PARP inhibitors slow progression and increases survival in men with BRCA gene mutations

The PROfound Trial has reported (here) significant improvements in progression-free survival in men with BRCA2, BRCA1, and ATM gene mutations who took the PARP inhibitor, olaparib (Lynparza). BRCA2, BRCA1, and ATM germline gene mutations are found in about 8% of men with metastatic castration-resistant prostate cancer (mCRPC). The study also included men in whom those genes were mutated in their tumors (called "somatic" mutations). PARP inhibitors inhibit an enzyme that supports the survival of DNA-damaged cancer cells. Lynparza is FDA-approved for ovarian cancer and breast cancer. Other FDA-approved PARP inhibitors comprise Rubraca (rucaparib) and Zejula (niraparib) for ovarian cancer, and Talzena (talaparib) for breast cancer. They are all in clinical trials for prostate cancer (see this link).

The PROfound Trial (details here) compared the effectiveness of Lynparza to either Xtandi or Zytiga (cohort B) in men who had already failed one of them. They compared the two groups in men who had somatic mutations in BRCA 1/2 or ATM (Cohort A, n=245) and in men who had somatic mutations in any of 12 other DNA-repair genes (Cohort B, n=142), and in men who had any of the 15 DNA-repair mutations (Cohort A+B, n=387). The trial was conducted at 229 sites. The 12 other DNA-repair mutated genes were BARD1, BRIP1, CDK12, CHK1/2, FANCL, PALB2, PPP2R2A, RAD51B/C/D, and RAD54L.

Their interim (median 1 year) findings comparing Lynparza vs Xtandi/Zytiga were as follows:

Median radiographic progression-free survival (rPFS):

• Cohort A: 7.4 months vs 3.6 months (HR=0.34, p<0.0001)
• Cohort A+B: 5.8 months vs 3.5 months (HR=0.49, p<0.0001)

Among the combined cohorts (A+B):

• 6-month rPFS: 60% vs 23%
• 12-month rPFS: 28% vs 9%
• Objective Response Rate: 33% vs 2%
• Time to pain progression: not reached vs 10 months

Median overall survival (OS) (updated 9/22/20 ):

• Cohort A: 19.1 months vs 14.7 months (HR=0.69, p=0.02)
• Cohort A+B: 17.3 months vs 14.0 months (not statistically significant)
• Cohort B: 14.1 months vs 11.5 months (not statistically significant)
• Two-thirds of controls crossed-over to receive olaparib
• After adjusting for cross-over, the hazard ratio improved to 0.42 in Cohort A, but were not significant in Cohort B or Cohort A+B

Adverse Events:

• Lynparza patients had more anemia, nausea, fatigue & asthenia, decreased appetite, diarrhea/constipation, vomiting, and respiratory issues.
• 16.4% discontinued with Lynparza vs 8.5% discontinued with hormonal therapy
• Nevertheless, they stuck with Lynparza for 7.4 months  vs 3.9 months with hormonal therapy

(update 5/19/20) The FDA approved Lynparza for mCRPC patients with germline or somatic homologous recombination repair mutations who have progressed on Zytiga or Xtandi.

In a small study (12 BRCA1/2-mutant, 5 ATM-mutant), Marshall et al. reported activity in men with BRCA1/2 mutations, but not ATM mutations:

• Reduction of PSA by at least 50% was seen in 83% of men with BRCA1/2 mutations vs 0% of men with ATM mutations.
• Progression-free survival was 12.3 months in men with BRCA1/2 mutations vs 3.3 months in men with ATM mutations.

Similarly good responses among men with bi-allelic (both genes mutated) BRCA1/2 mutations vs other DNA-repair mutations were reported in a Phase 2 trial of niraparib. The FDA has granted it "breakthrough therapy" designation.

Men with CDK12 mutations (one of the DNA repair mutations in Cohort B of the PROfound trial) unsurprisingly did not respond to PARP inhibitors (see this link).

Preliminary results of the TRITON 2 clinical trial of rucaparib in men with DNA-damage repair (DDR) deficiencies (either germline or somatic) were also reported. Clinical benefit (the % who had no radiographic progression and stayed with rucaparib) at 6 months and 12 months for each of the DDR genes found were as follows:

• BRCA1/2: 56% (47/84) at 6 mos., 25% (6/53) at 12 mos.
• ATM: 29% (14/48) at 6 mos., 8% (2/25) at 12 mos.
• CDK12: 21% (3/14) at 6 mos., 7% (1/14) at 12 mos.
• CHK2: 67% (2/3) at 6 mos., 0% (0/1) at 12 mos.
• Other DDR: 50% (6/12) at 6 mos., 33% (3/9) at 12 mos.

(update 8/23) The percent who had a reduction in PSA greater than 50%:

• BRCA1/2: 53%
• PALPB2: 55%
• ATM: 3.4%
• CDK1/2: 6.7%
• CHEK2: 14%
• Other DDR: 23%

There was high treatment-related toxicity in these heavily pre-treated patients:

• Treatment interruption or dose reduction in 54%
• Discontinuation in 9.5%
• Most common serious (grade 3+) adverse events: anemia (18%), fatigue (11%), thrombocytopenia (6%)
• 5 deaths (3%)

(Update 5/15/20) The FDA approved rucaparib for men who have the BRCA mutation (either germline or somatic, and have had prior taxane chemotherapy and AR-directed hormone therapy.

(Update 2/18/23) Triton 3  compared rucaparib to physician's choice of abiraterone, enzalutamide or docetaxel in 405 patients who were either BRCA+ or ATM+. After 62 months of follow-up:

• radiographic Progression Free Survival (rPFS) was 10.2 mos. vs 6.4 mos. -- 39% improvement for rucaparib.
• rPFS was 11.2 mos. vs 6.4 months in those who were BRCA+ (50% improvement)
• rPFS was not significantly different for ATM+ patients
• (update) rPFS improvement was 36% compared to docetaxel, and 53% compared to abi or enza
• In those with BRCA+, rPFS improvement was 47% compared to docetaxel, and 62% compared to abi or enza
• fatigue, nausea, and high BP were the most non-hematological frequent adverse events
• anemia and neutropenia were the most serious hematological events

(Update 2/22/21) Early results of the TALAPRO-1 trial of talaparib have been presented. The 128 patients were previously treated with docetaxel, and half had cabazitaxel too. The trial only included patients with genomic DNA damage-repair (DDR) defects.

• The overall objective response rate (ORR) was 30% 
• 46-50% for BRCA1/2
• 25% for PALB2
• 12% for ATM
• ORR took 3.4 months to be observable and lasted for 12.8 months
• Radiographic progression-free survival (rPFS) was 5.6 months
• 11.2 months for BRCA1/2
• 5.6 months for PALB2
• 3.5 months for ATM and other DDR defects
• Most saw a reduction in tumor burden (82%), PSA (72%), and CTC (82%)
• Reductions greatest BRCA1/2>PALB2>ATM (similar patterns in overall survival and time to PSA progression).
• The most common treatment-emergent adverse events were anemia (49%), nausea (33%), decreased appetite (28%) and asthenia (24%).
• Serious/life-threatening adverse events included anemia (31%), decreased platelet count (9%), neutropenia (8%), and pulmonary embolism (6%)
• 12% discontinued treatment due to adverse events

Patients are encouraged to get the relatively inexpensive ($249) germline test, or if negative for actionable mutations, a genomic test of a tumor biopsy or of cell-free DNA (from a blood test).

"Adjuvant" similar to "Early Salvage" Radiation Outcome in Meta-analysis

(updated)

Although at least three randomized clinical trials have told us that adjuvant radiation after prostatectomy often affords better results than just taking a "wait-and-see" approach, most radiation oncologists have been reluctant to immediately treat every man with poor post-prostatectomy pathology results (positive margins, stage T3/4, high Gleason score).  Now, some early combined results (called a meta-analysis) of three more randomized clinical trials suggest that oncological outcomes will be no worse if men wait to be treated until certain PSA cut-offs are reached.

The three randomized clinical trials were RADICALS-RT (UK & Canada), GETUG-AFU-17 (France), and RAVES (Australia & NZ). The meta-analysis, called "ARTISTIC" (critique here). comprised 2151 men, of whom 1074 were randomized to adjuvant radiation and 1077 were randomized to early salvage radiation. There have been 5 years of follow-up so far. ARTISTIC analyzed the early data based on "event-free survival," which for the most part meant freedom from a PSA-defined recurrence after radiation.

"Adjuvant" radiation (ART) was defined by all three trials as treatment within 6 months of prostatectomy. Note that this can be longer than the "immediate" treatment often given.

"Early salvage" radiation (eSRT) was defined variously as treatment when PSA ≥ 0.1ng/ml or 3 consecutive rises (RADICALS-RT), PSA≥0.2 ng/ml and rising (GETUG-AFU-17), or PSA≥0.2 ng/ml (RAVES).

Patients in all three trials had positive surgical margins, extracapsular extension, or penetration into the seminal vesicles. Most patients were intermediate risk:

• Most (77%) had a Gleason score of 7
• Very few (9-17%) had a Gleason score of 8-10
• About 1 in 5 had seminal vesicle invasion

After 5 years of median follow-up:

• Event-free (mostly PSA) survival was about the same for ART and eSRT (HR=1.1, p=0.47)
• 57% of patients randomized to SRT never had it because they didn't have biochemical progression

The following are the results for RADICALS-RT (1,496 patients followed up for 4.9 years):

• 64% of the patients randomized to receive eSRT, never experienced PSA progression
• At 5 years, biochemical progression-free survival (bRFS) was 85% for ART and 88% for eSRT (p=0.56, not statistically different)
• At 5 years, freedom from permanent ADT was not different (93% for ART, 92% for eSRT)
• Urinary incontinence at one year was 5.3% for ART vs 2.7% for eSRT (p=0.008, statistically different)
• Serious or life-threatening urethral stricture was 6% for ART vs 4% for eSRT (p=0.02, statistically different)

(10-yr update 4/2024) 

• 10-yr Freedom from Distant Metastases was 93% for ART and 90% for SRT, which are not statistically different.
• No difference in outcomes previously reported (bRFS and freedom from permanent ADT)
• Overall survival was not improved by ART.
• In addition to worse urinary incontinence, fecal incontinence was worse one year after ART, and remained worse 10 years later.

The following are the results for GETUG-AFU-17 (424 patients with 6.3 yrs of follow-up):

• 41% of the patients randomized to receive SRT, never experienced PSA progression
• 5-yr event-free survival (no PSA or clinical relapse) was the same (92% for ART, 90% for SRT)
• Late-term urinary toxicity (any grade) was worse for ART (73% for ART, 29% for SRT)
• incontinence:  54% for ART, 17% for SRT
• frequency: 39% for ART, 15% for SRT
• Late-term rectal toxicity (any grade) was worse for ART (44% for ART, 20% for SRT)
• Late-term erectile dysfunction (any grade) was worse for ART (36% for ART, 13% for SRT)

The following are the results for RAVES (333 patients with 6.1 yrs of follow-up):

• 47% of the patients randomized to receive SRT, never experienced PSA progression
• 5-yr freedom from biochemical relapse was the same (86% for ART, 87% for SRT)
• Late-term urinary toxicity (grade 2+) was worse for ART (70% for ART, 54% for SRT)
• Late-term rectal toxicity (grade 2+) was the same (14% for ART, 10% for SRT)

Pelvic lymph nodes

If pelvic lymph node dissection during prostatectomy revealed any positive nodes, or if scans suggest enlarged, cancerous pelvic lymph nodes, there is no question that adjuvant radiation is required. RTOG 0534 (SPPORT) showed that salvage radiation of pelvic lymph nodes with adjuvant ADT increased progression-free survival even when there were no detected cancerous lymph nodes, but only if PSA was high enough.

It is never worth waiting for PSA to rise to a point where newer PET scans can detect metastases just to find out where the largest sites of recurrence are. That would be a self-fulfilling prophecy - the goal is curative treatment before the cancer has time to metastasize. A/SRT must be given to the prostate bed, and possibly an extended pelvic lymph node field (see this link). The patient must treat what is still too small to see.

Adjuvant ADT

RADICALS-HD explored the effect of various durations of adjuvant hormone therapy, and found that 6 months was no more beneficial than none! However,  GETUG-AFU-16 proved that adding at least 6 months of ADT improved results of SRT. RTOG 0534 (SPPORT) also showed that adding ADT to SRT was often beneficial. But RTOG 9601 showed that adjuvant ADT did not improve results 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 metastatic risk may outweigh benefits when PSA is lower than 0.6 ng/ml. However, SPPORT found that men with a PSA above 0.35 (median, not a definitive cut-off) were more often cured if they got short-term ADT

See this link for updates on this topic.

Radiation Dose

GETUG-AFU-17 and RADICALS-RT used a radiation dose of 66 Gy in 33 treatments. RADICALS-RT also allowed a moderately hypofractionated dose (52.2 Gy in 20 treatments). RAVES used a slightly lower dose: 64 Gy in 32 treatments. SAKK 09/10 found that the salvage dose in the RAVES trial had equivalent biochemical outcomes. The effect of the higher dose on toxicity using the best linacs is unknown.

High Risk/Decipher

Most of the men in these trials were originally intermediate risk. It is entirely possible that originally high-risk men (Gleason 8-10, PSA≥20 or cT3/T4) may benefit more from ART rather than eSRT.  Men who were originally low risk (Gleason 6 and PSA<10 and T1/2) may be able to wait longer or indefinitely before SRT.

If the Decipher score is very high, that should also be taken into account in deciding between ART and eSRT. Genome Dx also provides scores that suggest whether the cancer is amenable to SRT, but those scores have yet to be prospectively validated.

We are starting to get a better handle on the ART vs eSRT decision, but none of what we have learned gives us hard-and-fast guidelines. Thee trial results do provide more fodder for discussion between the patient and his radiation oncologist.

Exceptions: see this link.

SABR to oligometastases slows progression via immune response

Stereotactic Ablative Body Radiation (SABR, or sometimes, SBRT) significantly slowed metastatic progression in men with 3 or fewer metastases (oligometastatic). SABR is a form of concentrated radiation accomplished in 1-5 treatments.

The ORIOLE trial has been previously described in detail here. To recap, it was a small (Phase 2) randomized trial with 36 men treated with SABR to bone scan/CT-detected oligometastases. There were 18 men in the untreated control group. The men were followed for 6 months to see if there was any progression of their cancer. Progression was defined as either PSA progression or new metastases detected on bone scan/CT or physical symptoms of decline (e.g., pain). Of course, with only 6 months of follow-up, most of the detected progression was PSA progression. Phuoc Tran, the lead investigator of the ORIOLE trial, reported the 6-month results here:

• Progression-free survival (PFS) was 81% in the SABR group vs 39% in the control group.
• Median PFS was not yet reached in the SABR group vs 5.8 months in the control group.
• The time to progression was increased by 70% by the treatment.
• Progression has not been reached among those treated patients followed for over a year.

Although patients were only treated for metastases discovered on a bone scan/CT, they were also given a PSMA-based PET scan (DCFPyL). Those in whom no additional metastases were discovered by the PET scan fared better:

• PFS was 84% in the fully treated group vs 36% in those with undiscovered metastases.
• Median PFS was not reached in the fully-treated group vs 11.8 months in those with undiscovered metastases.
• Distant metastasis-free survival (i.e., metastases distant from the ones that were treated) was 29 months in the fully-treated group vs 6 months in those with undiscovered metastases.

PFS in men in whom there were any untreated metastases was not improved compared to untreated men. This seems to be an all-or-nothing sort of thing.

SBRT has been found in lab studies to elicit a strong immune response. It releases cancer antigens into the bloodstream that are detected by T-cells, which become activated to find more cancer. That T cell response to radiation is thought to contribute to its effectiveness (called "the abscopal effect"). The investigators tracked the T cell response and found a significant response in the SABR-treated men.

Progression-free survival when most of the progression is PSA progression is not the endpoint we need to evaluate this therapy. SABR "treats" PSA. "Treating PSA" would occur if the radiation only provides excellent local control, while not necessarily delaying progression elsewhere. PSA is secreted in proportion to the size of the tumors, so treating only the tumors will do nothing to stop the micrometastases that are elsewhere. However, the strong T-cell response found by this study suggests that there may be a true delay in progression and not only a delay in PSA. Also, the fact that distant metastases were delayed by almost 2 years among those who had all of their PSMA-detected metastases irradiated, suggests a true response.

This is an important first step toward discovering whether oligometastasis-directed therapy provides a benefit, and how it works. It does not yet provide the answer to whether there is a survival benefit to such therapy. It also does not answer the question of whether ADT can be delayed when radiation has been given. There are several, larger clinical trials that will answer those questions more definitively. Meanwhile, the patient with rising PSA after prostate therapy should consider:

1. A PSMA-based PET scan (available in some clinical trials, and probably widely available within a year).
2. Talking to a radiation oncologist about SABR treatment of metastases if all discovered metastases are in places where it is entirely safe to treat them
3. Not forgoing ADT adjuvant to SABR treatment until there is more proof.

The definition of SECOND biochemical recurrence (after prostatectomy AND salvage radiation)

There is no standard definition of SECOND biochemical (PSA-detected) recurrence (BCR); that is, after both prostatectomy and salvage radiation (SRT). There are two reasons to have a standard definition of second BCR:

1. Time for next treatment: BCR (after any treatment) is the first indicator of treatment failure, and a signal that it may be time to consider additional treatment. It is not at all clear that immediate additional treatments are beneficial. If a treatment becomes the standard of care after biochemical failure, then it will be necessary to define the PSA or PSA doubling time (PSADT) at which that treatment should begin.
2. Comparison among radiation protocols: Lacking randomized clinical trials among all the variables of when and how salvage radiation are given (pathological characteristics, PSA, PSADT, radiation dose, adjuvant ADT, prostate bed radiation, radiation of pelvic lymph nodes), we can only look at effectiveness across studies to help us hypothesize that one strategy might be better than another. It helps if we have a consistent definition of success.

Miyake et al. looked at three definitions of second BCR:

1. NARA definition: PSA never falls below 0.2 ng/ml; or, it falls below 0.2 ng/ml but later rises over it in two consecutive readings.
2. RTOG 9601 definition: any post-SRT PSA over 0.5 ng/ml; or, nadir + 0.3 ng/ml; or the start of hormone therapy.
3. GETUG definition: nadir + 0.5

They evaluated 118 patients using the 3 definitions. With 49 months of median follow-up after salvage radiation:

• The Nara definition had the highest rate of second BCR; 53%, 45% and 40% for Nara,  RTOG and GETUG respectively.
• Gleason score and Pre-SRT PSA independently predicted Nara BCR, while negative margins and PSADT also predicted RTOG and GETUG BCR.
• There were no discrete cut-offs of the patient characteristics that reliably predicted BCR by any definition

It's worth noting that the definitions may differ for study entry and endpoint (it is usually called "biochemical progression" when used as an endpoint). Many clinical trials use the 0.2 ng/ml definition for the second BCR too.  This trial used PSA≥ 0.2 ng/ml or 3 consecutive rises after RP or SRT. We recently saw that another RTOG trial, the SPPORT trial, used a BCR endpoint definition of nadir + 2 because it correlated well with clinical recurrence. This is the definition advocated by PCWG2.

It is sometimes necessary to define a THIRD BCR as an endpoint to determine whether a therapy that began after a second BCR was successful. For example, an ongoing trial of hormonal therapies for SRT-recurrent men uses a second BCR definition of PSA > 0.5 ng/ml and PSADT ≤ 9 months, and a third BCR definition of a confirmed 25% rise in PSA and nadir + 2 during therapy, and a fourth BCR definition of a confirmed PSA > 0.2 after hormonal therapy.

The definition for FIRST BCR of a confirmed PSA after prostatectomy of 0.2 ng/ml was an artifact of the current lowest discernible PSA before the 21st century, which was 0.1 ng/ml at the time. The American Urological Association decided that anything higher than that would be deemed a BCR. The "ARTISTIC" meta-analysis established that for most patients, it was unnecessary to establish a PSA for first BCR below 0.1 or 0.2.

BCR is just one of a number of elements to be evaluated after SRT. A BCR with a high Decipher score may suggest that immediate salvage ADT is appropriate. With the new generation of PET scans, which can detect metastases at low PSAs, it may sometimes be beneficial to treat pelvic lymph node metastases and possibly distant metastases if SRT had only included the prostate bed.

This small, retrospective study will not establish a new definition, but it does raise the interesting question of whether we need a standard definition, or whether the definition ought to depend upon the purpose for which it is used. If we have definitive evidence that early treatment after failed SRT is beneficial, that will force researchers to investigate the optimum PSA (or PSADT) cutpoint. Until then, the PCWG2 definition (PSA≥ nadir + 2.0), PCWG3 definition (PSA≥nadir+ 1.0), or the combination of PSA and PSA doubling time used in the EMBARK protocol (PSA≥1 and PSADT≤ 9 months) or the PRESTO protocol (PSA≥0.5 and PSADT≤ 9 months) are all reasonable.

PSMA PET finds more cancer than Axumin

A PSMA PET scan (Ga-68-PSMA-11) detected more sites of cancer than an Axumin PET scan in the same recurrent patients. This prospective clinical trial was  conducted among 50 men at UCLA in 2018. All men had post-prostatectomy PSA from 0.2- 2.0 ng/ml.  The Calais et al. findings are summarized in the following table:

	Ga-68-PSMA-11	Axumin
Detected - % of patients	56%	26%
Prostate bed	14%	18%
Pelvic lymph nodes	38%	8%
Extra-pelvic lesions	16%	0%

The two scans performed equally well at detecting recurrence in the prostate bed, but the PSMA PET scan was able to detect more cancerous pelvic lymph nodes and non-regional metastases. The surprising result is that more recurrences are attributable to pelvic lymph nodes (stage N1) or to extra-pelvic metastases (stage M) than to cancer in the prostate bed. If this is true of all recurrent men, it indicates that salvage whole pelvic radiation is usually preferred over salvage prostate bed radiation. We saw (see this link) that salvage whole pelvic radiation improved progression-free survival compared to salvage prostate bed-only radiation. But in that SPPORT trial, the authors noted that the improvement did not hold up at low PSAs. Even the best PSMA PET/MRI has a tumor size detection limit of about 4 mm. If cancer in the pelvic lymph nodes is still curable, it may be necessary to treat cancer while it is still undetectable.

The detection rate by PSA was as follows, but is based on small numbers of patients in each PSA group. The differences in the detection rates are statistically significant for PSAs over 0.5:

PSA (ng/ml)	Ga-68-PSMA-11	Axumin
0.2-0.5 (n=26)	46%	27%
0.51-1.00 (n=18)	67%	28%
1.01-2.00 (n=6)	67%	17%

The other PSMA-based PET scan, DCFPyL, has completed recruiting.

(update 12/19/20) In a meta-analysis - in different patients - the detection rates were as follows:

PSA (ng/ml)	Ga-68-PSMA-11 n = 3,217 in 38 studies	Axumin n = 482 in 6 studies
0.2-0.5	45%	37%
0.51-1.00	59%	48%
1.01-2.00	80%	62%

The difference for PSAs from 1-2 ng/ml is statistically significant.

FDA has approved the Ga-68-PSMA PET/CT at UCLA and UCSF.