meeting,  researchers at the Mayo Clinic reported on 112 patients with metastatic castration-resistant prostate cancer (mCRPC).

  • Group A (80 men) had docetaxel (Taxotere) followed by one of the second-line hormonal therapies: either abiraterone (Zytiga) or enzalutamide (Xtandi)
  • Group B (32 men) had a second-line hormonal therapy followed by Taxotere.
  • Bone metastases were more common in Group B (87%) than Group A (58%)

Three-year survival was:

  • cancer-specific survival: 87% Group A vs 64% Group B
  • overall survival: 82% Group A vs 61% Group B
  • results were similar for men with high volume metastases, excluding those with lymph node-only
This was not a prospective randomized clinical trial. It reaches a different conclusion from a couple of earlier retrospective analyses.  Sonpavde et al.  reported an analysis of 1445 patients at VA hospitals. They found no difference in overall survival among those who started with taxanes vs. those that started with a second-line hormonal therapy. In a study at Johns Hopkins, Maughan et al. reported that there were no statistically significant differences in total progression-free survival related to the order in which the medicines (Taxotere or Zytiga) were given. Both studies adjusted for disease characteristics.

In the STAMPEDE trial of newly diagnosed men with metastatic hormone-sensitive prostate cancer (mHSPC), there was no difference in survival among men who were randomized to get Taxotere or Zytiga first (see this link). The difference in the Mayo study may be due to "selection bias" in the retrospective study - Group A may have received Taxotere first because they were healthier, and more likely to survive.

But even if the survival difference is an artifact of the study methodology, there are other reasons to do Taxotere first:
  • Side effects are less when chemo is given earlier
  • In fact, side effects are no worse for chemo or Zytiga (see this link). The differences are in the kinds of side effects, but not in their seriousness.
  • By starting with 6 infusions of Taxotere, one is able to use Zytiga after only 15 weeks; but if one starts with Zytiga, it may be 3 years before Taxotere can be tried (see this link).
There doesn't seem to be any cross-resistance between taxanes and Zytiga (as there is between Zytiga and Xtandi). A pilot trial combined the two without finding excessive toxicity, and larger trials of the combination are ongoing; for example, this one. However, a randomized trial of docetaxel+Xtandi vs docetaxel alone found there was no survival advantage to combining them, but toxicity was higher with the combination.

(2) Zytiga (abiraterone) before Xtandi (enzalutamide)

Khalaf et al reported the results of a randomized Phase 2 trial in British Columbia. 202 newly diagnosed mCRPC men were randomized to either Zytiga or Xtandi first. After progressing on the first therapy, they were given the second therapy (cross-over).
  • The Zytiga-first men progressed after 19 months vs 15 months in the Xtandi-first group
  • After cross-over, PSA was reduced by more than 30% in 36% of those who had Xtandi-second vs only in 4% of those who had Zytiga-second
Until we have a larger study that follows men for the rest of their lives, we can assume that the extended progression-free time among those who use Zytiga before Xtandi will translate to extended survival.

It's worth noting that it has been found that Zytiga can work a median of 10 months longer if one switches from prednisone (10 mg/day) to dexamethasone (0.5 mg/day) when progression begins (see this link).

A trial combining Zytiga and Xtandi (+ADT) found there was no benefit to combining the two drugs, but toxicity was worse than Xtandi (+ADT) alone. A small trial of Zytiga monotherapy (without ADT) showed that it can reduce testosterone on its own and another small trial suggested that oncological outcomes were not compromised by the monotherapy.

(Update 2/9/21) A trial combining Zytiga and Erleada (+ADT) found there was a benefit in radiographic progression-free survival (rPFS) to combining the two drugs. rPFS was extended 6 months (from 17 mos. to 23 mos.) by the combination compared to Zytiga (+ADT) alone. With median follow-up of 55 months, there was no significant difference in overall survival. Unlike Xtandi, Erleada reduces androgen receptor expression.

(Update  2/21/21) Tagawa et al. reported that in a retrospective analysis of chemo-naive patients treated at the VA, Xtandi-first patients had a 16% reduced risk of death vs Zytiga-first patients - 1.4 months longer. But if they later switched to the other drug, their overall survival was the same. There was also no difference in survival if they later had chemo.

(3) Jevtana (cabazitaxel) third (after Pluvicto)

Jevtana is currently FDA-approved for men in whom Taxotere has already been tried and failed. Jevtana and Taxotere (both taxanes) have been found to be virtually identical in oncological results when given as first-line therapy (see this link) with a similar degree of toxicity. If Taxotere and one of the second-line hormonal therapies (Zytiga or Xtandi) have already been tried, is it better to try the other second-line hormonal therapy next or is Jevtana a better choice for the third therapy? De Wit et al. found the answer in the CARD randomized clinical trial..

They randomized patients who already had Taxotere and one of the two second-line hormonal to receive either the other second-line hormonal or Jevtana.
  • 126 received Jevtana
  • 58 received Zytiga
  • 66 received Xtandi
After 9.2 months median follow-up, 
  • Imaging-based progression-free survival was 8.0 months for Jevtana vs 3.7 months for the hormonal therapy
  • The advantage for Jevtana was maintained regardless of risk characteristics and treatment history
  • The advantage for Jevtana was true regardless of which hormonal therapy it was compared to.
  • Overall survival was 13.6 months for Jevtana vs 11.0 months for hormonals.
  • PSA was reduced by at least 50% in 36% of men using Jevtana vs 14% using hormonals.
  • Tumors shrank in 37% of men using Jevtana vs 12% using hormonals
  • Serious adverse events of any grade were similar for all therapies at 39%.
  • Adverse events leading to death were more frequent with the hormonals (11%) than Jevtana (6%)
  • Pain was improved more by Jevtana (in 45% of men) than by hormonals (in 19% of men)
  • Skeletal events (fractures, spinal compression) occurred more frequently among those taking hormonals (51%) than Jevtana (29%)

Jevtana was at least as good or had a clear advantage on every measure of success.

(Update 9/16/20) Fizazi et al. reported the Quality of Life (QOL) outcomes of the CARD trial (above).
  • Pain response was better with Jevtana  than hormonals (46% vs 19%)
  • Time to pain progression was about twice as long with Jevtana (hazard ratio (HR)= 0.55)
  • Time to next symptomatic skeletal event was similarly longer with Jevtana (HR= 0.59)
  • Function scores and time to deterioration of function scores (e.g., ability to self-care, perform usual activities, mobility, mental status, sense of well-being, social/family well-being) were better with Jevtana



(4) Xtandi fourth

There is some evidence that taxanes (like Taxotere or Jevtana) can reverse one mode of hormonal resistance (AR-V7 splice variance). More evidence proved that Taxotere combined with Xtandi can extend its effectiveness even after it fails. Research continues on methods to reverse resistance (e.g., see subsection - "what's next?"). Although there is known cross-resistance between Zytiga and Xtandi, Xtandi usually works at least for a while after Zytiga.

Other medicines

Other medicines approved for men with mCRPC include older anti-androgens (like bicalutamide), Xofigo, Provenge, and Keytruda (but only in the rare event of MSI-hi/dMMR). It would save time if any of these could safely be piggybacked on top of another therapy.

Older anti-androgens (like Casodex or flutamide) are still used sometimes in the mCRPC setting, mostly in combination with a GnRH agonist (like Lupron). The combination is somewhat more beneficial (see this link) than a GnRH agonist alone, and provides a short-term benefit at low cost. Sometimes, the cancer learns how to feed on the anti-androgen, and removing it leads to a reduction in PSA (called antiandrogen withdrawal syndrome). Newer antiandrogens don't seem to do this as much, although it has been observed in a minority of patients for abiraterone and enzalutamide.

It is unknown where the newest antiandrogens fit into sequencing. Erleada and Nubeqa have been approved for other indications, but not yet for mCRPC. Others (like proxalutamide) haven't yet cleared the first hurdle.

Xofigo cannot be prescribed after any visceral metastases have been detected, although it may work well on the bone metastases nevertheless. It works better sooner rather than later, but a trial combining it with Zytiga was stopped early because of a high rate of skeletal events. Early results of a new trial combining Xofigo and Xtandi show that adding a bone-protective agent (Xgeva or Zometa)  can ameliorate the problem.

Provenge may synergize with radiotherapies or chemo because they present many cancer antigens for the amped up immune system to tune into. There is some evidence to suggest that it synergizes with Xofigo. There is evidence that an abscopal effect (systemic immune response) may be augmented. Other immunotherapies, which show little therapeutic promise alone, may be beneficial in combination with chemo or other therapies.

PARP inhibitors are in clinical trials, and seem to be especially effective when there are BRCA1/2 mutations (germline or somatic). Several clinical trials are combing carboplatin with taxanes. Transdermal estrogen is inexpensive and is available now. Optimal sequencing or combinations are yet to be determined. 

Lu-177-PSMA-617 ("Pluvicto") and similar radiopharmaceuticals are in ongoing trials. (Update: see this link.) The TheraP trial proved that Pluvicto is preferred as a third treatment over jevtana. The VISION trial used it only among men who had been pre-treated with chemo and Zytiga or Xtandi. If it gets FDA approval, it will be limited to use after those other treatments. However, trials are ongoing for earlier use and in combination therapy. There is probably an optimum time for use of PSMA-directed therapies. Combination with different PSMA-targeted radionuclides (like Ac-225), and with multiple membrane targets are being explored.

There are myriad other potential therapies in clinical trials. Many are pathway growth inhibitors that may work best in combinations. Therapies tailored to specific genomic mutations are in their infancy.